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Hereditary Neuropathy - complex v1.40 CASP8 Zornitza Stark Classified gene: CASP8 as Green List (high evidence)
Hereditary Neuropathy - complex v1.40 CASP8 Zornitza Stark Gene: casp8 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v1.39 CASP8 Zornitza Stark gene: CASP8 was added
gene: CASP8 was added to Hereditary Neuropathy - complex. Sources: Literature
Mode of inheritance for gene: CASP8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CASP8 were set to 41026346
Phenotypes for gene: CASP8 were set to Autoimmune lymphoproliferative syndrome, type IIB MIM#607271
Review for gene: CASP8 was set to GREEN
Added comment: 7 individuals from 5 families reported with ALPS. All had the same homozygous missense variant, p.Arg265Trp. Some known to be distantly related. CIDP was a common manifestation.

GREEN but any variants apart from the founder variant should be treated with caution.
Sources: Literature
Autoimmune Lymphoproliferative Syndrome v1.11 IKZF1 Zornitza Stark Marked gene: IKZF1 as ready
Autoimmune Lymphoproliferative Syndrome v1.11 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.11 IKZF1 Zornitza Stark Classified gene: IKZF1 as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.11 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.10 CASP8 Zornitza Stark Publications for gene: CASP8 were set to 12353035; 25814141; 12654726; 17213198; 16148088
Autoimmune Lymphoproliferative Syndrome v1.9 CASP8 Zornitza Stark Classified gene: CASP8 as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.9 CASP8 Zornitza Stark Gene: casp8 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.8 CASP8 Zornitza Stark changed review comment from: Additional individual reported, bring up total to 7 individuals from 5 families. All had the same homozygous missense variant, p.Arg265Trp. Some known to be distantly related. CIDP was a common manifestation. GREEN but any variants apart from the founder variant should be treated with caution.; to: Additional individual reported, bring up total to 7 individuals from 5 families. All had the same homozygous missense variant, p.Arg265Trp. Some known to be distantly related. CIDP was a common manifestation.

GREEN but any variants apart from the founder variant should be treated with caution.
Autoimmune Lymphoproliferative Syndrome v1.8 CASP8 Zornitza Stark reviewed gene: CASP8: Rating: GREEN; Mode of pathogenicity: None; Publications: 41026346; Phenotypes: Autoimmune lymphoproliferative syndrome, type IIB MIM#607271; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Disorders of immune dysregulation v1.33 CASP8 Zornitza Stark Publications for gene: CASP8 were set to 12353035; 25814141; 12654726; 17213198; 16148088
Disorders of immune dysregulation v1.32 CASP8 Zornitza Stark Classified gene: CASP8 as Green List (high evidence)
Disorders of immune dysregulation v1.32 CASP8 Zornitza Stark Gene: casp8 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.31 CASP8 Zornitza Stark Tag founder tag was added to gene: CASP8.
Disorders of immune dysregulation v1.31 CASP8 Zornitza Stark edited their review of gene: CASP8: Added comment: Additional individual reported, bring up total to 7 individuals from 5 families. All had the same homozygous missense variant, p.Arg265Trp. Some known to be distantly related. CIDP was a common manifestation.

GREEN but any variants apart from the founder variant should be treated with caution.; Changed rating: GREEN; Changed publications: 12353035, 25814141, 12654726, 17213198, 16148088, 41026346
Mendeliome v1.3427 CASP8 Zornitza Stark Publications for gene: CASP8 were set to 12353035; 25814141; 12654726; 17213198; 16148088
Mendeliome v1.3426 CASP8 Zornitza Stark Classified gene: CASP8 as Green List (high evidence)
Mendeliome v1.3426 CASP8 Zornitza Stark Gene: casp8 has been classified as Green List (High Evidence).
Mendeliome v1.3425 CASP8 Zornitza Stark Tag founder tag was added to gene: CASP8.
Mendeliome v1.3425 CASP8 Zornitza Stark edited their review of gene: CASP8: Added comment: Additional individual reported, bring up total to 7 individuals from 5 families. All had the same homozygous missense variant, p.Arg265Trp. Some known to be distantly related. CIDP was a common manifestation.

GREEN but any variants apart from the founder variant should be treated with caution.; Changed rating: GREEN; Changed publications: 41026346; Changed phenotypes: Autoimmune lymphoproliferative syndrome, type IIB MIM#607271; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3425 PTBP1 Zornitza Stark Phenotypes for gene: PTBP1 were changed from to Neurodevelopmental disorder (MONDO:0700092), PTBP1-related
Mendeliome v1.3424 PTBP1 Zornitza Stark Publications for gene: PTBP1 were set to
Mendeliome v1.3423 PTBP1 Zornitza Stark Mode of inheritance for gene: PTBP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3422 PTBP1 Zornitza Stark Classified gene: PTBP1 as Green List (high evidence)
Mendeliome v1.3422 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Green List (High Evidence).
Fetal anomalies v1.446 PTBP1 Zornitza Stark Marked gene: PTBP1 as ready
Fetal anomalies v1.446 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Green List (High Evidence).
Fetal anomalies v1.446 PTBP1 Zornitza Stark Classified gene: PTBP1 as Green List (high evidence)
Fetal anomalies v1.446 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.339 PTBP1 Zornitza Stark Marked gene: PTBP1 as ready
Skeletal dysplasia v0.339 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.339 PTBP1 Zornitza Stark Classified gene: PTBP1 as Green List (high evidence)
Skeletal dysplasia v0.339 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.372 PTBP1 Zornitza Stark Marked gene: PTBP1 as ready
Intellectual disability syndromic and non-syndromic v1.372 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.372 PTBP1 Zornitza Stark Classified gene: PTBP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.372 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.108 CACNB1 Zornitza Stark Marked gene: CACNB1 as ready
Muscular dystrophy and myopathy_Paediatric v1.108 CACNB1 Zornitza Stark Gene: cacnb1 has been classified as Amber List (Moderate Evidence).
Muscular dystrophy and myopathy_Paediatric v1.108 CACNB1 Zornitza Stark Classified gene: CACNB1 as Amber List (moderate evidence)
Muscular dystrophy and myopathy_Paediatric v1.108 CACNB1 Zornitza Stark Gene: cacnb1 has been classified as Amber List (Moderate Evidence).
Muscular dystrophy and myopathy_Paediatric v1.107 CACNB1 Zornitza Stark gene: CACNB1 was added
gene: CACNB1 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: CACNB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNB1 were set to 41023410
Phenotypes for gene: CACNB1 were set to Congenital muscular dystrophy MONDO:0020121, CACNB1-related
Review for gene: CACNB1 was set to AMBER
Added comment: PMID: 41023410 - Different phenotype - congenital muscular dystrophy. Only two consanguineous families have been reported with variants in this gene.

3 individuals from two unrelated consanguineous families present with myopathy, elevated CK levels and low body weight
Two biallelic rare variants were identified in CACNB1 - c.124_133del; p.(Asp42Argfs*37 and c.85-1G>A)
RNA assay was conducted on isolated RNA showed the generation of a PTC leading to a truncated protein.
Sources: Literature
Mendeliome v1.3421 CACNB1 Zornitza Stark Phenotypes for gene: CACNB1 were changed from Malignant hyperthermia susceptibility, MONDO:0800188, CACNB1-related to Congenital muscular dystrophy MONDO:0020121; Malignant hyperthermia susceptibility, MONDO:0800188, CACNB1-related
Mendeliome v1.3420 CACNB1 Zornitza Stark Publications for gene: CACNB1 were set to 27832566; 8943043; 29212769
Mendeliome v1.3419 CACNB1 Zornitza Stark Mode of inheritance for gene: CACNB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3418 CACNB1 Zornitza Stark Classified gene: CACNB1 as Amber List (moderate evidence)
Mendeliome v1.3418 CACNB1 Zornitza Stark Gene: cacnb1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.470 ZDHHC18 Zornitza Stark Marked gene: ZDHHC18 as ready
Congenital Heart Defect v0.470 ZDHHC18 Zornitza Stark Gene: zdhhc18 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3417 ZDHHC18 Zornitza Stark Marked gene: ZDHHC18 as ready
Mendeliome v1.3417 ZDHHC18 Zornitza Stark Gene: zdhhc18 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3417 SWSAP1 Zornitza Stark Marked gene: SWSAP1 as ready
Mendeliome v1.3417 SWSAP1 Zornitza Stark Gene: swsap1 has been classified as Red List (Low Evidence).
Mendeliome v1.3417 SWSAP1 Zornitza Stark Classified gene: SWSAP1 as Red List (low evidence)
Mendeliome v1.3417 SWSAP1 Zornitza Stark Gene: swsap1 has been classified as Red List (Low Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.362 SWSAP1 Zornitza Stark Marked gene: SWSAP1 as ready
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.362 SWSAP1 Zornitza Stark Gene: swsap1 has been classified as Red List (Low Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.362 SWSAP1 Zornitza Stark Classified gene: SWSAP1 as Red List (low evidence)
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.362 SWSAP1 Zornitza Stark Gene: swsap1 has been classified as Red List (Low Evidence).
Hereditary Neuropathy_CMT - isolated v1.67 NAMPT Zornitza Stark Marked gene: NAMPT as ready
Hereditary Neuropathy_CMT - isolated v1.67 NAMPT Zornitza Stark Gene: nampt has been classified as Red List (Low Evidence).
Hereditary Neuropathy_CMT - isolated v1.67 NAMPT Zornitza Stark gene: NAMPT was added
gene: NAMPT was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature
Mode of inheritance for gene: NAMPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAMPT were set to 41004591
Phenotypes for gene: NAMPT were set to hereditary motor and sensory neuropathy MONDO:0015358
Review for gene: NAMPT was set to RED
Added comment: Two individuals from a single family reported with sensory and motor neuropathy with motor coordination impairment, muscle atrophy/weakness, foot/hand deformities, loss of sensation and positive Babinski sign

Homozygous missense, c.472G>C (p.P158A), absent from gnomAD.

Functional Studies: recombinant NAMPT protein activity assay; thermal shift stability assay; patient fibroblast bioenergetic, mitochondrial and oxidative stress assays; CRISPR‑generated isogenic fibroblasts; homozygous p.P158A mouse model showing metabolic, synaptic and motor neuron defects; rescue with NMN/P7C3
Sources: Literature
Fetal anomalies v1.445 FAP Zornitza Stark Marked gene: FAP as ready
Fetal anomalies v1.445 FAP Zornitza Stark Gene: fap has been classified as Red List (Low Evidence).
Fetal anomalies v1.445 FAP Zornitza Stark gene: FAP was added
gene: FAP was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FAP were set to 40949908
Phenotypes for gene: FAP were set to congenital pulmonary airway malformation MONDO:0016580
Review for gene: FAP was set to RED
Added comment: Only 1 reported fetus with a diagnosis of congenital pulmonary airway malformation Heterozygous variant identified - c.T269G:p.L90W. The variant is present in gnomAD v4.1 - EAS AF - 0.007% (4 hets)
Sources: Literature
Mendeliome v1.3416 FAP Zornitza Stark Marked gene: FAP as ready
Mendeliome v1.3416 FAP Zornitza Stark Gene: fap has been classified as Red List (Low Evidence).
Mendeliome v1.3416 FAP Zornitza Stark Classified gene: FAP as Red List (low evidence)
Mendeliome v1.3416 FAP Zornitza Stark Gene: fap has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.371 DBX1 Zornitza Stark Marked gene: DBX1 as ready
Intellectual disability syndromic and non-syndromic v1.371 DBX1 Zornitza Stark Gene: dbx1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.371 DBX1 Zornitza Stark gene: DBX1 was added
gene: DBX1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DBX1 were set to 40995053
Phenotypes for gene: DBX1 were set to central hypoventilation syndrome, congenital MONDO:0800031
Review for gene: DBX1 was set to RED
Added comment: Single individual reported with congenital central hypoventilation syndrome (atypical CCHS) with central hypotonia, global developmental delay, seizures, autoaggressive behaviour. Consanguineous parents, hmz frameshift variant c.340_341delGC, absent from gnomAD.
Mouse Dbx1 knockout is lethal indicating essential role in respiration.
Sources: Literature
Central Hypoventilation v1.6 DBX1 Zornitza Stark Marked gene: DBX1 as ready
Central Hypoventilation v1.6 DBX1 Zornitza Stark Gene: dbx1 has been classified as Red List (Low Evidence).
Central Hypoventilation v1.6 DBX1 Zornitza Stark gene: DBX1 was added
gene: DBX1 was added to Central Hypoventilation. Sources: Literature
Mode of inheritance for gene: DBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DBX1 were set to 40995053
Phenotypes for gene: DBX1 were set to central hypoventilation syndrome, congenital MONDO:0800031
Review for gene: DBX1 was set to RED
Added comment: Single individual reported with congenital central hypoventilation syndrome (atypical CCHS) with central hypotonia, global developmental delay, seizures, autoaggressive behaviour. Consanguineous parents, hmz frameshift variant c.340_341delGC, absent from gnomAD.
Mouse Dbx1 knockout is lethal indicating essential role in respiration.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.370 NFXL1 Zornitza Stark Marked gene: NFXL1 as ready
Intellectual disability syndromic and non-syndromic v1.370 NFXL1 Zornitza Stark Gene: nfxl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.370 NFXL1 Zornitza Stark Classified gene: NFXL1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.370 NFXL1 Zornitza Stark Gene: nfxl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.369 NFXL1 Zornitza Stark gene: NFXL1 was added
gene: NFXL1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NFXL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFXL1 were set to 40430072; 41024252
Phenotypes for gene: NFXL1 were set to Syndromic disease (MONDO:0002254), NFXL1-related
Review for gene: NFXL1 was set to AMBER
Added comment: PMID: 40430072 2 siblings with psychosis and schizophrenia, homozygous for Cys441Tyr. Some modelling suggested a deleterious affect but no functional studies performed.

PMID: 41024252 8 patients from 7 families with joint hyperlaxity, with or without short stature and renal disease. 6 families were homozygous for p.(Cys539Trpfs*64) while the other two were homozygous for p.(Lys681*). Paper described both as founder variants but they are rare/absent in gnomad.

Joint hyperlaxity (7), chronic kidney disease/FSGS (2) small echogenic kidneys (3), acute kidney injury (1), dysmorphic features (6), short stature (6), speech delay (3).

One patient also had epilepsy, developmental delay and spasticity however c.728+1G>A in WDR45 explained this part of her phenotype. Other patients also had more severe outlying symptoms with no other explanation mentioned: 1 with developmental delay, hearing loss, brain malformations, skeletal abnormalities, and another a 3 year old who passed away following a complex medical course including blue sclera, proximal tibial fracture, severe respiratory distress due to a chest infection, and acute kidney injury.

Amber given the variable phenotype findings of the reported patients and only 2 homozygous variants identified so far.

Extent of associated DD/ID currently unclear but adding on this panel as it is often ordered in children with multi-system features suggestive of an underlying syndrome.
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.159 NFXL1 Zornitza Stark Marked gene: NFXL1 as ready
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.159 NFXL1 Zornitza Stark Gene: nfxl1 has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.159 NFXL1 Zornitza Stark Classified gene: NFXL1 as Amber List (moderate evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.159 NFXL1 Zornitza Stark Gene: nfxl1 has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.158 NFXL1 Zornitza Stark gene: NFXL1 was added
gene: NFXL1 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: NFXL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFXL1 were set to 40430072; 41024252
Phenotypes for gene: NFXL1 were set to Syndromic disease (MONDO:0002254), NFXL1-related
Review for gene: NFXL1 was set to AMBER
Added comment: PMID: 40430072 2 siblings with psychosis and schizophrenia, homozygous for Cys441Tyr. Some modelling suggested a deleterious affect but no functional studies performed.

PMID: 41024252 8 patients from 7 families with joint hyperlaxity, with or without short stature and renal disease. 6 families were homozygous for p.(Cys539Trpfs*64) while the other two were homozygous for p.(Lys681*). Paper described both as founder variants but they are rare/absent in gnomad.

Joint hyperlaxity (7), chronic kidney disease/FSGS (2) small echogenic kidneys (3), acute kidney injury (1), dysmorphic features (6), short stature (6), speech delay (3).

One patient also had epilepsy, developmental delay and spasticity however c.728+1G>A in WDR45 explained this part of her phenotype. Other patients also had more severe outlying symptoms with no other explanation mentioned: 1 with developmental delay, hearing loss, brain malformations, skeletal abnormalities, and another a 3 year old who passed away following a complex medical course including blue sclera, proximal tibial fracture, severe respiratory distress due to a chest infection, and acute kidney injury.

Amber given the variable phenotype findings of the reported patients and only 2 homozygous variants identified so far. Kidney phenotype not entirely clear but likely to be within syndromic CAKUT spectrum.
Sources: Literature
Mendeliome v1.3415 NFXL1 Zornitza Stark Marked gene: NFXL1 as ready
Mendeliome v1.3415 NFXL1 Zornitza Stark Gene: nfxl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3415 NFXL1 Zornitza Stark Classified gene: NFXL1 as Amber List (moderate evidence)
Mendeliome v1.3415 NFXL1 Zornitza Stark Gene: nfxl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3414 ZSWIM7 Zornitza Stark Marked gene: ZSWIM7 as ready
Mendeliome v1.3414 ZSWIM7 Zornitza Stark Gene: zswim7 has been classified as Green List (High Evidence).
Mendeliome v1.3414 ZSWIM7 Zornitza Stark Classified gene: ZSWIM7 as Green List (high evidence)
Mendeliome v1.3414 ZSWIM7 Zornitza Stark Gene: zswim7 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.45 ZSWIM7 Zornitza Stark Marked gene: ZSWIM7 as ready
Infertility and Recurrent Pregnancy Loss v1.45 ZSWIM7 Zornitza Stark Gene: zswim7 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.45 ZSWIM7 Zornitza Stark Classified gene: ZSWIM7 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.45 ZSWIM7 Zornitza Stark Gene: zswim7 has been classified as Green List (High Evidence).
Mendeliome v1.3413 PTBP2 Zornitza Stark Marked gene: PTBP2 as ready
Mendeliome v1.3413 PTBP2 Zornitza Stark Gene: ptbp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3413 PTBP2 Zornitza Stark Classified gene: PTBP2 as Amber List (moderate evidence)
Mendeliome v1.3413 PTBP2 Zornitza Stark Gene: ptbp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.368 PTBP2 Zornitza Stark Marked gene: PTBP2 as ready
Intellectual disability syndromic and non-syndromic v1.368 PTBP2 Zornitza Stark Gene: ptbp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.368 PTBP2 Zornitza Stark Classified gene: PTBP2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.368 PTBP2 Zornitza Stark Gene: ptbp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3412 KLK15 Zornitza Stark Marked gene: KLK15 as ready
Mendeliome v1.3412 KLK15 Zornitza Stark Gene: klk15 has been classified as Red List (Low Evidence).
Mendeliome v1.3412 KLK15 Zornitza Stark Classified gene: KLK15 as Red List (low evidence)
Mendeliome v1.3412 KLK15 Zornitza Stark Gene: klk15 has been classified as Red List (Low Evidence).
Mendeliome v1.3411 KLK15 Zornitza Stark reviewed gene: KLK15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.100 KLK15 Zornitza Stark Marked gene: KLK15 as ready
Aortopathy_Connective Tissue Disorders v1.100 KLK15 Zornitza Stark Gene: klk15 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v1.100 KLK15 Zornitza Stark Classified gene: KLK15 as Red List (low evidence)
Aortopathy_Connective Tissue Disorders v1.100 KLK15 Zornitza Stark Gene: klk15 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v1.99 KLK15 Zornitza Stark reviewed gene: KLK15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3411 INCENP Zornitza Stark Marked gene: INCENP as ready
Mendeliome v1.3411 INCENP Zornitza Stark Gene: incenp has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3411 INCENP Zornitza Stark Classified gene: INCENP as Amber List (moderate evidence)
Mendeliome v1.3411 INCENP Zornitza Stark Gene: incenp has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.44 INCENP Zornitza Stark Marked gene: INCENP as ready
Infertility and Recurrent Pregnancy Loss v1.44 INCENP Zornitza Stark Gene: incenp has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.44 INCENP Zornitza Stark Classified gene: INCENP as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.44 INCENP Zornitza Stark Gene: incenp has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3410 GSTZ1 Zornitza Stark Marked gene: GSTZ1 as ready
Mendeliome v1.3410 GSTZ1 Zornitza Stark Gene: gstz1 has been classified as Green List (High Evidence).
Mendeliome v1.3410 GSTZ1 Zornitza Stark Classified gene: GSTZ1 as Green List (high evidence)
Mendeliome v1.3410 GSTZ1 Zornitza Stark Gene: gstz1 has been classified as Green List (High Evidence).
Aminoacidopathy v1.137 GSTZ1 Zornitza Stark Publications for gene: GSTZ1 were set to 27876694
Aminoacidopathy v1.136 GSTZ1 Zornitza Stark Classified gene: GSTZ1 as Green List (high evidence)
Aminoacidopathy v1.136 GSTZ1 Zornitza Stark Gene: gstz1 has been classified as Green List (High Evidence).
Mendeliome v1.3409 FSIP2 Zornitza Stark Marked gene: FSIP2 as ready
Mendeliome v1.3409 FSIP2 Zornitza Stark Gene: fsip2 has been classified as Green List (High Evidence).
Mendeliome v1.3409 FSIP2 Zornitza Stark Classified gene: FSIP2 as Green List (high evidence)
Mendeliome v1.3409 FSIP2 Zornitza Stark Gene: fsip2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.43 FSIP2 Zornitza Stark Marked gene: FSIP2 as ready
Infertility and Recurrent Pregnancy Loss v1.43 FSIP2 Zornitza Stark Gene: fsip2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.43 FSIP2 Zornitza Stark Classified gene: FSIP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.43 FSIP2 Zornitza Stark Gene: fsip2 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.234 CDK9 Zornitza Stark Marked gene: CDK9 as ready
Syndromic Retinopathy v0.234 CDK9 Zornitza Stark Gene: cdk9 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.234 CDK9 Zornitza Stark Classified gene: CDK9 as Green List (high evidence)
Syndromic Retinopathy v0.234 CDK9 Zornitza Stark Gene: cdk9 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.233 CDK9 Zornitza Stark gene: CDK9 was added
gene: CDK9 was added to Syndromic Retinopathy. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 40954203; 33640901; 30237576; 26633546
Phenotypes for gene: CDK9 were set to multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome MONDO:0015160; CHARGE-like syndrome with retinal dystrophy
Review for gene: CDK9 was set to GREEN
Added comment: Biallelic variants in at least six families, though 4 may be related:
1) proband that displays retinal dystrophy without a CHARGE-like malformation syndrome (c.862G>A/p.A288T + c.961C>T/p.P321S).
2) A boy with a phenotype resembling CHARGE syndrome (multiple anomalies involving the eyes, ears, cleft lip, and palate, and intellectual disability) with retinal dystrophy (p.A288T/p.R303C),
3-7) 4 consanguineous families homozygous for p.R225C, including a set of cousins.
CDK9 variants demonstrated decreased kinase activity. One of the studies suggested the extent the kinase activity is reduced may account for the absence/presence of the CHARGE-like phenotype with retinal dystrophy
Sources: Literature
Fetal anomalies v1.444 CDK9 Zornitza Stark Marked gene: CDK9 as ready
Fetal anomalies v1.444 CDK9 Zornitza Stark Gene: cdk9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.444 CDK9 Zornitza Stark Classified gene: CDK9 as Amber List (moderate evidence)
Fetal anomalies v1.444 CDK9 Zornitza Stark Gene: cdk9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.443 CDK9 Zornitza Stark gene: CDK9 was added
gene: CDK9 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 33640901; 30237576; 26633546
Phenotypes for gene: CDK9 were set to multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome MONDO:0015160; CHARGE-like syndrome with retinal dystrophy
Review for gene: CDK9 was set to AMBER
Added comment: Two independent reports of relevance to this panel:
1) A boy with a phenotype resembling CHARGE syndrome (multiple anomalies involving the eyes, ears, cleft lip, and palate, and intellectual disability) with retinal dystrophy (p.A288T/p.R303C),
2) 4 consanguineous families homozygous for p.R225C, including a set of cousins. CDK9 variants demonstrated decreased kinase activity. One of the studies suggested the extent the kinase activity is reduced may account for the absence/presence of the CHARGE-like phenotype with retinal dystrophy.

One additional family with retinal dystrophy only.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.367 CDK9 Zornitza Stark Marked gene: CDK9 as ready
Intellectual disability syndromic and non-syndromic v1.367 CDK9 Zornitza Stark Gene: cdk9 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.367 CDK9 Zornitza Stark Classified gene: CDK9 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.367 CDK9 Zornitza Stark Gene: cdk9 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.366 CDK9 Zornitza Stark gene: CDK9 was added
gene: CDK9 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 33640901; 30237576; 26633546
Phenotypes for gene: CDK9 were set to multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome MONDO:0015160; CHARGE-like syndrome with retinal dystrophy
Review for gene: CDK9 was set to AMBER
Added comment: Two independent reports:
1) A boy with a phenotype resembling CHARGE syndrome (multiple anomalies involving the eyes, ears, cleft lip, and palate, and intellectual disability) with retinal dystrophy (p.A288T/p.R303C),
2) 4 consanguineous families homozygous for p.R225C, including a set of cousins.
CDK9 variants demonstrated decreased kinase activity. One of the studies suggested the extent the kinase activity is reduced may account for the absence/presence of the CHARGE-like phenotype with retinal dystrophy

One additional family with retinal dystrophy only.
Sources: Literature
Mendeliome v1.3408 CDK9 Zornitza Stark Marked gene: CDK9 as ready
Mendeliome v1.3408 CDK9 Zornitza Stark Gene: cdk9 has been classified as Green List (High Evidence).
Mendeliome v1.3407 ABCB4 Chirag Patel Publications for gene ABCB4 were changed from 8666348; 17726488; 18482588; 28924228; 32376413; 9419367; 26474921; 32793533; 11313315 to 8666348; 17726488; 18482588; 28924228; 32376413; 9419367; 26474921; 32793533; 11313315
Mendeliome v1.3406 ABCB4 Chirag Patel Source Victorian Clinical Genetics Services was removed from ABCB4.
Phenotypes for gene: ABCB4 were changed from Cholestasis, progressive familial intrahepatic 3 MIM#602347; disorder of bile acid metabolism; Gallbladder disease 1 (MIM#600803) to Progressive familial intrahepatic cholestasis type 3, MONDO:0011214; Cholestasis, intrahepatic, of pregnancy, 3 MIM#614972; disorder of bile acid metabolism; Gallbladder disease 1 (MIM#600803)
Miscellaneous Metabolic Disorders v1.56 ABCB4 Chirag Patel Phenotypes for gene: ABCB4 were changed from Cholestasis, progressive familial intrahepatic 3 MIM#602347; disorder of bile acid metabolism to Progressive familial intrahepatic cholestasis type 3, MONDO:0011214
Publications for gene ABCB4 were changed from 8666348, 9419367, 26474921, 32793533, 11313315 to 8666348, 9419367, 26474921, 32793533, 11313315
Liver Failure_Paediatric v1.28 ABCB4 Chirag Patel Phenotypes for gene: ABCB4 were changed from Cholestasis, progressive familial intrahepatic 3, MIM# 602347 to Progressive familial intrahepatic cholestasis type 3, MONDO:0011214
Publications for gene ABCB4 were changed from 17726488, 9419367, 26474921, 32793533, 11313315 to 17726488, 9419367, 26474921, 32793533, 11313315
Mendeliome v1.3405 ABCC8 Chirag Patel Source Victorian Clinical Genetics Services was removed from ABCC8.
Source Expert list was added to ABCC8.
Phenotypes for gene: ABCC8 were changed from Maturity-onset diabetes of the young, type 12, MIM# 621196; Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800 to Maturity-onset diabetes of the young, type 12, MIM# 621196; Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800; Pulmonary arterial hypertension, MONDO:0015924, ABCC8-related
Publications for gene ABCC8 were changed from 21054355, 32027066, 32376986, 30354297, 35811711, 32934261, 31727138 to 21054355, 32027066, 32376986, 30354297, 35811711, 32934261, 31727138
Pulmonary Arterial Hypertension v1.44 ABCC8 Chirag Patel Phenotypes for gene: ABCC8 were changed from Diabetes mellitus; Hypoglycaemia; Pulmonary arterial hypertension to Pulmonary arterial hypertension, MONDO:0015924, ABCC8-related
Publications for gene ABCC8 were changed from 30354297, 35811711, 32934261, 31727138 to 30354297, 35811711, 32934261, 31727138
Intellectual disability syndromic and non-syndromic v1.365 AGTPBP1 Chirag Patel Phenotypes for gene: AGTPBP1 were changed from Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276 to Neurodegeneration, childhood-onset, with cerebellar atrophy, MONDO:0032650
Publications for gene AGTPBP1 were changed from 30420557, 28600779, 30976113, 38153683, 28325758 to 30420557, 28600779, 30976113, 38153683, 28325758
Hereditary Neuropathy - complex v1.38 AGTPBP1 Chirag Patel Phenotypes for gene: AGTPBP1 were changed from Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276 to Neurodegeneration, childhood-onset, with cerebellar atrophy, MONDO:0032650
Publications for gene AGTPBP1 were changed from 30420557, 28600779, 30976113, 38153683, 28325758 to 30420557, 28600779, 30976113, 38153683, 28325758
Regression v0.588 AGTPBP1 Chirag Patel Phenotypes for gene: AGTPBP1 were changed from Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276 to Neurodegeneration, childhood-onset, with cerebellar atrophy, MONDO:0032650
Publications for gene AGTPBP1 were changed from 30420557, 28600779, 30976113, 38153683, 28325758 to 30420557, 28600779, 30976113, 38153683, 28325758
Ataxia v1.58 AGTPBP1 Chirag Patel Phenotypes for gene: AGTPBP1 were changed from Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276 to Neurodegeneration, childhood-onset, with cerebellar atrophy, MONDO:0032650
Publications for gene AGTPBP1 were changed from 30420557, 28600779, 30976113, 38153683, 28325758 to 30420557, 28600779, 30976113, 38153683, 28325758
Mendeliome v1.3404 AGTPBP1 Chirag Patel Phenotypes for gene: AGTPBP1 were changed from Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276 to Neurodegeneration, childhood-onset, with cerebellar atrophy, MONDO:0032650
Publications for gene AGTPBP1 were changed from 30420557, 28600779, 30976113, 38153683, 28325758 to 30420557, 28600779, 30976113, 38153683, 28325758
Polymicrogyria and Schizencephaly v0.201 ATP1A3 Chirag Patel Source Literature was removed from ATP1A3.
Source Expert list was added to ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Polymicrogyria; epilepsy; developmental delay to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 33762331, 33880529, 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 33762331, 33880529, 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Alternating Hemiplegia and Hemiplegic Migraine v0.61 ATP1A3 Chirag Patel Source Victorian Clinical Genetics Services was removed from ATP1A3.
Source Expert list was added to ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Alternating hemiplegia of childhood 2, MIM# 614820 to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 22850527, 24842602,15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 22850527, 24842602,15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Brain Channelopathies v1.5 ATP1A3 Chirag Patel Source Victorian Clinical Genetics Services was removed from ATP1A3.
Source Expert list was added to ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Alternating hemiplegia of childhood 2, MIM# 614820; CAPOS syndrome, MIM# 601338; Dystonia-12, MIM# 128235 to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Cerebral Palsy v1.397 ATP1A3 Chirag Patel Phenotypes for gene: ATP1A3 were changed from Alternating hemiplegia of childhood 2, MIM# 614820; CAPOS syndrome, MIM# 601338; Dystonia-12, MIM# 128235 to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Genetic Epilepsy v1.253 ATP1A3 Chirag Patel Source Victorian Clinical Genetics Services was removed from ATP1A3.
Source Australian Genomics Health Alliance Epilepsy Flagship was removed from ATP1A3.
Phenotypes for gene: ATP1A3 were changed from developmental and epileptic encephalopathy; early or neonatal onset seizures, polymicrogyria to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 33880529, 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 33880529, 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Mendeliome v1.3403 ATP1A3 Chirag Patel Source Victorian Clinical Genetics Services was removed from ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Alternating hemiplegia of childhood 2, MIM# 614820; CAPOS syndrome, MIM# 601338; Dystonia-12, MIM# 128235; Polymicrogyria to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Regression v0.587 ATP1A3 Chirag Patel Source Victorian Clinical Genetics Services was removed from ATP1A3.
Source Expert list was added to ATP1A3.
Mode of inheritance for gene ATP1A3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ATP1A3 were changed from to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Intellectual disability syndromic and non-syndromic v1.364 ATP1A3 Chirag Patel Source Genetic Health Queensland was removed from ATP1A3.
Source Expert list was added to ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Alternating hemiplegia of childhood 2, MIM#614820; Developmental and epileptic encephalopathy, polymicrogyria to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 33880529, 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 33880529, 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Paroxysmal Dyskinesia v0.144 ATP1A3 Chirag Patel Source Royal Children's Hospital Neurology Department was removed from ATP1A3.
Source Victorian Clinical Genetics Services was removed from ATP1A3.
Source Expert list was added to ATP1A3.
Mode of inheritance for gene ATP1A3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ATP1A3 were changed from to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Ataxia v1.57 ATP1A3 Chirag Patel Source Victorian Clinical Genetics Services was removed from ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Alternating hemiplegia of childhood 2 MIM#614820; CAPOS syndrome MIM#601338 to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Dystonia - isolated/combined v1.42 ATP1A3 Chirag Patel Source Royal Melbourne Hospital was removed from ATP1A3.
Source Expert list was added to ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Dystonia-12, MIM# 128235; Rapid dystonia-parkinsonism MONDO:0007496 to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953; 17282997; 19351654, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953; 17282997; 19351654, 22842232, 24468074, 33762331, 29861155, 31425744
Fetal anomalies v1.442 ATP1A3 Chirag Patel Source Genomics England PanelApp was removed from ATP1A3.
Source Literature was removed from ATP1A3.
Source Genetic Health Queensland was removed from ATP1A3.
Source Expert list was added to ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Developmental and epileptic encephalopathy 99, MIM# 619606; Polymicrogyria to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Intellectual disability syndromic and non-syndromic v1.363 ALS2 Chirag Patel Source Genetic Health Queensland was removed from ALS2.
Source ClinGen was added to ALS2.
Phenotypes for gene: ALS2 were changed from Spastic paralysis, infantile onset ascending, MIM#607225 to ALS2-related motor neuron disease, MONDO:0100227
Motor Neurone Disease v1.39 ALS2 Chirag Patel Source Literature was removed from ALS2.
Source Melbourne Genomics Health Alliance Complex Neurology Flagship was removed from ALS2.
Source Victorian Clinical Genetics Services was removed from ALS2.
Source ClinGen was added to ALS2.
Phenotypes for gene: ALS2 were changed from Amyotrophic lateral sclerosis 2, juvenile (MIM# 205100; MONDO: MONDO:0008780) to ALS2-related motor neuron disease, MONDO:0100227
Publications for gene ALS2 were changed from 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358 to 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358
Cerebral Palsy v1.396 ALS2 Chirag Patel Phenotypes for gene: ALS2 were changed from Spastic paralysis, infantile onset ascending, MIM# 607225 to ALS2-related motor neuron disease, MONDO:0100227
Publications for gene ALS2 were changed from 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358 to 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358
Hereditary Spastic Paraplegia v1.101 ALS2 Chirag Patel Source Royal Melbourne Hospital was removed from ALS2.
Source ClinGen was added to ALS2.
Phenotypes for gene: ALS2 were changed from Spastic paralysis, infantile onset ascending, MIM# 607225 to ALS2-related motor neuron disease, MONDO:0100227
Publications for gene ALS2 were changed from 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358 to 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358
Mendeliome v1.3402 ALS2 Chirag Patel Source Literature was removed from ALS2.
Source ClinGen was added to ALS2.
Phenotypes for gene: ALS2 were changed from Infantile onset ascending spastic paralysis (MIM#607225); Juvenile amyotrophic lateral sclerosis 2 (MIM#205100); Juvenile primary lateral sclerosis (MIM#606353) to ALS2-related motor neuron disease, MONDO:0100227
Publications for gene ALS2 were changed from 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358 to 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358
Muscular dystrophy and myopathy_Paediatric v1.106 ALG14 Chirag Patel reviewed gene: ALG14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Muscular dystrophy and myopathy_Paediatric v1.106 ALG14 Chirag Patel Classified gene: ALG14 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.106 ALG14 Chirag Patel Gene: alg14 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.105 ALG14 Chirag Patel Phenotypes for gene: ALG14 were changed from congenital myopathy MONDO:0019952 to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Disorder of N-glycosylation
Publications for gene ALG14 were changed from 30221345, 23404334, 28733338, 33751823, 34971077 to 30221345, 23404334, 28733338, 33751823, 34971077
Intellectual disability syndromic and non-syndromic v1.362 ALG14 Chirag Patel Source Genetic Health Queensland was removed from ALG14.
Source Expert list was added to ALG14.
Publications for gene ALG14 were changed from 30221345, 23404334, 28733338, 33751823, 34971077 to 30221345, 23404334, 28733338, 33751823, 34971077
Congenital Myasthenia v1.16 ALG14 Chirag Patel Classified gene: ALG14 as Green List (high evidence)
Congenital Myasthenia v1.16 ALG14 Chirag Patel Gene: alg14 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.252 ALG14 Chirag Patel Publications for gene ALG14 were changed from 30221345, 23404334, 28733338, 33751823, 34971077 to 30221345, 23404334, 28733338, 33751823, 34971077
Regression v0.586 ALG14 Chirag Patel Publications for gene ALG14 were changed from 30221345, 23404334, 28733338, 33751823, 34971077 to 30221345, 23404334, 28733338, 33751823, 34971077
Congenital Myasthenia v1.15 ALG14 Chirag Patel Source Royal Melbourne Hospital was removed from ALG14.
Source Expert list was added to ALG14.
Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Disorder of N-glycosylation
Publications for gene ALG14 were changed from 30221345, 23404334, 28733338, 33751823, 34971077 to 30221345, 23404334, 28733338, 33751823, 34971077
Congenital Disorders of Glycosylation v1.78 ALG14 Chirag Patel Source Victorian Clinical Genetics Services was removed from ALG14.
Source Expert list was added to ALG14.
Publications for gene ALG14 were changed from 30221345, 23404334, 28733338, 33751823, 34971077 to 30221345, 23404334, 28733338, 33751823, 34971077
Mendeliome v1.3401 ALG14 Chirag Patel Source Victorian Clinical Genetics Services was removed from ALG14.
Source Expert list was added to ALG14.
Publications for gene ALG14 were changed from 30221345, 23404334, 28733338, 33751823, 34971077 to 30221345, 23404334, 28733338, 33751823, 34971077
Mitochondrial disease v0.1085 AGK Chirag Patel Source Victorian Clinical Genetics Services was removed from AGK.
Source Australian Genomics Health Alliance Mitochondrial Flagship was removed from AGK.
Source Expert list was added to AGK.
Mode of inheritance for gene AGK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AGK were changed from to Sengers syndrome, MIM#212350
Publications for gene AGK were changed from 22415731; 25208612; 22415731; 25208612 to 22415731; 25208612; 22415731; 25208612
Mendeliome v1.3400 AGK Chirag Patel Source Victorian Clinical Genetics Services was removed from AGK.
Source Expert list was added to AGK.
Deafness_IsolatedAndComplex v1.234 ATP6V1B2 Chirag Patel Source Literature was removed from ATP6V1B2.
Source Expert list was added to ATP6V1B2.
Mode of inheritance for gene ATP6V1B2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3399 DHX9 Chirag Patel Source Literature was removed from DHX9.
Source Expert list was added to DHX9.
Phenotypes for gene: DHX9 were changed from Intellectual developmental disorder, autosomal dominant 75, MIM# 620988; Charcot-Marie-Tooth disease, MONDO:0015626 to Intellectual developmental disorder, autosomal dominant 75, MIM# 620988; Charcot-Marie-Tooth disease, MONDO:0015626, DHX9-related
Liver Failure_Paediatric v1.27 DGUOK Chirag Patel Phenotypes for gene: DGUOK were changed from Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM#251880 to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880; Portal hypertension, noncirrhotic, 1, MIM# 617068; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, MIM# 617070
Publications for gene DGUOK were changed from 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938 to 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938
Mitochondrial disease v0.1084 DGUOK Chirag Patel Source Victorian Clinical Genetics Services was removed from DGUOK.
Source Australian Genomics Health Alliance Mitochondrial Flagship was removed from DGUOK.
Source Victorian Clinical Genetics Services was removed from DGUOK.
Source ClinGen was added to DGUOK.
Mode of inheritance for gene DGUOK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DGUOK were changed from to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880; Portal hypertension, noncirrhotic, 1, MIM# 617068; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, MIM# 617070
Publications for gene DGUOK were changed from 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938 to 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938
Cholestasis v1.5 DGUOK Chirag Patel Source Victorian Clinical Genetics Services was removed from DGUOK.
Source ClinGen was added to DGUOK.
Phenotypes for gene: DGUOK were changed from Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880 to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880; Portal hypertension, noncirrhotic, 1, MIM# 617068; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, MIM# 617070
Publications for gene DGUOK were changed from 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938 to 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938
Hereditary Neuropathy - complex v1.37 DGUOK Chirag Patel Phenotypes for gene: DGUOK were changed from Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), 251880 Portal hypertension, noncirrhotic, 617068 Neonatal liver failure, myopathy, sensory-motor axonal neuropathy to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880; Portal hypertension, noncirrhotic, 1, MIM# 617068; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, MIM# 617070
Publications for gene DGUOK were changed from 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938 to 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938
Mendeliome v1.3398 DGUOK Chirag Patel Source Victorian Clinical Genetics Services was removed from DGUOK.
Source ClinGen was added to DGUOK.
Publications for gene DGUOK were changed from 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938 to 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938
Mendeliome v1.3397 DHH Chirag Patel Classified gene: DHH as Green List (high evidence)
Mendeliome v1.3397 DHH Chirag Patel Gene: dhh has been classified as Green List (High Evidence).
Differences of Sex Development v1.24 DHH Chirag Patel Source Victorian Clinical Genetics Services was removed from DHH.
Source Expert list was added to DHH.
Phenotypes for gene: DHH were changed from 46XY partial gonadal dysgenesis, with minifascicular neuropathy, MIM# 607080 to 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, MONDO:0011766
Mendeliome v1.3396 DHH Chirag Patel Source Victorian Clinical Genetics Services was removed from DHH.
Source Expert list was added to DHH.
Phenotypes for gene: DHH were changed from 46XY gonadal dysgenesis with minifascicular neuropathy MIM#607080; 46XY sex reversal 7 MIM#233420 to 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, MONDO:0011766
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary Neuropathy - complex v1.36 DHH Chirag Patel Phenotypes for gene: DHH were changed from 46XY partial gonadal dysgenesis, with minifascicular neuropathy, MIM# 607080 to 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, MONDO:0011766
Infertility and Recurrent Pregnancy Loss v1.42 DHH Chirag Patel Phenotypes for gene: DHH were changed from MONDO:0011766 to 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, MONDO:0011766
Infertility and Recurrent Pregnancy Loss v1.41 DHH Chirag Patel Source Literature was removed from DHH.
Source Expert list was added to DHH.
Phenotypes for gene: DHH were changed from 46XY gonadal dysgenesis with minifascicular neuropathy, MIM# 607080 to MONDO:0011766
Genetic Epilepsy v1.251 DNAJC6 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAJC6.
Source Australian Genomics Health Alliance Epilepsy Flagship was removed from DNAJC6.
Source Expert list was added to DNAJC6.
Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19b, early-onset, MIM#615528 to Parkinson disease 19a, juvenile-onset - MIM#615528; Parkinson disease 19b, early-onset - MIM#615528
Publications for gene DNAJC6 were changed from 22563501, 23211418, 26528954, 33983693 to 22563501, 23211418, 26528954, 33983693
Early-onset Parkinson disease v2.43 DNAJC6 Chirag Patel Publications for gene DNAJC6 were changed from 22563501, 23211418, 26528954, 33983693 to 22563501, 23211418, 26528954, 33983693
Mendeliome v1.3394 DNAJC6 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAJC6.
Source Expert list was added to DNAJC6.
Publications for gene DNAJC6 were changed from 22563501, 23211418, 26528954, 33983693 to 22563501, 23211418, 26528954, 33983693
Early-onset Parkinson disease v2.42 DNAJC6 Chirag Patel Source Melbourne Genomics Health Alliance Complex Neurology Flagship was removed from DNAJC6.
Source Victorian Clinical Genetics Services was removed from DNAJC6.
Source Expert list was added to DNAJC6.
Phenotypes for gene: DNAJC6 were changed from juvenile onset Parkinson disease 19A MONDO:0014231 to Parkinson disease 19a, juvenile-onset - MIM#615528; Parkinson disease 19b, early-onset - MIM#615528
Ciliary Dyskinesia v1.58 DNAH8 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAH8.
Source ClinGen was added to DNAH8.
Phenotypes for gene: DNAH8 were changed from Spermatogenic failure 46, MIM#619095; Asthenozoospermia; primary ciliary dyskinesia to Primary ciliary dyskinesia, MONDO:0016575, DNAH8-related
Publications for gene DNAH8 were changed from 24307375 to 24307375
Mendeliome v1.3393 DNAH8 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAH8.
Source ClinGen was added to DNAH8.
Phenotypes for gene: DNAH8 were changed from Spermatogenic failure 46, MIM#619095; Asthenozoospermia; primary ciliary dyskinesia to Spermatogenic failure 46, MONDO:0033673; Primary ciliary dyskinesia, MONDO:0016575, DNAH8-related
Publications for gene DNAH8 were changed from 31178125, 32619401, 32681648, 33704367, 24307375 to 31178125, 32619401, 32681648, 33704367, 24307375
Fetal anomalies v1.441 DNAH8 Chirag Patel Phenotypes for gene: DNAH8 were changed from primary ciliary dyskinesia to Primary ciliary dyskinesia, MONDO:0016575, DNAH8-related
Publications for gene DNAH8 were changed from 24307375 to 24307375
Infertility and Recurrent Pregnancy Loss v1.40 DNAH8 Chirag Patel Source Literature was removed from DNAH8.
Source ClinGen was added to DNAH8.
Phenotypes for gene: DNAH8 were changed from Spermatogenic failure 46, MIM# 619095 to Spermatogenic failure 46, MONDO:0033673
Publications for gene DNAH8 were changed from 31178125, 32619401, 32681648, 33704367 to 31178125, 32619401, 32681648, 33704367
Mendeliome v1.3392 DNAH1 Chirag Patel Classified gene: DNAH1 as Green List (high evidence)
Mendeliome v1.3392 DNAH1 Chirag Patel Gene: dnah1 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.57 DNAH1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAH1.
Source ClinGen was added to DNAH1.
Phenotypes for gene: DNAH1 were changed from ?Ciliary dyskinesia, primary, 37 617577; Spermatogenic failure 18 617576 to Primary ciliary dyskinesia 7, MONDO:0012748
Publications for gene DNAH1 were changed from 25927852, 31765523, 33577779, 34210339 to 25927852, 31765523, 33577779, 34210339
Heterotaxy v1.43 DNAH1 Chirag Patel Phenotypes for gene: DNAH1 were changed from ?Ciliary dyskinesia, primary, 37 617577 to Primary ciliary dyskinesia 7, MONDO:0012748
Mendeliome v1.3391 DNAH1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAH1.
Source ClinGen was added to DNAH1.
Phenotypes for gene: DNAH1 were changed from primary ciliary dyskinesia,37 MIM#617577; Spermatogenic failure 18 MIM#617576 to Spermatogenic failure 18, MONDO:0054615; Primary ciliary dyskinesia 7, MONDO:0012748
Publications for gene DNAH1 were changed from 34867808, 31507630, 24360805, 27798045, 11371505, 27798045, 29449551, 25927852, 31765523, 33577779, 34210339 to 34867808, 31507630, 24360805, 27798045, 11371505, 27798045, 29449551, 25927852, 31765523, 33577779, 34210339
Rating Changed from Green List (high evidence) to Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v1.39 DNAH1 Chirag Patel Source Literature was removed from DNAH1.
Source ClinGen was added to DNAH1.
Phenotypes for gene: DNAH1 were changed from Spermatogenic failure 18 , MIM# 617576 to Spermatogenic failure 18, MONDO:0054615
Publications for gene DNAH1 were changed from 34867808, 31507630, 24360805, 27798045, 11371505, 27798045, 29449551 to 34867808, 31507630, 24360805, 27798045, 11371505, 27798045, 29449551
Skeletal Dysplasia_Fetal v0.239 DHCR24 Chirag Patel Phenotypes for gene: DHCR24 were changed from Desmosterolosis - MIM#602398 to Desmosterolosis, MONDO:0011217
Skeletal dysplasia v0.338 DHCR24 Chirag Patel Source Victorian Clinical Genetics Services was removed from DHCR24.
Phenotypes for gene: DHCR24 were changed from Desmosterolosis 602398 to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Miscellaneous Metabolic Disorders v1.55 DHCR24 Chirag Patel Phenotypes for gene: DHCR24 were changed from Desmosterolosis MIM#602398; Disorders of the metabolism of sterols to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Intellectual disability syndromic and non-syndromic v1.361 DHCR24 Chirag Patel Source Genetic Health Queensland was removed from DHCR24.
Source ClinGen was added to DHCR24.
Phenotypes for gene: DHCR24 were changed from Desmosterolosis, MIM# 602398 to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Fetal anomalies v1.440 DHCR24 Chirag Patel Source Genomics England PanelApp was removed from DHCR24.
Phenotypes for gene: DHCR24 were changed from Desmosterolosis, MIM# 602398 to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Genetic Epilepsy v1.250 DHCR24 Chirag Patel Source Victorian Clinical Genetics Services was removed from DHCR24.
Source Australian Genomics Health Alliance Epilepsy Flagship was removed from DHCR24.
Source Victorian Clinical Genetics Services was removed from DHCR24.
Phenotypes for gene: DHCR24 were changed from Desmosterolosis, MIM# 602398 to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Callosome v0.562 DHCR24 Chirag Patel Source Victorian Clinical Genetics Services was removed from DHCR24.
Source ClinGen was added to DHCR24.
Phenotypes for gene: DHCR24 were changed from to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Hydrocephalus_Ventriculomegaly v0.131 DHCR24 Chirag Patel Source Victorian Clinical Genetics Services was removed from DHCR24.
Source ClinGen was added to DHCR24.
Phenotypes for gene: DHCR24 were changed from Desmosterolosis, MIM# 602398 to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Mendeliome v1.3390 DHCR24 Chirag Patel Source Victorian Clinical Genetics Services was removed from DHCR24.
Phenotypes for gene: DHCR24 were changed from Desmosterolosis MIM#602398; Disorders of the metabolism of sterols to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Arthrogryposis v0.427 DHCR24 Chirag Patel Phenotypes for gene: DHCR24 were changed from Desmosterolosis, MIM# 602398 to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Disorders of immune dysregulation v1.31 DEF6 Chirag Patel Phenotypes for gene: DEF6 were changed from Immunodeficiency 87 and autoimmunity, MIM# 619573; Systemic autoimmunity to Immunodeficiency 87 and autoimmunity, MONDO:0030457
Mendeliome v1.3389 DEF6 Chirag Patel Phenotypes for gene: DEF6 were changed from Immunodeficiency 87 and autoimmunity, MIM# 619573; Systemic autoimmunity to Immunodeficiency 87 and autoimmunity, MONDO:0030457
Intellectual disability syndromic and non-syndromic v1.360 DDX11 Chirag Patel Source Genetic Health Queensland was removed from DDX11.
Source ClinGen was added to DDX11.
Phenotypes for gene: DDX11 were changed from Warsaw breakage syndrome, MIM# 613398; MONDO:0013252 to Warsaw breakage syndrome, MONDO:0013252
Publications for gene DDX11 were changed from 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203 to 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203
Microcephaly v1.349 DDX11 Chirag Patel Source Literature was removed from DDX11.
Source ClinGen was added to DDX11.
Phenotypes for gene: DDX11 were changed from Warsaw breakage syndrome, MIM# 613398; MONDO:0013252 to Warsaw breakage syndrome, MONDO:0013252
Publications for gene DDX11 were changed from 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203 to 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203
Fetal anomalies v1.439 DDX11 Chirag Patel Source Genomics England PanelApp was removed from DDX11.
Source Literature was removed from DDX11.
Source Genetic Health Queensland was removed from DDX11.
Source ClinGen was added to DDX11.
Phenotypes for gene: DDX11 were changed from Warsaw breakage syndrome, MIM# 613398; MONDO:0013252 to Warsaw breakage syndrome, MONDO:0013252
Publications for gene DDX11 were changed from 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203 to 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203
Chromosome Breakage Disorders v1.24 DDX11 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDX11.
Source ClinGen was added to DDX11.
Phenotypes for gene: DDX11 were changed from Warsaw breakage syndrome, MIM# 613398; MONDO:0013252 to Warsaw breakage syndrome, MONDO:0013252
Publications for gene DDX11 were changed from 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203 to 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203
Growth failure v1.83 DDX11 Chirag Patel Phenotypes for gene: DDX11 were changed from Warsaw breakage syndrome, MIM# 613398; MONDO:0013252 to Warsaw breakage syndrome, MONDO:0013252
Publications for gene DDX11 were changed from 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203 to 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203
Mendeliome v1.3388 DDX11 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDX11.
Source ClinGen was added to DDX11.
Phenotypes for gene: DDX11 were changed from Warsaw breakage syndrome, MIM# 613398; MONDO:0013252 to Warsaw breakage syndrome, MONDO:0013252
Publications for gene DDX11 were changed from 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203 to 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203
Hereditary Neuropathy - complex v1.35 DDHD1 Chirag Patel Source Royal Melbourne Hospital was removed from DDHD1.
Source ClinGen was added to DDHD1.
Phenotypes for gene: DDHD1 were changed from Spastic paraplegia, occasionally cerebellar eye signs and subclinical axonal neuropathy to Hereditary spastic paraplegia 28, MONDO:0012256
Publications for gene DDHD1 were changed from 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578 to 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578
Hereditary Spastic Paraplegia v1.100 DDHD1 Chirag Patel Phenotypes for gene: DDHD1 were changed from Spastic paraplegia 28, autosomal recessive, MIM# 609340; MONDO:0012256 to Hereditary spastic paraplegia 28, MONDO:0012256
Publications for gene DDHD1 were changed from 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578 to 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578
Mendeliome v1.3387 DDHD1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDHD1.
Source ClinGen was added to DDHD1.
Phenotypes for gene: DDHD1 were changed from Spastic paraplegia 28, autosomal recessive, 609340; MONDO:0012256 to Hereditary spastic paraplegia 28, MONDO:0012256
Publications for gene DDHD1 were changed from 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578 to 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578
Hereditary Neuropathy - complex v1.34 DDHD1 Chirag Patel Classified gene: DDHD1 as Green List (high evidence)
Hereditary Neuropathy - complex v1.34 DDHD1 Chirag Patel Gene: ddhd1 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v1.33 DDHD1 Chirag Patel reviewed gene: DDHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578; Phenotypes: Hereditary spastic paraplegia 28, MONDO:0012256; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.126 DCLRE1C Chirag Patel Source Victorian Clinical Genetics Services was removed from DCLRE1C.
Source Expert list was added to DCLRE1C.
Mode of inheritance for gene DCLRE1C was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DCLRE1C were changed from to Severe combined immunodeficiency due to DCLRE1C deficiency, MONDO:0011225
Publications for gene DCLRE1C were changed from 12055248, 34220820, 11336668, 19953608, 15731174, 16540517, 18034425, 12504013, 15699179 to 12055248, 34220820, 11336668, 19953608, 15731174, 16540517, 18034425, 12504013, 15699179
Combined Immunodeficiency v1.135 DCLRE1C Chirag Patel Source Melbourne Genomics Health Alliance Immunology Flagship was removed from DCLRE1C.
Source Victorian Clinical Genetics Services was removed from DCLRE1C.
Source Expert list was added to DCLRE1C.
Phenotypes for gene: DCLRE1C were changed from Severe combined immunodeficiency, Athabascan type MIM# 602450; Omenn syndrome MIM# 603554 to Severe combined immunodeficiency due to DCLRE1C deficiency, MONDO:0011225
Publications for gene DCLRE1C were changed from 12055248, 34220820, 11336668, 19953608, 15731174, 16540517, 18034425, 12504013, 15699179 to 12055248, 34220820, 11336668, 19953608, 15731174, 16540517, 18034425, 12504013, 15699179
Mendeliome v1.3386 DCLRE1C Chirag Patel Source Victorian Clinical Genetics Services was removed from DCLRE1C.
Source Expert list was added to DCLRE1C.
Phenotypes for gene: DCLRE1C were changed from Severe combined immunodeficiency, Athabascan type MIM# 602450; Omenn syndrome, MIM# 603554 to Severe combined immunodeficiency due to DCLRE1C deficiency, MONDO:0011225
Publications for gene DCLRE1C were changed from 12055248, 34220820, 11336668, 19953608, 15731174, 16540517, 18034425, 12504013, 15699179 to 12055248, 34220820, 11336668, 19953608, 15731174, 16540517, 18034425, 12504013, 15699179
Vasculitis v0.93 DCLRE1C Chirag Patel Classified gene: DCLRE1C as Red List (low evidence)
Vasculitis v0.93 DCLRE1C Chirag Patel Gene: dclre1c has been classified as Red List (Low Evidence).
Vasculitis v0.92 DCLRE1C Chirag Patel reviewed gene: DCLRE1C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3385 DCDC2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DCDC2.
Source Victorian Clinical Genetics Services was removed from DCDC2.
Source Expert list was added to DCDC2.
Phenotypes for gene: DCDC2 were changed from Nephronophthisis 19, MIM# 616217; Sclerosing cholangitis, neonatal, MIM# 617394 to Nephronophthisis 19, MIM# 616217; Sclerosing cholangitis, neonatal, MIM# 617394; Deafness, autosomal recessive 66, MIM# 610212
Mendeliome v1.3384 DBR1 Chirag Patel Publications for gene DBR1 were changed from 39023559, 29474921, 37656279 to 39023559, 29474921, 37656279
Genomic newborn screening: ICoNS v0.16 PAH Lilian Downie gene: PAH was added
gene: PAH was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: PAH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAH were set to PMID: 39630157; 40378670
Phenotypes for gene: PAH were set to Phenylketonuria MIM#261600
Review for gene: PAH was set to GREEN
Added comment: Definitive gene disease association
Definitive for actionability in childhood
Included in traditional newborn screening in all jurisdictions
Sources: Expert list
Mendeliome v1.3383 DNM2 Chirag Patel Publications for gene DNM2 were changed from 15731758; 17636067; 33459893; 31628461; 23092955; 16227997; 33458580; 30232666; 24465259; 23938035 to 15731758; 17636067; 33459893; 31628461; 23092955; 16227997; 33458580; 30232666; 24465259; 23938035
Mendeliome v1.3382 MAFA Sangavi Sivagnanasundram gene: MAFA was added
gene: MAFA was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MAFA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAFA were set to 29339498
Phenotypes for gene: MAFA were set to Insulinomatosis and diabetes mellitus, OMIM #:147630
Review for gene: MAFA was set to GREEN
Added comment: Addition of this review to Mendeliome, was only on the hyperinsulinism panel

2 families with 36 individuals with AD inheritance of diabetes mellitus or insulinomatosis (adult-onset recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumours of pancreas). WES identified the same missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes in both families. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.
Sources: Other
Mendeliome v1.3382 DHX38 Arina Puzriakova changed review comment from: - PMID: 35719279 (2022) - another consanguineous family from Saudi Arabia with two sisters presented affected by retinitis pigmentosa since childhood. Whole exome sequencing identified a missense homozygous variant (c.2571C>T, p.(Ala857=)) in the DHX38 gene which segregated with the phenotype. No functional studies performed.

PMID: 37867960 (2023) - zebrafish knockout model shows a role in the development of the retina; to: - PMID: 35719279 (2022) - another consanguineous family from Saudi Arabia with two sisters presented affected by retinitis pigmentosa since childhood. Whole exome sequencing identified a missense homozygous variant (c.2571C>T, p.(Ala857=)) in the DHX38 gene which segregated with the phenotype. No functional studies performed.

- PMID: 37867960 (2023) - zebrafish knockout model shows a role in the development of the retina
Mendeliome v1.3382 DHX38 Arina Puzriakova reviewed gene: DHX38: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v1.359 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Intellectual disability syndromic and non-syndromic v1.358 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Genetic Epilepsy v1.249 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from to Congenital disorder of glycosylation, type IICC, MIM# 621381
Genetic Epilepsy v1.248 UGGT1 Zornitza Stark Publications for gene: UGGT1 were set to
Genetic Epilepsy v1.247 UGGT1 Zornitza Stark Mode of inheritance for gene: UGGT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.246 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Renal Macrocystic Disease v0.91 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Renal Macrocystic Disease v0.90 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Microcephaly v1.348 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Microcephaly v1.347 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Mendeliome v1.3382 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Mendeliome v1.3381 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Differences of Sex Development v1.23 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Differences of Sex Development v1.22 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Congenital Heart Defect v0.470 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Congenital Heart Defect v0.469 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Congenital Disorders of Glycosylation v1.77 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Congenital Disorders of Glycosylation v1.76 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Autism v0.223 UGGT1 Zornitza Stark Marked gene: UGGT1 as ready
Autism v0.223 UGGT1 Zornitza Stark Gene: uggt1 has been classified as Green List (High Evidence).
Autism v0.223 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Autism v0.222 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v1.358 NAA20 Chern Lim reviewed gene: NAA20: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37191084; Phenotypes: Intellectual developmental disorder, autosomal recessive 73, MIM# 619717; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Infertility and Recurrent Pregnancy Loss v1.38 INCENP Rylee Peters gene: INCENP was added
gene: INCENP was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: INCENP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INCENP were set to 41005306
Phenotypes for gene: INCENP were set to Oocyte/zygote/embryo maturation arrest MONDO:0014769, INCENP-related
Review for gene: INCENP was set to AMBER
Added comment: 3 unrelated women presenting with abnormal oocyte morphology and/or low fertilisation rate from a large cohort of 3627 individuals. WES identified biallelic missense variants:
R267Q (gnomAD v4: 1717 hets, 12 homs), R280W (5 hets, 0 homs), P444L (207 hets, 0 homs), R693W (686 hets, 1 hom), K816T (110 hets, 1 hom), K890E (3 hets, 0 homs).

siRNA-mediated knock-down of INCENP in mouse oocytes reduced polar-body extrusion rates, demonstrating that loss of function of the protein affects oocyte maturation.
Sources: Literature
Mendeliome v1.3381 INCENP Rylee Peters gene: INCENP was added
gene: INCENP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INCENP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INCENP were set to 41005306
Phenotypes for gene: INCENP were set to Oocyte/zygote/embryo maturation arrest MONDO:0014769, INCENP-related
Review for gene: INCENP was set to AMBER
Added comment: 3 unrelated women presenting with abnormal oocyte morphology and/or low fertilisation rate from a large cohort of 3627 individuals. WES identified biallelic missense variants:
R267Q (gnomAD v4: 1717 hets, 12 homs), R280W (5 hets, 0 homs), P444L (207 hets, 0 homs), R693W (686 hets, 1 hom), K816T (110 hets, 1 hom), K890E (3 hets, 0 homs).

siRNA-mediated knock-down of INCENP in mouse oocytes reduced polar-body extrusion rates, demonstrating that loss of function of the protein affects oocyte maturation.
Sources: Literature
Mendeliome v1.3381 ANKRD24 Rylee Peters reviewed gene: ANKRD24: Rating: RED; Mode of pathogenicity: None; Publications: 40989574; Phenotypes: Sensorineural hearing loss disorder MONDO:0020678, ANKRD24-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.361 SWSAP1 Rylee Peters gene: SWSAP1 was added
gene: SWSAP1 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature
Mode of inheritance for gene: SWSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SWSAP1 were set to 40991243
Phenotypes for gene: SWSAP1 were set to Primary ovarian insufficiency, MONDO:0005387, SWSAP1-related
Review for gene: SWSAP1 was set to RED
Added comment: Cohort with severe isolated premature ovarian insufficiency. 1x individual homozygous for a frameshift SWSAP1 variant, c.353del, p.(Gly118AlafsTer2), absent from gnomAD v4.

Functional: western-blot indicates reduced stability of the truncated protein; the truncated SWSAP1 variant fails to complement the IH-HR (interhomolog homologous recombination) defect of Swsap1−/− cells (undetected IH-HR activity).
Sources: Literature
Mendeliome v1.3381 SWSAP1 Rylee Peters gene: SWSAP1 was added
gene: SWSAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SWSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SWSAP1 were set to 40991243
Phenotypes for gene: SWSAP1 were set to Primary ovarian insufficiency, MONDO:0005387, SWSAP1-related
Review for gene: SWSAP1 was set to RED
Added comment: Cohort with severe isolated premature ovarian insufficiency. 1x individual homozygous for a frameshift SWSAP1 variant, c.353del, p.(Gly118AlafsTer2), absent from gnomAD v4.

Functional: western-blot indicates reduced stability of the truncated protein; the truncated SWSAP1 variant fails to complement the IH-HR (interhomolog homologous recombination) defect of Swsap1−/− cells (undetected IH-HR activity).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.38 FSIP2 Rylee Peters gene: FSIP2 was added
gene: FSIP2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FSIP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FSIP2 were set to 30137358; 40968718; 36632462; 33631238
Phenotypes for gene: FSIP2 were set to Spermatogenic failure 34, MIM#618153
Review for gene: FSIP2 was set to GREEN
Added comment: Multiple unrelated cases with multiple morphological abnormalities of the sperm flagella (MMAF) carrying biallelic variants.
Sources: Literature
Mendeliome v1.3381 FSIP2 Rylee Peters gene: FSIP2 was added
gene: FSIP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FSIP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FSIP2 were set to 30137358; 40968718; 36632462; 33631238
Phenotypes for gene: FSIP2 were set to Spermatogenic failure 34, MIM#618153
Review for gene: FSIP2 was set to GREEN
Added comment: Multiple unrelated cases with multiple morphological abnormalities of the sperm flagella (MMAF) carrying biallelic variants.
Sources: Literature
Hydrocephalus_Ventriculomegaly v0.130 AMOT Rylee Peters gene: AMOT was added
gene: AMOT was added to Hydrocephalus_Ventriculomegaly. Sources: Literature
Mode of inheritance for gene: AMOT was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AMOT were set to 40892511
Phenotypes for gene: AMOT were set to Congenital hydrocephalus MONDO:0016349, AMOT-related
Review for gene: AMOT was set to AMBER
Added comment: 1x family with isolated X-linked congenital hydrocephalus – clinical presentation considered late, identified in the third trimester. Variant segregated with disease in 6x affected hemizygous males (4x live-born and 2x terminated male fetuses). Carrier females are apparently normal (no brain MRI was performed).

Exome sequencing identified start loss variant, c.2T>C p.(Met1Thr). Functional analyses identify that the variant results in a protein lacking 91 amino acids from the N-terminus and leads to abnormally increased AMOT protein levels (increased stability due to loss of degradation signals), which disrupts epithelial and endothelial barrier integrity.
Sources: Literature
Fetal anomalies v1.438 AMOT Rylee Peters gene: AMOT was added
gene: AMOT was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: AMOT was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AMOT were set to 40892511
Phenotypes for gene: AMOT were set to Congenital hydrocephalus MONDO:0016349, AMOT-related
Review for gene: AMOT was set to AMBER
Added comment: 1x family with isolated X-linked congenital hydrocephalus – clinical presentation considered late, identified in the third trimester. Variant segregated with disease in 6x affected hemizygous males (4x live-born and 2x terminated male fetuses). Carrier females are apparently normal (no brain MRI was performed).

Exome sequencing identified start loss variant, c.2T>C p.(Met1Thr). Functional analyses identify that the variant results in a protein lacking 91 amino acids from the N-terminus and leads to abnormally increased AMOT protein levels (increased stability due to loss of degradation signals), which disrupts epithelial and endothelial barrier integrity.
Sources: Literature
Mendeliome v1.3381 AMOT Rylee Peters gene: AMOT was added
gene: AMOT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AMOT was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AMOT were set to 40892511
Phenotypes for gene: AMOT were set to Congenital hydrocephalus MONDO:0016349, AMOT-related
Review for gene: AMOT was set to AMBER
Added comment: 1x family with isolated X-linked congenital hydrocephalus – clinical presentation considered late, identified in the third trimester. Variant segregated with disease in 6x affected hemizygous males (4x live-born and 2x terminated male fetuses). Carrier females are apparently normal (no brain MRI was performed).

Exome sequencing identified start loss variant, c.2T>C p.(Met1Thr). Functional analyses identify that the variant results in a protein lacking 91 amino acids from the N-terminus and leads to abnormally increased AMOT protein levels (increased stability due to loss of degradation signals), which disrupts epithelial and endothelial barrier integrity.
Sources: Literature
Mendeliome v1.3381 HECTD4 Elena Savva reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28191890, 31981491, 31785789; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.246 MDGA2 Sangavi Sivagnanasundram gene: MDGA2 was added
gene: MDGA2 was added to Genetic Epilepsy. Sources: Other
Mode of inheritance for gene: MDGA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDGA2 were set to https://doi.org/10.1101/2025.08.28.25330873; 40168357; 27608760
Phenotypes for gene: MDGA2 were set to MDGA2-related neurodevelopmental disorder MONDO:0700092
Review for gene: MDGA2 was set to GREEN
Added comment: Affected individuals present with a broad neurodevelopmental impairment-like phenotype.

Pre-print - https://doi.org/10.1101/2025.08.28.25330873
Individuals with developmental and epileptic encephalopathy (DEE)
8 individuals from 6 consanguineous families exhibiting infantile hypotonia, severe neurodevelopmental delay, intractable seizures, progressive brain atrophy, and consistent dysmorphic features.
7 different biallelic LoF variants were identified
p.Tyr913Ter, p.Arg404Ter, p.Leu920Ter, c.421-1G>A, p.Lys391SerfsTer7 and c.421-96_595+99del - all variants are rare or absent in gnomAD v4.1
In vitro functional studies of three nonsense variants in mammalian expression systems and hippocampal cultured neurons that resulted in impaired MDGA2 membrane trafficking are supportive of a loss-of-function mechanism.

PMID: 40168357, 27608760
A knockout mouse model showed that MGAD2-deficient mice presented with autism-like behaviours (social deficits, repetitive behaviour, and cognitive impairment).
The mice also showed abnormalities in excitatory synapses.
Sources: Other
Mendeliome v1.3381 MDGA2 Sangavi Sivagnanasundram changed review comment from: Affected individuals present with a broad neurodevelopmental impairment phenotype.

Pre-print - https://doi.org/10.1101/2025.08.28.25330873
Individuals with developmental and epileptic encephalopathy (DEE)
8 individuals from 6 consanguineous families exhibiting infantile hypotonia, severe neurodevelopmental delay, intractable seizures, progressive brain atrophy, and consistent dysmorphic features.
7 different biallelic LoF variants were identified
p.Tyr913Ter, p.Arg404Ter, p.Leu920Ter, c.421-1G>A, p.Lys391SerfsTer7 and c.421-96_595+99del - all variants are rare or absent in gnomAD v4.1
In vitro functional studies of three nonsense variants in mammalian expression systems and hippocampal cultured neurons that resulted in impaired MDGA2 membrane trafficking are supportive of a loss-of-function mechanism.

PMID: 40168357, 27608760
A knockout mouse model showed that MGAD2-deficient mice presented with autism-like behaviours (social deficits, repetitive behaviour, and cognitive impairment).
The mice also showed abnormalities in excitatory synapses.
Sources: Other; to: Affected individuals present with a broad neurodevelopmental impairment-like phenotype.

Pre-print - https://doi.org/10.1101/2025.08.28.25330873
Individuals with developmental and epileptic encephalopathy (DEE)
8 individuals from 6 consanguineous families exhibiting infantile hypotonia, severe neurodevelopmental delay, intractable seizures, progressive brain atrophy, and consistent dysmorphic features.
7 different biallelic LoF variants were identified
p.Tyr913Ter, p.Arg404Ter, p.Leu920Ter, c.421-1G>A, p.Lys391SerfsTer7 and c.421-96_595+99del - all variants are rare or absent in gnomAD v4.1
In vitro functional studies of three nonsense variants in mammalian expression systems and hippocampal cultured neurons that resulted in impaired MDGA2 membrane trafficking are supportive of a loss-of-function mechanism.

PMID: 40168357, 27608760
A knockout mouse model showed that MGAD2-deficient mice presented with autism-like behaviours (social deficits, repetitive behaviour, and cognitive impairment).
The mice also showed abnormalities in excitatory synapses.
Sources: Other
Mendeliome v1.3381 MDGA2 Sangavi Sivagnanasundram gene: MDGA2 was added
gene: MDGA2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MDGA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDGA2 were set to https://doi.org/10.1101/2025.08.28.25330873; 40168357; 27608760
Phenotypes for gene: MDGA2 were set to MDGA2-related neurodevelopmental disorder MONDO:0700092
Review for gene: MDGA2 was set to GREEN
Added comment: Affected individuals present with a broad neurodevelopmental impairment phenotype.

Pre-print - https://doi.org/10.1101/2025.08.28.25330873
Individuals with developmental and epileptic encephalopathy (DEE)
8 individuals from 6 consanguineous families exhibiting infantile hypotonia, severe neurodevelopmental delay, intractable seizures, progressive brain atrophy, and consistent dysmorphic features.
7 different biallelic LoF variants were identified
p.Tyr913Ter, p.Arg404Ter, p.Leu920Ter, c.421-1G>A, p.Lys391SerfsTer7 and c.421-96_595+99del - all variants are rare or absent in gnomAD v4.1
In vitro functional studies of three nonsense variants in mammalian expression systems and hippocampal cultured neurons that resulted in impaired MDGA2 membrane trafficking are supportive of a loss-of-function mechanism.

PMID: 40168357, 27608760
A knockout mouse model showed that MGAD2-deficient mice presented with autism-like behaviours (social deficits, repetitive behaviour, and cognitive impairment).
The mice also showed abnormalities in excitatory synapses.
Sources: Other
Mendeliome v1.3381 CACNB1 Sangavi Sivagnanasundram reviewed gene: CACNB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 41023410; Phenotypes: Congenital muscular dystrophy MONDO:0020121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.438 ATP5O Bryony Thompson Tag new gene name tag was added to gene: ATP5O.
Intellectual disability syndromic and non-syndromic v1.358 ATP5O Bryony Thompson Tag new gene name tag was added to gene: ATP5O.
Mitochondrial disease v0.1083 ATP5O Bryony Thompson Tag new gene name tag was added to gene: ATP5O.
Mendeliome v1.3381 ATP5O Bryony Thompson Tag new gene name tag was added to gene: ATP5O.
Infertility and Recurrent Pregnancy Loss v1.38 DDOST Bryony Thompson Marked gene: DDOST as ready
Infertility and Recurrent Pregnancy Loss v1.38 DDOST Bryony Thompson Gene: ddost has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.38 DDOST Bryony Thompson Classified gene: DDOST as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.38 DDOST Bryony Thompson Gene: ddost has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.37 DDOST Bryony Thompson gene: DDOST was added
gene: DDOST was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DDOST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDOST were set to 41005306
Phenotypes for gene: DDOST were set to inherited oocyte maturation defect MONDO:0014769
Review for gene: DDOST was set to AMBER
Added comment: 3 cases with embryonic arrest/abnormal fertilisation with biallelic DDOST variants (1 homozygous & 2 chets, phase not confirmed). No mention of any other phenotypes or assessment of transferrin glycolysation status in cases. Unsure if cases have DDOST-CDG. DDOST knock‑down in mouse oocytes reduces polar‑body extrusion & mutant DDOST proteins displayed altered subcellular localization in HeLa cells.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.358 DDOST Bryony Thompson Phenotypes for gene: DDOST were changed from Congenital disorder of glycosylation, type Ir, MIM# 614507 to DDOST-congenital disorder of glycosylation MONDO:0013789
Intellectual disability syndromic and non-syndromic v1.357 DDOST Bryony Thompson Publications for gene: DDOST were set to 22305527
Intellectual disability syndromic and non-syndromic v1.356 DDOST Bryony Thompson Classified gene: DDOST as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.356 DDOST Bryony Thompson Gene: ddost has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.355 DDOST Bryony Thompson Classified gene: DDOST as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.355 DDOST Bryony Thompson Gene: ddost has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.354 DDOST Bryony Thompson edited their review of gene: DDOST: Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v1.354 DDOST Bryony Thompson reviewed gene: DDOST: Rating: ; Mode of pathogenicity: None; Publications: 22305527, 34462534, 36214423, 37848450, 33413482, 36631682; Phenotypes: DDOST-congenital disorder of glycosylation MONDO:0013789; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Disorders of Glycosylation v1.76 DDOST Bryony Thompson Phenotypes for gene: DDOST were changed from Congenital disorder of glycosylation, type Ir, MIM# 614507 to DDOST-congenital disorder of glycosylation MONDO:0013789
Congenital Disorders of Glycosylation v1.75 DDOST Bryony Thompson Classified gene: DDOST as Green List (high evidence)
Congenital Disorders of Glycosylation v1.75 DDOST Bryony Thompson Gene: ddost has been classified as Green List (High Evidence).
Congenital Disorders of Glycosylation v1.74 DDOST Bryony Thompson reviewed gene: DDOST: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305527, 34462534, 36214423, 37848450, 33413482, 36631682; Phenotypes: DDOST-congenital disorder of glycosylation MONDO:0013789; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3381 DDOST Bryony Thompson Phenotypes for gene: DDOST were changed from Congenital disorder of glycosylation, type Ir, MIM# 614507 to DDOST-congenital disorder of glycosylation MONDO:0013789; inherited oocyte maturation defect MONDO:0014769
Mendeliome v1.3380 DDOST Bryony Thompson Publications for gene: DDOST were set to 22305527
Mendeliome v1.3379 DDOST Bryony Thompson Classified gene: DDOST as Green List (high evidence)
Mendeliome v1.3379 DDOST Bryony Thompson Gene: ddost has been classified as Green List (High Evidence).
Mendeliome v1.3378 DDOST Bryony Thompson reviewed gene: DDOST: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305527, 34462534, 36214423, 37848450, 33413482, 36631682, 41005306; Phenotypes: DDOST-congenital disorder of glycosylation MONDO:0013789, inherited oocyte maturation defect MONDO:0014769; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.246 RNU4-2 Chirag Patel Classified gene: RNU4-2 as Green List (high evidence)
Genetic Epilepsy v1.246 RNU4-2 Chirag Patel Gene: rnu4-2 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.245 RNU4-2 Chirag Patel gene: RNU4-2 was added
gene: RNU4-2 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: RNU4-2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU4-2 were set to 38991538
Phenotypes for gene: RNU4-2 were set to Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language, MIM# 620851
Review for gene: RNU4-2 was set to GREEN
Added comment: Over 100 individuals with ID found to have de novo variants in this gene. Please note difficult to identify on ES. Epilepsy seen in 50% cases.
Sources: Expert list
Mendeliome v1.3378 MIA3 Sangavi Sivagnanasundram reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 40948380, 40119123; Phenotypes: odontochondrodysplasia MONDO:0031169; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.469 RYR3 Bryony Thompson Marked gene: RYR3 as ready
Congenital Heart Defect v0.469 RYR3 Bryony Thompson Gene: ryr3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.469 RYR3 Bryony Thompson Classified gene: RYR3 as Green List (high evidence)
Congenital Heart Defect v0.469 RYR3 Bryony Thompson Gene: ryr3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.468 RYR3 Bryony Thompson gene: RYR3 was added
gene: RYR3 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: RYR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RYR3 were set to 39762984; 41022857
Phenotypes for gene: RYR3 were set to congenital heart disease MONDO:0005453
Review for gene: RYR3 was set to GREEN
Added comment: Congenital heart disease - at least 4 rare de novo missense and a supporting knockout zebrafish model
PMID: 39762984 - a proband with CHD phenotype (Duodenal atresia, Ventricular septal defect, Secundum atrial septal defect, Tricuspid valve prolapse, Vesicoureteral reflux) with a de novo stopgain variant (c.12295G>T). Zebrafish knockout shows enlarged atria and ventricle, matching patient phenotype
PMID: 41022857 - 4 de novo missense (L110I, S2130L, Y2743C, F2957L - Y2743C has a homozygote & AF in gnomAD higher than expected for AD disease - AF=0.0002760) identified in a CHD cohort
Sources: Literature
Mendeliome v1.3378 RYR3 Bryony Thompson Classified gene: RYR3 as Green List (high evidence)
Mendeliome v1.3378 RYR3 Bryony Thompson Gene: ryr3 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.244 RYR3 Bryony Thompson Publications for gene: RYR3 were set to 25262651
Genetic Epilepsy v1.243 RYR3 Bryony Thompson Classified gene: RYR3 as Amber List (moderate evidence)
Genetic Epilepsy v1.243 RYR3 Bryony Thompson Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.242 RYR3 Bryony Thompson edited their review of gene: RYR3: Added comment: Epilepsy - mild to severe phenotypes reported with both de novo heterozygous (3) and biallelic (7). However, no supporting functional evidence for a gene-disease association
PMID: 39840699
Families: 7 families (7 unrelated)
Patients: 7 patients
Phenotype: partial seizures, febrile seizures, normal brain MRI
Mode of inheritance: Monoallelic and biallelic (1 de novo heterozygous; 6 compound heterozygous inherited from asymptomatic parents)
Variants: c.12947A>G (missense); c.2747A>C (missense); c.12514G>A (missense); c.3697G>A (missense); c.9994A>G (missense); c.4936G>A (missense); c.10859G>T (missense); c.9917A>G (missense); c.12463G>A (missense); c.11386G>C (missense); c.13690G>C (missense); c.11798C>G (missense); c.13363G>A (missense)
Population Frequency: gnomAD: 0–0.00022 (overall); up to 0.0031 in East Asian controls
Functional: protein modeling (I‑TASSER, PyMOL) and stability predictions (I‑Mutant)
PMID: 39220738, 25262651, 29667327
Families: 4 families (4 unrelated)
Patients: 4 patients
Phenotype: infantile spasm syndrome, developmental regression, multifocal EEG discharges, intractable seizures
Mode of inheritance: Monoallelic (de novo heterozygous; also 1 AR compound heterozygote reported); Changed publications: 25262651, 39840699, 39220738, 29667327; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3377 RYR3 Bryony Thompson Phenotypes for gene: RYR3 were changed from Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062) to congenital heart disease MONDO:0005453; Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062)
Mendeliome v1.3376 RYR3 Bryony Thompson Publications for gene: RYR3 were set to 29498452; 32451403; 31230720; 25262651
Mendeliome v1.3375 RYR3 Bryony Thompson reviewed gene: RYR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39762984, 41022857, 39840699, 39220738, 25262651, 29667327; Phenotypes: congenital heart disease MONDO:0005453, developmental and epileptic encephalopathy MONDO:0100062; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.467 ZDHHC18 Bryony Thompson Classified gene: ZDHHC18 as Amber List (moderate evidence)
Congenital Heart Defect v0.467 ZDHHC18 Bryony Thompson Gene: zdhhc18 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.466 ZDHHC18 Bryony Thompson gene: ZDHHC18 was added
gene: ZDHHC18 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ZDHHC18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZDHHC18 were set to 41022857
Phenotypes for gene: ZDHHC18 were set to congenital heart disease MONDO:0005453
Review for gene: ZDHHC18 was set to AMBER
Added comment: ZDHHC18 appears among significant CHD genes in the de novo enrichment analysis. Two de novo missense variants (W290L, G297A) were identified in 2 probands via trio analysis in a CHD cohort. No functional assays conducted.
Sources: Literature
Mendeliome v1.3375 ZDHHC18 Bryony Thompson Classified gene: ZDHHC18 as Amber List (moderate evidence)
Mendeliome v1.3375 ZDHHC18 Bryony Thompson Gene: zdhhc18 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3374 ZDHHC18 Bryony Thompson changed review comment from: ZDHHC18 appears among significant CHD genes in the de novo enrichment analysis. Two de novo missense variants (W290L, G297A) were identified in 2 probands via trio analysis in a CHD cohort.
Sources: Literature; to: ZDHHC18 appears among significant CHD genes in the de novo enrichment analysis. Two de novo missense variants (W290L, G297A) were identified in 2 probands via trio analysis in a CHD cohort. No functional assays conducted.
Sources: Literature
Mendeliome v1.3374 ZDHHC18 Bryony Thompson gene: ZDHHC18 was added
gene: ZDHHC18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZDHHC18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZDHHC18 were set to 41022857
Phenotypes for gene: ZDHHC18 were set to congenital heart disease MONDO:0005453
Review for gene: ZDHHC18 was set to AMBER
Added comment: ZDHHC18 appears among significant CHD genes in the de novo enrichment analysis. Two de novo missense variants (W290L, G297A) were identified in 2 probands via trio analysis in a CHD cohort.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.354 TM2D3 Zornitza Stark Phenotypes for gene: TM2D3 were changed from Neurodevelopmental disorder, MONDO:0700092, TM2D3-related to Neurocardiorenal malformation syndrome, MIM# 621379
Intellectual disability syndromic and non-syndromic v1.353 TM2D3 Zornitza Stark edited their review of gene: TM2D3: Changed phenotypes: Neurocardiorenal malformation syndrome, MIM# 621379
Microcephaly v1.347 TM2D3 Zornitza Stark Phenotypes for gene: TM2D3 were changed from Neurodevelopmental disorder, MONDO:0700092, TM2D3-related to Neurocardiorenal malformation syndrome, MIM# 621379
Microcephaly v1.346 TM2D3 Zornitza Stark edited their review of gene: TM2D3: Changed phenotypes: Neurocardiorenal malformation syndrome, MIM# 621379
Mendeliome v1.3373 TM2D3 Zornitza Stark Phenotypes for gene: TM2D3 were changed from Neurodevelopmental disorder, MONDO:0700092, TM2D3-related to Neurocardiorenal malformation syndrome, MIM# 621379
Mendeliome v1.3372 TM2D3 Zornitza Stark edited their review of gene: TM2D3: Changed phenotypes: Neurocardiorenal malformation syndrome, MIM# 621379
Intellectual disability syndromic and non-syndromic v1.353 ATXN7L3 Zornitza Stark Phenotypes for gene: ATXN7L3 were changed from Neurodevelopmental disorder, MONDO_0100500, ATXN7L3-related to Harel-Tora neurodevelopmental syndrome, MIM# 621377
Intellectual disability syndromic and non-syndromic v1.352 ATXN7L3 Zornitza Stark reviewed gene: ATXN7L3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Harel-Tora neurodevelopmental syndrome, MIM# 621377; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3372 ATXN7L3 Zornitza Stark Phenotypes for gene: ATXN7L3 were changed from Neurodevelopmental disorder, MONDO_0100500, ATXN7L3-related to Harel-Tora neurodevelopmental syndrome, MIM# 621377
Mendeliome v1.3371 ATXN7L3 Zornitza Stark reviewed gene: ATXN7L3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Harel-Tora neurodevelopmental syndrome, MIM# 621377; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3371 NAMPT Bryony Thompson Marked gene: NAMPT as ready
Mendeliome v1.3371 NAMPT Bryony Thompson Gene: nampt has been classified as Red List (Low Evidence).
Mendeliome v1.3371 NAMPT Bryony Thompson gene: NAMPT was added
gene: NAMPT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAMPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAMPT were set to 41004591
Phenotypes for gene: NAMPT were set to hereditary motor and sensory neuropathy MONDO:0015358
Review for gene: NAMPT was set to RED
Added comment: A single family reported.
Disease Context: sensory and motor neuropathy with motor coordination impairment, muscle atrophy/weakness, foot/hand deformities, loss of sensation and positive Babinski sign
Families: 1 family
Patients: 2
Phenotype: impaired motor coordination, muscle atrophy/weakness, foot and hand deformities, diminished sensation, positive Babinski sign
Mode of inheritance: Biallelic (autosomal recessive; parents heterozygous carriers, affected siblings homozygous). No mention of consanguinity
Variants: c.472G>C (p.P158A) (missense)
Population Frequency: gnomAD: 0
Segregation: parents heterozygous, both affected siblings homozygous (pedigree confirmed)
Functional Studies: recombinant NAMPT protein activity assay; thermal shift stability assay; patient fibroblast bioenergetic, mitochondrial and oxidative stress assays; CRISPR‑generated isogenic fibroblasts; homozygous p.P158A mouse model showing metabolic, synaptic and motor neuron defects; rescue with NMN/P7C3
Prior Reports: none.
Sources: Literature
Mendeliome v1.3370 DBX1 Bryony Thompson Marked gene: DBX1 as ready
Mendeliome v1.3370 DBX1 Bryony Thompson Gene: dbx1 has been classified as Red List (Low Evidence).
Mendeliome v1.3370 DBX1 Bryony Thompson gene: DBX1 was added
gene: DBX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DBX1 were set to 40995053
Phenotypes for gene: DBX1 were set to central hypoventilation syndrome, congenital MONDO:0800031
Review for gene: DBX1 was set to RED
Added comment: Disease Context: Congenital central hypoventilation syndrome (atypical CCHS) with central hypotonia, global developmental delay, seizures, autoaggressive behavior
Families: 1 (1 unrelated)
Patients: 1
Phenotype: congenital central hypoventilation, central hypotonia, global developmental delay, seizures, autoaggressive behavior
Mode of inheritance: Biallelic (consanguineous parents (first cousins))
Variants: c.340_341delGC (frameshift)
Population Frequency: NR
Segregation: NR
Functional Studies: mouse Dbx1 knockout lethality indicating essential role in respiration
Prior Reports: 0
Sources: Literature
Retinitis pigmentosa v0.179 TRIM49 Bryony Thompson Marked gene: TRIM49 as ready
Retinitis pigmentosa v0.179 TRIM49 Bryony Thompson Gene: trim49 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3369 TRIM49 Bryony Thompson Marked gene: TRIM49 as ready
Mendeliome v1.3369 TRIM49 Bryony Thompson Gene: trim49 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3369 TRIM49 Bryony Thompson Classified gene: TRIM49 as Amber List (moderate evidence)
Mendeliome v1.3369 TRIM49 Bryony Thompson Gene: trim49 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa v0.179 TRIM49 Bryony Thompson Classified gene: TRIM49 as Amber List (moderate evidence)
Retinitis pigmentosa v0.179 TRIM49 Bryony Thompson Gene: trim49 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3368 TRIM49 Bryony Thompson changed review comment from: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not (Box 438, Box 440, Box 439). This constitutes convincing functional evidence for pathogenicity in two families.
Sources: Literature; to: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not. This constitutes convincing functional evidence for pathogenicity in two families.
Sources: Literature
Retinitis pigmentosa v0.178 TRIM49 Bryony Thompson gene: TRIM49 was added
gene: TRIM49 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
Mode of inheritance for gene: TRIM49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM49 were set to 40956390
Phenotypes for gene: TRIM49 were set to retinitis pigmentosa MONDO:0019200
Review for gene: TRIM49 was set to AMBER
Added comment: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not. This constitutes convincing functional evidence for pathogenicity in two families.
Sources: Literature
Mendeliome v1.3368 TRIM49 Bryony Thompson gene: TRIM49 was added
gene: TRIM49 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM49 were set to 40956390
Phenotypes for gene: TRIM49 were set to retinitis pigmentosa MONDO:0019200
Review for gene: TRIM49 was set to AMBER
Added comment: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not (Box 438, Box 440, Box 439). This constitutes convincing functional evidence for pathogenicity in two families.
Sources: Literature
Mendeliome v1.3367 PCDHA9 Bryony Thompson Marked gene: PCDHA9 as ready
Mendeliome v1.3367 PCDHA9 Bryony Thompson Gene: pcdha9 has been classified as Red List (Low Evidence).
Mendeliome v1.3367 PCDHA9 Bryony Thompson gene: PCDHA9 was added
gene: PCDHA9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCDHA9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCDHA9 were set to 29477871; 40988636
Phenotypes for gene: PCDHA9 were set to Hirschsprung disease MONDO:0018309; root resorption MONDO:0001997
Review for gene: PCDHA9 was set to RED
Added comment: Single publication reporting an association with Hirschsprung disease, including a missense in a family (p.Gly572Arg) that is too common in gnomAD to be associated with disease and 2 rare missense in 2 sporadic cases. Knockdown in a cell line increased proliferation and
migration, but suppressed apoptosis. A single publication with a single missense reported in association with short root anomaly.
Sources: Literature
Incidentalome v0.349 PCDHA9 Bryony Thompson Marked gene: PCDHA9 as ready
Incidentalome v0.349 PCDHA9 Bryony Thompson Gene: pcdha9 has been classified as Amber List (Moderate Evidence).
Incidentalome v0.349 PCDHA9 Bryony Thompson Classified gene: PCDHA9 as Amber List (moderate evidence)
Incidentalome v0.349 PCDHA9 Bryony Thompson Gene: pcdha9 has been classified as Amber List (Moderate Evidence).
Motor Neurone Disease v1.38 PCDHA9 Bryony Thompson Marked gene: PCDHA9 as ready
Motor Neurone Disease v1.38 PCDHA9 Bryony Thompson Gene: pcdha9 has been classified as Amber List (Moderate Evidence).
Motor Neurone Disease v1.38 PCDHA9 Bryony Thompson Classified gene: PCDHA9 as Amber List (moderate evidence)
Motor Neurone Disease v1.38 PCDHA9 Bryony Thompson Gene: pcdha9 has been classified as Amber List (Moderate Evidence).
Incidentalome v0.348 PCDHA9 Bryony Thompson gene: PCDHA9 was added
gene: PCDHA9 was added to Incidentalome. Sources: Literature
Mode of inheritance for gene: PCDHA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHA9 were set to 38467605
Phenotypes for gene: PCDHA9 were set to amyotrophic lateral sclerosis MONDO:0004976
Review for gene: PCDHA9 was set to AMBER
Added comment: Three unrelated families (one consanguineous and 2 living in close proximity) carry a homozygous c.2099T>C (p.Leu700Pro) missense variant in the transmembrane domain of PCDHA9; detailed clinical data: age at onset 36‑42 yr, limb weakness, UMN/LMN signs, EMG abnormalities, disease duration <4 yr; the variant is rare (gnomAD East Asian MAF≈0.00022, no homozygotes) and absent in 392 ALS controls; functional studies (mouse knock‑in and deletion models, HEK293 protein‑stability assays) demonstrate loss‑of‑function effects supporting pathogenicity.
Sources: Literature
Motor Neurone Disease v1.37 PCDHA9 Bryony Thompson gene: PCDHA9 was added
gene: PCDHA9 was added to Motor Neurone Disease. Sources: Literature
Mode of inheritance for gene: PCDHA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHA9 were set to 38467605
Phenotypes for gene: PCDHA9 were set to amyotrophic lateral sclerosis MONDO:0004976
Review for gene: PCDHA9 was set to AMBER
Added comment: Three unrelated families (one consanguineous and 2 living in close proximity) carry a homozygous c.2099T>C (p.Leu700Pro) missense variant in the transmembrane domain of PCDHA9; detailed clinical data: age at onset 36‑42 yr, limb weakness, UMN/LMN signs, EMG abnormalities, disease duration <4 yr; the variant is rare (gnomAD East Asian MAF≈0.00022, no homozygotes) and absent in 392 ALS controls; functional studies (mouse knock‑in and deletion models, HEK293 protein‑stability assays) demonstrate loss‑of‑function effects supporting pathogenicity.
Sources: Literature
Genetic Epilepsy v1.242 RNU6ATAC Zornitza Stark Classified gene: RNU6ATAC as Red List (low evidence)
Genetic Epilepsy v1.242 RNU6ATAC Zornitza Stark Gene: rnu6atac has been classified as Red List (Low Evidence).
Mendeliome v1.3366 RNU6ATAC Zornitza Stark Marked gene: RNU6ATAC as ready
Mendeliome v1.3366 RNU6ATAC Zornitza Stark Gene: rnu6atac has been classified as Red List (Low Evidence).
Mendeliome v1.3366 RNU6ATAC Zornitza Stark Classified gene: RNU6ATAC as Red List (low evidence)
Mendeliome v1.3366 RNU6ATAC Zornitza Stark Gene: rnu6atac has been classified as Red List (Low Evidence).
Microcephaly v1.346 RNU6ATAC Zornitza Stark Marked gene: RNU6ATAC as ready
Microcephaly v1.346 RNU6ATAC Zornitza Stark Gene: rnu6atac has been classified as Red List (Low Evidence).
Microcephaly v1.346 RNU6ATAC Zornitza Stark Classified gene: RNU6ATAC as Red List (low evidence)
Microcephaly v1.346 RNU6ATAC Zornitza Stark Gene: rnu6atac has been classified as Red List (Low Evidence).
Microcephaly v1.345 RNU6ATAC Zornitza Stark reviewed gene: RNU6ATAC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3365 HYPK Zornitza Stark Publications for gene: HYPK were set to Clinical Genetics Early View
Intellectual disability syndromic and non-syndromic v1.352 HYPK Zornitza Stark Publications for gene: HYPK were set to Clinical Genetics Early View
Mendeliome v1.3364 DNAH14 Zornitza Stark reviewed gene: DNAH14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3364 TLN1 Zornitza Stark Publications for gene: TLN1 were set to 30888838; 35861643
Bleeding and Platelet Disorders v1.62 TLN1 Zornitza Stark Publications for gene: TLN1 were set to 35861643
Bleeding and Platelet Disorders v1.61 TLN1 Zornitza Stark Classified gene: TLN1 as Amber List (moderate evidence)
Bleeding and Platelet Disorders v1.61 TLN1 Zornitza Stark Gene: tln1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3363 BCAT1 Zornitza Stark Marked gene: BCAT1 as ready
Mendeliome v1.3363 BCAT1 Zornitza Stark Gene: bcat1 has been classified as Red List (Low Evidence).
Mendeliome v1.3363 BCAT1 Zornitza Stark Classified gene: BCAT1 as Red List (low evidence)
Mendeliome v1.3363 BCAT1 Zornitza Stark Gene: bcat1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.351 BCAT1 Zornitza Stark Marked gene: BCAT1 as ready
Intellectual disability syndromic and non-syndromic v1.351 BCAT1 Zornitza Stark Gene: bcat1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.351 BCAT1 Zornitza Stark Classified gene: BCAT1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v1.351 BCAT1 Zornitza Stark Gene: bcat1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.350 BCAT1 Lucy Spencer gene: BCAT1 was added
gene: BCAT1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: BCAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAT1 were set to 41029903
Phenotypes for gene: BCAT1 were set to Neurodevelopmental disorder (MONDO:0700092), BCAT1-related
Review for gene: BCAT1 was set to RED
Added comment: PMID: 41029903 One patient with a suspected neurometabolic disorder; congenital blindness and suspected Leber Congenital Amaurosis, microcephaly, failure to thrive, profound global developmental delay and extensive delayed myelination on MRI. AT 10 he was non-verbal and non-ambulatory with regression of motor skills and -3SD for height and weight. Compound heterozygous for Phe264Leu (539 hets but no homs in gnomad v4) and Glu348Lys (over 8000 hets and 24 homs in gnomad v4).

in compound heterozygous iPSCs a severe 75% reduction in BCAT1 protein levels was seen, but mRNA levels were normal suggesting the variants affect protein stability or increased degradation.
Sources: Literature
Mendeliome v1.3362 BCAT1 Lucy Spencer gene: BCAT1 was added
gene: BCAT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BCAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAT1 were set to 41029903
Phenotypes for gene: BCAT1 were set to Neurodevelopmental disorder (MONDO:0700092), BCAT1-related
Review for gene: BCAT1 was set to RED
Added comment: PMID: 41029903 One patient with a suspected neurometabolic disorder; congenital blindness and suspected Leber Congenital Amaurosis, microcephaly, failure to thrive, profound global developmental delay and extensive delayed myelination on MRI. AT 10 he was non-verbal and non-ambulatory with regression of motor skills and -3SD for height and weight. Compound heterozygous for Phe264Leu (539 hets but no homs in gnomad v4) and Glu348Lys (over 8000 hets and 24 homs in gnomad v4).

in compound heterozygous iPSCs a severe 75% reduction in BCAT1 protein levels was seen, but mRNA levels were normal suggesting the variants affect protein stability or increased degradation.
Sources: Literature
Bleeding and Platelet Disorders v1.60 TLN1 Lucy Spencer reviewed gene: TLN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 40960860; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3362 TLN1 Lucy Spencer edited their review of gene: TLN1: Added comment: PMID: 40960860 de novo L353F identified in a patient with increased nuchal translucency, leukopenia, thrombocytopenia, congenital cataracts, multiple episodes of acute bronchitis, skin lesions and swelling after exercise in cold weather. Overlapping authors with PMID: 35861643, and they are postulating this is a 2nd case of the condition reported there. Some functional studies showing decreased thermal stability, has slower cellular migration and that it was slightly more aggregation-prone than WT.

Shared symptoms between both patients; leukopenia, thrombocytopenia, congenital cataract, and recurring episodes of acute bronchitis. Both mutations situated in the talin-1 head F2F3 domains and both have been shown to have defects in cellular migration and integrin activation.; Changed rating: AMBER; Changed publications: 40960860; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3362 TLN1 Lucy Spencer reviewed gene: TLN1: Rating: RED; Mode of pathogenicity: None; Publications: 39704176; Phenotypes: Capillary leak syndrome MONDO:0001956, TLN1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.3362 DNAH14 Lucy Spencer reviewed gene: DNAH14: Rating: AMBER; Mode of pathogenicity: None; Publications: 36344539, 41002930; Phenotypes: Neurodevelopmental disorder MONDO:0700092, DNAH14-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Transplant Co-Morbidity v0.20 Bryony Thompson Panel name changed from Transplant Co-Morbidity Superpanel to Transplant Co-Morbidity
Intellectual disability syndromic and non-syndromic v1.350 HYPK Sangavi Sivagnanasundram reviewed gene: HYPK: Rating: ; Mode of pathogenicity: None; Publications: 40986405; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, HYPK-related; Mode of inheritance: None
Mendeliome v1.3362 HYPK Sangavi Sivagnanasundram reviewed gene: HYPK: Rating: ; Mode of pathogenicity: None; Publications: 40986405; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, HYPK-related; Mode of inheritance: None
Microcephaly v1.345 RNU6ATAC Lucy Spencer gene: RNU6ATAC was added
gene: RNU6ATAC was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062
Phenotypes for gene: RNU6ATAC were set to Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related
Review for gene: RNU6ATAC was set to AMBER
Added comment: PMID: 40975062 1 patient compound heterozygous for n.36T>G and n.28C>T. Has short stature, microcephaly, hypotonia, neurodevelopmental delay, ID, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus and oculomotor apraxia. Identified in a cohort of individuals with an excess of significant intron retention outliers in minor intron containing genes which are usually removed by the minor spliceosome of which RNU6ATAC is a part (as is RNU4ATAC). Proband had no candidate variants in RNU4ATAC or RNU12. Both RNU6ATAC variants are in a highly conserved 39bp region, and affect nucleotides predicted to be important for binding to U4ATAC.
Sources: Literature
Genetic Epilepsy v1.241 RNU6ATAC Lucy Spencer gene: RNU6ATAC was added
gene: RNU6ATAC was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062
Phenotypes for gene: RNU6ATAC were set to Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related
Review for gene: RNU6ATAC was set to RED
Added comment: PMID: 40975062 1 patient compound heterozygous for n.36T>G and n.28C>T. Has short stature, microcephaly, hypotonia, neurodevelopmental delay, ID, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus and oculomotor apraxia. Identified in a cohort of individuals with an excess of significant intron retention outliers in minor intron containing genes which are usually removed by the minor spliceosome of which RNU6ATAC is a part (as is RNU4ATAC). Proband had no candidate variants in RNU4ATAC or RNU12. Both RNU6ATAC variants are in a highly conserved 39bp region, and affect nucleotides predicted to be important for binding to U4ATAC.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.350 RNU6ATAC Lucy Spencer gene: RNU6ATAC was added
gene: RNU6ATAC was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062
Phenotypes for gene: RNU6ATAC were set to Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related
Review for gene: RNU6ATAC was set to RED
Added comment: PMID: 40975062 1 patient compound heterozygous for n.36T>G and n.28C>T. Has short stature, microcephaly, hypotonia, neurodevelopmental delay, ID, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus and oculomotor apraxia. Identified in a cohort of individuals with an excess of significant intron retention outliers in minor intron containing genes which are usually removed by the minor spliceosome of which RNU6ATAC is a part (as is RNU4ATAC). Proband had no candidate variants in RNU4ATAC or RNU12. Both RNU6ATAC variants are in a highly conserved 39bp region, and affect nucleotides predicted to be important for binding to U4ATAC.
Sources: Literature
Mendeliome v1.3362 RNU6ATAC Lucy Spencer gene: RNU6ATAC was added
gene: RNU6ATAC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062
Phenotypes for gene: RNU6ATAC were set to Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related
Review for gene: RNU6ATAC was set to RED
Added comment: PMID: 40975062 1 patient compound heterozygous for n.36T>G and n.28C>T. Has short stature, microcephaly, hypotonia, neurodevelopmental delay, ID, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus and oculomotor apraxia. Identified in a cohort of individuals with an excess of significant intron retention outliers in minor intron containing genes which are usually removed by the minor spliceosome of which RNU6ATAC is a part (as is RNU4ATAC). Proband had no candidate variants in RNU4ATAC or RNU12. Both RNU6ATAC variants are in a highly conserved 39bp region, and affect nucleotides predicted to be important for binding to U4ATAC.
Sources: Literature
Mendeliome v1.3362 NFXL1 Lucy Spencer gene: NFXL1 was added
gene: NFXL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NFXL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFXL1 were set to 40430072; 41024252
Phenotypes for gene: NFXL1 were set to Syndromic disease (MONDO:0002254), NFXL1-related
Review for gene: NFXL1 was set to AMBER
Added comment: PMID: 40430072 2 siblings with psychosis and schizophrenia, homozygous for Cys441Tyr. Some modelling suggested a deleterious affect but no functional studies performed.

PMID: 41024252 8 patients from 7 families with joint hyperlaxity, with or without short stature and renal disease. 6 families were homozygous for p.(Cys539Trpfs*64) while the other two were homozygous for p.(Lys681*). Paper described both as founder variants but they are rare/absent in gnomad.

Joint hyperlaxity (7), chronic kidney disease/FSGS (2) small echogenic kidneys (3), acute kidney injury (1), dysmorphic features (6), short stature (6), speech delay (3).

One patient also had epilepsy, developmental delay and spasticity however c.728+1G>A in WDR45 explained this part of her phenotype. Other patients also had more severe outlying symptoms with no other explanation mentioned: 1 with developmental delay, hearing loss, brain malformations, skeletal abnormalities, and another a 3 year old who passed away following a complex medical course including blue sclera, proximal tibial fracture, severe respiratory distress due to a chest infection, and acute kidney injury.

Amber given the variable phenotype findings of the reported patients and only 2 homozygous variants identified so far
Sources: Literature
Fetal anomalies v1.438 PTBP1 Lucy Spencer gene: PTBP1 was added
gene: PTBP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP1 were set to 40965981
Phenotypes for gene: PTBP1 were set to Neurodevelopmental disorder (MONDO:0700092), PTBP1-related
Review for gene: PTBP1 was set to GREEN
Added comment: PMID: 40965981 27 individuals with abnormal prenatal ultrasound in thirteen (48%) including short femora, IUGR, hydramnios, increased nuchal translucency, asymmetry of heart cavities, and bilateral hydronephrosis. Skeletal anomalies were seen in 24 (89%), short stature/limbs in 63%, facial dysmorphism 25 (93%), developmental delay in 78%, behavioral problems in 30% and ID in 26% generally mild/moderate, 43% had variable brain MRI abnormalities. additional features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%).

Variants a mix of missense and startloss, and were confirmed de novo in 23/17 cases.

Various functional studies showed reduced nuclear localization and enhanced cytoplasmic retention, with start-loss variants also leading to increased protein stability.
Sources: Literature
Skeletal dysplasia v0.337 PTBP1 Lucy Spencer gene: PTBP1 was added
gene: PTBP1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP1 were set to 40965981
Phenotypes for gene: PTBP1 were set to Neurodevelopmental disorder (MONDO:0700092), PTBP1-related
Review for gene: PTBP1 was set to GREEN
Added comment: PMID: 40965981 27 individuals with abnormal prenatal ultrasound in thirteen (48%) including short femora, IUGR, hydramnios, increased nuchal translucency, asymmetry of heart cavities, and bilateral hydronephrosis. Skeletal anomalies were seen in 24 (89%), short stature/limbs in 63%, facial dysmorphism 25 (93%), developmental delay in 78%, behavioral problems in 30% and ID in 26% generally mild/moderate, 43% had variable brain MRI abnormalities. additional features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%).

Variants a mix of missense and startloss, and were confirmed de novo in 23/17 cases.

Various functional studies showed reduced nuclear localization and enhanced cytoplasmic retention, with start-loss variants also leading to increased protein stability.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.350 PTBP1 Lucy Spencer gene: PTBP1 was added
gene: PTBP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP1 were set to 40965981
Phenotypes for gene: PTBP1 were set to Neurodevelopmental disorder (MONDO:0700092), PTBP1-related
Review for gene: PTBP1 was set to GREEN
Added comment: PMID: 40965981 27 individuals with abnormal prenatal ultrasound in thirteen (48%) including short femora, IUGR, hydramnios, increased nuchal translucency, asymmetry of heart cavities, and bilateral hydronephrosis. Skeletal anomalies were seen in 24 (89%), short stature/limbs in 63%, facial dysmorphism 25 (93%), developmental delay in 78%, behavioral problems in 30% and ID in 26% generally mild/moderate, 43% had variable brain MRI abnormalities. additional features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%).

Variants a mix of missense and startloss, and were confirmed de novo in 23/17 cases.

Various functional studies showed reduced nuclear localization and enhanced cytoplasmic retention, with start-loss variants also leading to increased protein stability.
Sources: Literature
Mendeliome v1.3362 PTBP1 Lucy Spencer changed review comment from: PMID: 40965981 27 individuals with abnormal prenatal ultrasound in thirteen (48%) including short femora, IUGR, hydramnios, increased nuchal translucency, asymmetry of heart cavities, and bilateral hydronephrosis. Skeletal anomalies were seen in 24 (89%), short stature/limbs in 63%, facial dysmorphism 25 (93%), developmental delay in 78%, behavioral problems in 30% and ID in 26% generally mild/moderate, 43% had variable brain MRI abnormalities. additional features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%).

Various functional studies showed reduced nuclear localization and enhanced cytoplasmic retention, with start-loss
variants also leading to increased protein stability.; to: PMID: 40965981 27 individuals with abnormal prenatal ultrasound in thirteen (48%) including short femora, IUGR, hydramnios, increased nuchal translucency, asymmetry of heart cavities, and bilateral hydronephrosis. Skeletal anomalies were seen in 24 (89%), short stature/limbs in 63%, facial dysmorphism 25 (93%), developmental delay in 78%, behavioral problems in 30% and ID in 26% generally mild/moderate, 43% had variable brain MRI abnormalities. additional features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%).

Variants a mix of missense and startloss, and were confirmed de novo in 23/17 cases.

Various functional studies showed reduced nuclear localization and enhanced cytoplasmic retention, with start-loss
variants also leading to increased protein stability.
Mendeliome v1.3362 PTBP1 Lucy Spencer reviewed gene: PTBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40965981; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), PTBP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.350 PTBP2 Lucy Spencer gene: PTBP2 was added
gene: PTBP2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PTBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP2 were set to 40965981
Phenotypes for gene: PTBP2 were set to Neurodevelopmental disorder (MONDO:0700092), PTBP2-related
Review for gene: PTBP2 was set to AMBER
Added comment: PMID: 40965981 2 males with developmental delay, ID, autistic features. 1 had some dysmorphic features and tonic-clonic seizures. both probands had a de novo variant in PTBP2 NM_021190.4:c.2T>C (p.Met1?) and NM_021190.4:c.41G>C (p.Arg14Thr), absent from gnomad. Transfection of the variants in transfection in NIH-3T3 cells showed the missense had cytoplasmic retention and colocalization with processing bodies, and that there were 2 alternative downstream start sites Met32 and Met35 that may be used instead.
Sources: Literature
Mendeliome v1.3362 PTBP2 Lucy Spencer gene: PTBP2 was added
gene: PTBP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP2 were set to 40965981
Phenotypes for gene: PTBP2 were set to Neurodevelopmental disorder (MONDO:0700092), PTBP2-related
Review for gene: PTBP2 was set to AMBER
Added comment: PMID: 40965981 2 males with developmental delay, ID, autistic features. 1 had some dysmorphic features and tonic-clonic seizures. both probands had a de novo variant in PTBP2 NM_021190.4:c.2T>C (p.Met1?) and NM_021190.4:c.41G>C (p.Arg14Thr), absent from gnomad. Transfection of the variants in transfection in NIH-3T3 cells showed the missense had cytoplasmic retention and colocalization with processing bodies, and that there were 2 alternative downstream start sites Met32 and Met35 that may be used instead.
Sources: Literature
Mendeliome v1.3362 GSTZ1 Lucy Spencer changed review comment from: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years.

PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development.

PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron.
Sources: Literature; to: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years.

PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development.

PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron. Val99Met has 1170 hets and 4 homs in gnomad, as this condition appears to be clinically benign this is not a concern.

Currently rated as moderate by ClinGen, the review does not include the most recent paper
Sources: Literature
Aminoacidopathy v1.135 GSTZ1 Lucy Spencer reviewed gene: GSTZ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27876694, 38535121, 41009955; Phenotypes: Maleylacetoacetate isomerase deficiency MIM#617596; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3362 GSTZ1 Lucy Spencer gene: GSTZ1 was added
gene: GSTZ1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GSTZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSTZ1 were set to 27876694; 38535121; 41009955
Phenotypes for gene: GSTZ1 were set to Maleylacetoacetate isomerase deficiency MIM#617596
Review for gene: GSTZ1 was set to GREEN
Added comment: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years.

PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development.

PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron.
Sources: Literature
Fetal anomalies v1.438 ITGAV Zornitza Stark Phenotypes for gene: ITGAV were changed from Syndromic disease, MONDO:0002254, ITGAV-related to Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Fetal anomalies v1.437 ITGAV Zornitza Stark Classified gene: ITGAV as Green List (high evidence)
Fetal anomalies v1.437 ITGAV Zornitza Stark Gene: itgav has been classified as Green List (High Evidence).
Fetal anomalies v1.436 ITGAV Zornitza Stark edited their review of gene: ITGAV: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Intellectual disability syndromic and non-syndromic v1.350 ITGAV Zornitza Stark Phenotypes for gene: ITGAV were changed from Syndromic disease, MONDO:0002254, ITGAV-related to Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Intellectual disability syndromic and non-syndromic v1.349 ITGAV Zornitza Stark Classified gene: ITGAV as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.349 ITGAV Zornitza Stark Gene: itgav has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.348 ITGAV Zornitza Stark edited their review of gene: ITGAV: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Disorders of immune dysregulation v1.30 ITGAV Zornitza Stark Phenotypes for gene: ITGAV were changed from Syndromic disease, MONDO:0002254, ITGAV-related to Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Disorders of immune dysregulation v1.29 ITGAV Zornitza Stark Classified gene: ITGAV as Green List (high evidence)
Disorders of immune dysregulation v1.29 ITGAV Zornitza Stark Gene: itgav has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.28 ITGAV Zornitza Stark edited their review of gene: ITGAV: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Mendeliome v1.3362 ITGAV Zornitza Stark Phenotypes for gene: ITGAV were changed from Syndromic disease, MONDO:0002254, ITGAV-related to Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Mendeliome v1.3361 ITGAV Zornitza Stark Classified gene: ITGAV as Green List (high evidence)
Mendeliome v1.3361 ITGAV Zornitza Stark Gene: itgav has been classified as Green List (High Evidence).
Mendeliome v1.3360 ITGAV Zornitza Stark edited their review of gene: ITGAV: Changed phenotypes: Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Mendeliome v1.3360 ITGAV Zornitza Stark edited their review of gene: ITGAV: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372
Intellectual disability syndromic and non-syndromic v1.348 UBR5 Zornitza Stark Phenotypes for gene: UBR5 were changed from Neurodevelopmental disorder MONDO:0700092, UBR5-related to Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372
Intellectual disability syndromic and non-syndromic v1.347 UBR5 Zornitza Stark reviewed gene: UBR5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372; Mode of inheritance: None
Genetic Epilepsy v1.241 UBR5 Zornitza Stark Phenotypes for gene: UBR5 were changed from Neurodevelopmental disorder MONDO:0700092, UBR5-related to Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372
Genetic Epilepsy v1.240 UBR5 Zornitza Stark reviewed gene: UBR5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372; Mode of inheritance: None
Mendeliome v1.3360 UBR5 Zornitza Stark Phenotypes for gene: UBR5 were changed from Neurodevelopmental disorder MONDO:0700092, UBR5-related to Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372
Mendeliome v1.3359 UBR5 Zornitza Stark reviewed gene: UBR5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372; Mode of inheritance: None
Differences of Sex Development v1.22 UBR5 Zornitza Stark Phenotypes for gene: UBR5 were changed from Neurodevelopmental disorder MONDO:0700092, UBR5-related to Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372
Differences of Sex Development v1.21 UBR5 Zornitza Stark reviewed gene: UBR5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372; Mode of inheritance: None
Autism v0.222 UBR5 Zornitza Stark Phenotypes for gene: UBR5 were changed from Neurodevelopmental disorder MONDO:0700092, UBR5-related to Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372
Autism v0.221 UBR5 Zornitza Stark reviewed gene: UBR5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372; Mode of inheritance: None
Mendeliome v1.3359 CDK9 Bryony Thompson Classified gene: CDK9 as Green List (high evidence)
Mendeliome v1.3359 CDK9 Bryony Thompson Gene: cdk9 has been classified as Green List (High Evidence).
Mendeliome v1.3358 CDK9 Bryony Thompson gene: CDK9 was added
gene: CDK9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 40954203; 33640901; 30237576; 26633546
Phenotypes for gene: CDK9 were set to multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome MONDO:0015160; CHARGE-like syndrome with retinal dystrophy
Review for gene: CDK9 was set to GREEN
Added comment: Biallelic variants in at least six unrelated families:
1) proband that displays retinal dystrophy without a CHARGE-like malformation syndrome (c.862G>A/p.A288T + c.961C>T/p.P321S).
2) A boy with a phenotype resembling CHARGE syndrome (multiple anomalies involving the eyes, ears, cleft lip, and palate, and intellectual disability) with retinal dystrophy (p.A288T/p.R303C),
3-7) 4 consanguineous families homozygous for p.R225C, including a set of cousins.
CDK9 variants demonstrated decreased kinase activity. One of the studies suggested the extent the kinase activity is reduced may account for the absence/presence of the CHARGE-like phenotype with retinal dystrophy
Sources: Literature
Early-onset Dementia v1.48 DNMT1 Chirag Patel Publications for gene DNMT1 were changed from 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424 to 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424
Mendeliome v1.3357 DNMT1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNMT1.
Source ClinGen was added to DNMT1.
Source Literature was added to DNMT1.
Phenotypes for gene: DNMT1 were changed from Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, 604121; Neuropathy, hereditary sensory, type IE, 614116 to Hereditary sensory neuropathy-deafness-dementia syndrome, MONDO:0013584
Publications for gene DNMT1 were changed from 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424 to 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424
Deafness_IsolatedAndComplex v1.232 DNMT1 Chirag Patel Source Melbourne Genomics Health Alliance Deafness Flagship was removed from DNMT1.
Source Victorian Clinical Genetics Services was removed from DNMT1.
Source ClinGen was added to DNMT1.
Source Literature was added to DNMT1.
Phenotypes for gene: DNMT1 were changed from Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, 604121; Neuropathy, hereditary sensory, type IE, 614116 to Hereditary sensory neuropathy-deafness-dementia syndrome, MONDO:0013584
Publications for gene DNMT1 were changed from 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424 to 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424
Hereditary Neuropathy_CMT - isolated v1.66 DNMT1 Chirag Patel Source Royal Melbourne Hospital was removed from DNMT1.
Source ClinGen was added to DNMT1.
Source Literature was added to DNMT1.
Phenotypes for gene: DNMT1 were changed from Neuropathy, hereditary sensory, type IE, 614116; Dementia, Deafness, and Sensory Neuropathy; HSAN/SFN to Hereditary sensory neuropathy-deafness-dementia syndrome, MONDO:0013584
Publications for gene DNMT1 were changed from 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424 to 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424
Early-onset Dementia v1.47 DNMT1 Chirag Patel Source Melbourne Genomics Health Alliance Complex Neurology Flagship was removed from DNMT1.
Source Victorian Clinical Genetics Services was removed from DNMT1.
Source ClinGen was added to DNMT1.
Mode of inheritance for gene DNMT1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DNMT1 were changed from to Hereditary sensory neuropathy-deafness-dementia syndrome, MONDO:0013584
Publications for gene DNMT1 were changed from 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457 to 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457
Mendeliome v1.3356 DNM1L Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM1L.
Source Literature was added to DNM1L.
Source ClinGen was added to DNM1L.
Phenotypes for gene: DNM1L were changed from Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388 (AD, AR); Optic atrophy 5 - MIM#610708 (AD) to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MONDO:0013726; Optic atrophy 5 - MIM#610708 (AD)
Publications for gene DNM1L were changed from 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748, 28969390, 30850373, 17460227 to 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748, 28969390, 30850373, 17460227
Intellectual disability syndromic and non-syndromic v1.347 DNM1L Chirag Patel Source Genetic Health Queensland was removed from DNM1L.
Source ClinGen was added to DNM1L.
Source Literature was added to DNM1L.
Mode of pathogenicity for gene DNM1L was changed from to Other
Phenotypes for gene: DNM1L were changed from Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MIM#614388 to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MONDO:0013726
Publications for gene DNM1L were changed from 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748 to 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748
Mitochondrial disease v0.1082 DNM1L Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM1L.
Source Australian Genomics Health Alliance Mitochondrial Flagship was removed from DNM1L.
Source ClinGen was added to DNM1L.
Source Literature was added to DNM1L.
Mode of inheritance for gene DNM1L was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mode of pathogenicity for gene DNM1L was changed from to Other
Phenotypes for gene: DNM1L were changed from to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MONDO:0013726
Publications for gene DNM1L were changed from 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748 to 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748
Peroxisomal Disorders v0.55 DNM1L Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM1L.
Source Literature was added to DNM1L.
Source ClinGen was added to DNM1L.
Mode of inheritance for gene DNM1L was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mode of pathogenicity for gene DNM1L was changed from to Other
Phenotypes for gene: DNM1L were changed from to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MONDO:0013726
Publications for gene DNM1L were changed from 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748 to 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748
Genetic Epilepsy v1.239 DNM1L Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM1L.
Source Australian Genomics Health Alliance Epilepsy Flagship was removed from DNM1L.
Source ClinGen was added to DNM1L.
Source Literature was added to DNM1L.
Mode of pathogenicity for gene DNM1L was changed from to Other
Phenotypes for gene: DNM1L were changed from Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388 (AD, AR) to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MONDO:0013726
Publications for gene DNM1L were changed from 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748 to 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748
Fetal anomalies v1.436 DNM1L Chirag Patel Source Genomics England PanelApp was removed from DNM1L.
Source Genetic Health Queensland was removed from DNM1L.
Source ClinGen was added to DNM1L.
Source Literature was added to DNM1L.
Phenotypes for gene: DNM1L were changed from Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, 614388 to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MONDO:0013726
Publications for gene DNM1L were changed from 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748 to 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748
Mendeliome v1.3355 DES Chirag Patel Source Victorian Clinical Genetics Services was removed from DES.
Source ClinGen was added to DES.
Source Literature was added to DES.
Phenotypes for gene: DES were changed from Cardiomyopathy, dilated, 1I, MIM# 604765; Myopathy, myofibrillar, 1 , MIM#601419; Arrhythmogenic right ventricular cardiomyopathy to Cardiomyopathy, dilated, 1I, MIM# 604765; Myofibrillar myopathy 1, MONDO:0011076; Arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587
Publications for gene DES were changed from 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 19879535, 33947203, 19879535, 20423733, 23168288, 20829228, 22403400, 29212896, 22395865, 20718792 to 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 19879535, 33947203, 19879535, 20423733, 23168288, 20829228, 22403400, 29212896, 22395865, 20718792
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.63 DES Chirag Patel Phenotypes for gene: DES were changed from Myopathy, myofibrillar, 1 601419 to Myofibrillar myopathy 1, MONDO:0011076
Publications for gene DES were changed from 22395865, 20718792 to 22395865, 20718792
Arrhythmogenic Cardiomyopathy v0.73 DES Chirag Patel Publications for gene DES were changed from 19879535, 20423733, 23168288, 20829228, 22403400, 29212896, 22395865, 20718792 to 19879535, 20423733, 23168288, 20829228, 22403400, 29212896, 22395865, 20718792
Arrhythmogenic Cardiomyopathy v0.72 DES Chirag Patel Phenotypes for gene: DES were changed from Cardiomyopathy, dilated, 1I, MIM# 604765; Myopathy, myofibrillar, 1 , MIM#601419; Arrhythmogenic right ventricular cardiomyopathy to Arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587
Publications for gene DES were changed from 19879535, 20423733, 23168288, 20829228, 22403400, 29212896, 20718792 to 19879535, 20423733, 23168288, 20829228, 22403400, 29212896, 20718792
Dilated Cardiomyopathy v1.47 DES Chirag Patel Source Victorian Clinical Genetics Services was removed from DES.
Source ClinGen was added to DES.
Publications for gene DES were changed from 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 19879535, 33947203 to 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 19879535, 33947203
Proteinuria v0.231 DAAM2 Chirag Patel Publications for gene DAAM2 were changed from 33232676; 38860410 to 33232676; 38860410
Mendeliome v1.3354 DAAM2 Chirag Patel Publications for gene DAAM2 were changed from 33232676; 38860410; 36972684 to 33232676; 38860410; 36972684
Mendeliome v1.3353 FAP Sangavi Sivagnanasundram gene: FAP was added
gene: FAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FAP were set to 40949908
Phenotypes for gene: FAP were set to congenital pulmonary airway malformation MONDO:0016580
Review for gene: FAP was set to RED
Added comment: Only 1 reported fetus with a diagnosis of congenital pulmonary airway malformation
Heterozygous variant identified - c.T269G:p.L90W.
The variant is present in gnomAD v4.1 - EAS AF - 0.007% (4 hets)
Sources: Literature
Fetal anomalies v1.435 PDIA6 Sarah Milton reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40974269, 35856135, 33495992; Phenotypes: multiple congenital anomalies, MONDO:0019042, PDIA6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic Diabetes v0.147 PDIA6 Sarah Milton reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40974269, 35856135, 33495992; Phenotypes: multiple congenital anomalies, MONDO:0019042, PDIA6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Ciliopathies and Nephronophthisis v1.40 PDIA6 Sarah Milton reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40974269, 35856135, 33495992; Phenotypes: multiple congenital anomalies, MONDO:0019042, PDIA6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Short Rib Polydactyly_Jeune Asphyxiating Thoracic Dystrophy_Skeletal Ciliopathy v1.15 PDIA6 Sarah Milton reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40974269, 35856135, 33495992; Phenotypes: multiple congenital anomalies, MONDO:0019042, PDIA6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliopathies v1.88 PDIA6 Sarah Milton reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40974269, 35856135, 33495992; Phenotypes: multiple congenital anomalies, MONDO:0019042, PDIA6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3353 PDIA6 Sarah Milton edited their review of gene: PDIA6: Changed phenotypes: multiple congenital anomalies, MONDO:0019042, PDIA6-related
Intellectual disability syndromic and non-syndromic v1.346 SF1 Sarah Milton changed review comment from: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
Variant types included missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature; to: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
12 confirmed to have de novo variants including missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature
Mendeliome v1.3353 SF1 Sarah Milton changed review comment from: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
Variant types included missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature; to: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
12 confirmed to have de novo variants including missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature
Hereditary Neuropathy_CMT - isolated v1.65 DCTN1 Chirag Patel Source Royal Melbourne Hospital was removed from DCTN1.
Source Literature was added to DCTN1.
Phenotypes for gene: DCTN1 were changed from Neuronopathy, distal hereditary motor, type VIIB, MIM# 607641; MONDO:0011879 to Neuronopathy, distal hereditary motor, type 7B, MONDO:0011879
Motor Neurone Disease v1.36 DCTN1 Chirag Patel Phenotypes for gene: DCTN1 were changed from Perry syndrome, MIM# 168605 to Perry syndrome, MONDO:0008201
Publications for gene DCTN1 were changed from 20945553, 19136952, 24343258 to 20945553, 19136952, 24343258
Early-onset Dementia v1.46 DCTN1 Chirag Patel Phenotypes for gene: DCTN1 were changed from Perry syndrome, MIM# 168605 to Perry syndrome, MONDO:0008201
Publications for gene DCTN1 were changed from 20945553, 19136952, 24343258 to 20945553, 19136952, 24343258
Early-onset Parkinson disease v2.41 DCTN1 Chirag Patel Source Melbourne Genomics Health Alliance Complex Neurology Flagship was removed from DCTN1.
Source Victorian Clinical Genetics Services was removed from DCTN1.
Source Expert list was added to DCTN1.
Phenotypes for gene: DCTN1 were changed from Perry syndrome MONDO:0008201 to Perry syndrome, MONDO:0008201
Publications for gene DCTN1 were changed from 20945553, 19136952, 24343258 to 20945553, 19136952, 24343258
Intellectual disability syndromic and non-syndromic v1.346 SF1 Sarah Milton gene: SF1 was added
gene: SF1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF1 were set to PMID: 40987292
Phenotypes for gene: SF1 were set to Neurodevelopmental disorder, MONDO:0700092, SF1-related
Review for gene: SF1 was set to GREEN
Added comment: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
Variant types included missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature
Mendeliome v1.3353 SF1 Sarah Milton gene: SF1 was added
gene: SF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF1 were set to PMID: 40987292
Phenotypes for gene: SF1 were set to Neurodevelopmental disorder, MONDO:0700092, SF1-related
Review for gene: SF1 was set to GREEN
Added comment: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
Variant types included missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature
Motor Neurone Disease v1.35 DCTN1 Chirag Patel Source Royal Melbourne Hospital was removed from DCTN1.
Source Victorian Clinical Genetics Services was removed from DCTN1.
Source Melbourne Genomics Health Alliance Complex Neurology Flagship was removed from DCTN1.
Source Victorian Clinical Genetics Services was removed from DCTN1.
Source Literature was added to DCTN1.
Mode of inheritance for gene DCTN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DCTN1 were changed from to Perry syndrome, MIM# 168605
Publications for gene DCTN1 were changed from 19136952, 24343258 to 19136952, 24343258
Early-onset Dementia v1.45 DCTN1 Chirag Patel Source Melbourne Genomics Health Alliance Complex Neurology Flagship was removed from DCTN1.
Source Victorian Clinical Genetics Services was removed from DCTN1.
Source Literature was added to DCTN1.
Publications for gene DCTN1 were changed from 19136952, 24343258 to 19136952, 24343258
Skeletal dysplasia v0.337 DDR2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDR2.
Source ClinGen was added to DDR2.
Phenotypes for gene: DDR2 were changed from Spondylometaepiphyseal dysplasia, short limb-hand type 271665; Spondylometaepiphyseal dysplasia, short limb-hand type 271665, at least 3 cases reported to Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome, MONDO:0010077
Publications for gene DDR2 were changed from 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872 to 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872
Skeletal Dysplasia_Fetal v0.238 DDR2 Chirag Patel Source Genomics England PanelApp was removed from DDR2.
Source Genetic Health Queensland was removed from DDR2.
Source Victorian Clinical Genetics Services was removed from DDR2.
Source Melbourne Genomics Health Alliance Perinatal Autopsy Flagship was removed from DDR2.
Source ClinGen was added to DDR2.
Phenotypes for gene: DDR2 were changed from Spondylometaepiphyseal dysplasia, short limb-hand type, MIM#271665 to Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome, MONDO:0010077
Publications for gene DDR2 were changed from 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872 to 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872
Fetal anomalies v1.435 DDR2 Chirag Patel Source Genomics England PanelApp was removed from DDR2.
Source Genetic Health Queensland was removed from DDR2.
Source ClinGen was added to DDR2.
Phenotypes for gene: DDR2 were changed from Spondylometaepiphyseal dysplasia, short limb-hand type, MIM#271665, AR to Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome, MONDO:0010077
Publications for gene DDR2 were changed from 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872 to 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872
Mendeliome v1.3353 DDR2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDR2.
Source Literature was added to DDR2.
Phenotypes for gene: DDR2 were changed from Spondylometaepiphyseal dysplasia, short limb-hand type, MIM#271665; Warburg-Cinotti syndrome, MIM# 618175 to Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome, MONDO:0010077; Warburg-cinotti syndrome, MONDO:0032579
Publications for gene DDR2 were changed from 30449416, 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872 to 30449416, 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872
Mendeliome v1.3352 DEPDC5 Chirag Patel Source Victorian Clinical Genetics Services was removed from DEPDC5.
Source Literature was added to DEPDC5.
Publications for gene DEPDC5 were changed from 31444548; 23542697; 23542701; 36067010; 32848577 to 31444548; 23542697; 23542701; 36067010; 32848577
Mendeliome v1.3351 DHDDS Chirag Patel Source Victorian Clinical Genetics Services was removed from DHDDS.
Source Literature was added to DHDDS.
Publications for gene DHDDS were changed from 27343064, 21295283, 28130426, 29276052, 32483926, 36046393, 24078709, 28005406, 36046393, 29100083, 36628425, 34382076 to 27343064, 21295283, 28130426, 29276052, 32483926, 36046393, 24078709, 28005406, 36046393, 29100083, 36628425, 34382076
Intellectual disability syndromic and non-syndromic v1.346 DHDDS Chirag Patel Publications for gene DHDDS were changed from 29100083, 36628425, 34382076 to 29100083, 36628425, 34382076
Intellectual disability syndromic and non-syndromic v1.345 DHDDS Chirag Patel Publications for gene DHDDS were changed from 29100083, 36628425 to 29100083, 36628425
Mendeliome v1.3350 DHTKD1 Chirag Patel Classified gene: DHTKD1 as Green List (high evidence)
Mendeliome v1.3350 DHTKD1 Chirag Patel Gene: dhtkd1 has been classified as Green List (High Evidence).
Hereditary Neuropathy_CMT - isolated v1.64 DHTKD1 Chirag Patel Source Royal Melbourne Hospital was removed from DHTKD1.
Source Victorian Clinical Genetics Services was removed from DHTKD1.
Source Literature was added to DHTKD1.
Phenotypes for gene: DHTKD1 were changed from HMSN; Charcot Marie Tooth disease, axonal, type 2Q, 615025; 2 aminoadipic 2 oxoadipic aciduria, 204750 to Charcot-Marie-Tooth disease axonal type 2Q MONDO:0014012
Publications for gene DHTKD1 were changed from 23141294, 29661920, 28902413 to 23141294, 29661920, 28902413
Mendeliome v1.3349 DHTKD1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DHTKD1.
Source Victorian Clinical Genetics Services was removed from DHTKD1.
Source ClinGen was added to DHTKD1.
Phenotypes for gene: DHTKD1 were changed from Alpha-aminoadipic and alpha-ketoadipic aciduria MIM#204750, AR; Charcot-Marie-Tooth disease, axonal, type 2Q, MIM#615025 to 2-aminoadipic 2-oxoadipic aciduria MONDO:0008774; Charcot-Marie-Tooth disease axonal type 2Q MONDO:0014012
Publications for gene DHTKD1 were changed from 26141459, 25860818, 23141293, 23141294, 29661920, 28902413 to 26141459, 25860818, 23141293, 23141294, 29661920, 28902413
Rating Changed from Green List (high evidence) to Red List (low evidence)
Miscellaneous Metabolic Disorders v1.54 DHTKD1 Chirag Patel Phenotypes for gene: DHTKD1 were changed from 2-aminoadipic 2-oxoadipic aciduria MIM#204750; Disorders of histidine, tryptophan or lysine metabolism to 2-aminoadipic 2-oxoadipic aciduria MONDO:0008774
Publications for gene DHTKD1 were changed from 26141459, 25860818, 23141293 to 26141459, 25860818, 23141293
Mendeliome v1.3348 DHX37 Chirag Patel Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS); Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731 to 46,XY sex reversal 11, MONDO:8000015; Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Publications for gene DHX37 were changed from 31337883; 31745530; 31287541; 26539891; 31256877 to 31337883; 31745530; 31287541; 26539891; 31256877
Differences of Sex Development v1.21 DHX37 Chirag Patel Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) to 46,XY sex reversal 11, MONDO:8000015
Publications for gene DHX37 were changed from 31337883; 31745530; 31287541 to 31337883; 31745530; 31287541
IBMDx study v0.38 DIAPH1 Chirag Patel Source IBMDx Study was removed from DIAPH1.
Mode of inheritance for gene DIAPH1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DIAPH1 were changed from Macrothrombocytopenia and sensorineural hearing loss to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635
Publications for gene DIAPH1 were changed from 27707755, 27808407, 28003573, 28815995, 26912466 to 27707755, 27808407, 28003573, 28815995, 26912466
Genetic Epilepsy v1.238 DIAPH1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DIAPH1.
Source Australian Genomics Health Alliance Epilepsy Flagship was removed from DIAPH1.
Source Literature was added to DIAPH1.
Phenotypes for gene: DIAPH1 were changed from Seizures, cortical blindness, microcephaly syndrome, MIM# 616632 to Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714
Publications for gene DIAPH1 were changed from 24781755, 26463574, 33662367, 36212620, 39076976, 39120629 to 24781755, 26463574, 33662367, 36212620, 39076976, 39120629
Combined Immunodeficiency v1.134 DIAPH1 Chirag Patel Phenotypes for gene: DIAPH1 were changed from Seizures, cortical blindness, microcephaly syndrome, MIM# 616632; Combined Immune deficiency to Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714; Combined Immune deficiency
Publications for gene DIAPH1 were changed from 24781755, 26463574, 33662367, 36212620, 39076976, 39120629 to 24781755, 26463574, 33662367, 36212620, 39076976, 39120629
Intellectual disability syndromic and non-syndromic v1.344 DIAPH1 Chirag Patel Source Genetic Health Queensland was removed from DIAPH1.
Source Literature was added to DIAPH1.
Phenotypes for gene: DIAPH1 were changed from progressive microcephaly-seizures-cortical blindness-developmental delay syndrome MONDO:0014714 to Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714
Publications for gene DIAPH1 were changed from 24781755, 26463574, 33662367, 36212620, 39076976, 39120629 to 24781755, 26463574, 33662367, 36212620, 39076976, 39120629
Fetal anomalies v1.434 DIAPH1 Chirag Patel Source Genomics England PanelApp was removed from DIAPH1.
Source Expert Review was removed from DIAPH1.
Source Literature was added to DIAPH1.
Phenotypes for gene: DIAPH1 were changed from Seizures, cortical blindness, microcephaly syndrome, MIM#616632 to Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714
Publications for gene DIAPH1 were changed from 24781755, 26463574, 33662367, 36212620, 39076976, 39120629 to 24781755, 26463574, 33662367, 36212620, 39076976, 39120629
Microcephaly v1.345 DIAPH1 Chirag Patel Source Expert Review was removed from DIAPH1.
Source Literature was added to DIAPH1.
Phenotypes for gene: DIAPH1 were changed from Seizures, cortical blindness, microcephaly syndrome 616632 to Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714
Publications for gene DIAPH1 were changed from 24781755, 26463574, 33662367, 36212620, 39076976, 39120629 to 24781755, 26463574, 33662367, 36212620, 39076976, 39120629
Mendeliome v1.3347 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26912466; 24781755; 26463574; 33662367; 36212620; 39076976; 39120629 to 27808407; 28003573; 28815995; 26912466; 24781755; 26463574; 33662367; 36212620; 39076976; 39120629
Infertility and Recurrent Pregnancy Loss v1.36 ZSWIM7 Sangavi Sivagnanasundram changed review comment from: Established gene-disease association. Reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature; to: Established gene-disease association. Biallelic variants reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature
Mendeliome v1.3346 ZSWIM7 Sangavi Sivagnanasundram changed review comment from: Established gene-disease association. Reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature; to: Established gene-disease association. Biallelic variants reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature
Mendeliome v1.3346 ZSWIM7 Sangavi Sivagnanasundram gene: ZSWIM7 was added
gene: ZSWIM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZSWIM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZSWIM7 were set to 32719396, 33713115, 40991243, 40991243
Phenotypes for gene: ZSWIM7 were set to Spermatogenic failure 71 MONDO:0030787; Ovarian dysgenesis 10 MONDO:0030736
Review for gene: ZSWIM7 was set to GREEN
Added comment: Established gene-disease association. Reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature
Mendeliome v1.3346 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26912466; 24781755; 26463574 to 27808407; 28003573; 28815995; 26912466; 24781755; 26463574
Mendeliome v1.3345 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26463574; 26912466; 24781755 to 27808407; 28003573; 28815995; 26463574; 26912466; 24781755
Deafness_IsolatedAndComplex v1.231 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27707755; 27808407; 28003573; 28815995; 26912466 to 27707755; 27808407; 28003573; 28815995; 26912466
Bleeding and Platelet Disorders v1.60 DIAPH1 Chirag Patel Phenotypes for gene: DIAPH1 were changed from Deafness, autosomal dominant 1, with or without thrombocytopenia, MIM# 124900 to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635
Publications for gene DIAPH1 were changed from 26912466; 27808407; 27707755; 28003573; 28815995 to 26912466; 27808407; 27707755; 28003573; 28815995
Infertility and Recurrent Pregnancy Loss v1.36 ZSWIM7 Sangavi Sivagnanasundram gene: ZSWIM7 was added
gene: ZSWIM7 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ZSWIM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZSWIM7 were set to 32719396, 33713115, 40991243, 40991243
Phenotypes for gene: ZSWIM7 were set to Spermatogenic failure 71 MONDO:0030787; Ovarian dysgenesis 10 MONDO:0030736
Review for gene: ZSWIM7 was set to GREEN
Added comment: Established gene-disease association. Reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature
Deafness_IsolatedAndComplex v1.230 DIAPH1 Chirag Patel commented on gene: DIAPH1
Deafness_IsolatedAndComplex v1.230 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27707755; 27808407; 28003573; 28815995 to 27707755; 27808407; 28003573; 28815995
Mendeliome v1.3344 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26463574; 24781755 to 27808407; 28003573; 28815995; 26463574; 24781755
Mendeliome v1.3343 DIAPH1 Chirag Patel Phenotypes for gene: DIAPH1 were changed from DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635 to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714
Publications for gene DIAPH1 were changed from 24781755; 24781755; 27808407; 28003573; 28815995; 26463574 to 24781755; 24781755; 27808407; 28003573; 28815995; 26463574
Deafness_IsolatedAndComplex v1.229 DIAPH1 Chirag Patel Source Melbourne Genomics Health Alliance Deafness Flagship was removed from DIAPH1.
Source Victorian Clinical Genetics Services was removed from DIAPH1.
Source Literature was added to DIAPH1.
Phenotypes for gene: DIAPH1 were changed from Deafness, autosomal dominant 1, with or without thrombocytopenia, MIM# 124900 to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635
Mendeliome v1.3342 DIAPH1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DIAPH1.
Source Literature was added to DIAPH1.
Phenotypes for gene: DIAPH1 were changed from Deafness; thrombocytopenia 124900; Seizures; cortical blindness; microcephaly 616632 to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635
Mendeliome v1.3341 PDIA6 Sarah Milton reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40974269, 35856135, 33495992; Phenotypes: Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes and polycystic kidney disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v1.12 DLX3 Chirag Patel reviewed gene: DLX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9467018, 15666299; Phenotypes: Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v1.12 DLX3 Chirag Patel Source Genomics England PanelApp was removed from DLX3.
Source Literature was added to DLX3.
Phenotypes for gene: DLX3 were changed from Amelogenesis imperfecta, type IV, MIM# 104510; Trichodontoosseous syndrome, MIM# 190320 to Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093
Publications for gene DLX3 were changed from 9467018, 15666299 to 9467018, 15666299
Skeletal dysplasia v0.336 DLX3 Chirag Patel Phenotypes for gene: DLX3 were changed from Trichodontoosseous syndrome 190320 to Tricho-dento-osseous syndrome, MONDO:0008592
Mendeliome v1.3341 DLX3 Chirag Patel reviewed gene: DLX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15666299, 9467018, 18203197, 9783705, 10466415, 9467018; Phenotypes: Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093, Tricho-dento-osseous syndrome, MONDO:0008592; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3341 DLX3 Chirag Patel Phenotypes for gene: DLX3 were changed from Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093 to Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093; Tricho-dento-osseous syndrome, MONDO:0008592
Publications for gene DLX3 were changed from 15666299, 9467018, 18203197, 9783705, 10466415, 9467018 to 15666299, 9467018, 18203197, 9783705, 10466415, 9467018
Skeletal dysplasia v0.335 DLX3 Chirag Patel Publications for gene DLX3 were changed from 9467018, 18203197, 9783705, 10466415 to 9467018, 18203197, 9783705, 10466415
Mendeliome v1.3340 DLX3 Chirag Patel Classified gene: DLX3 as Green List (high evidence)
Mendeliome v1.3340 DLX3 Chirag Patel Gene: dlx3 has been classified as Green List (High Evidence).
Mendeliome v1.3339 DLX3 Chirag Patel Source Victorian Clinical Genetics Services was removed from DLX3.
Source Literature was added to DLX3.
Phenotypes for gene: DLX3 were changed from Amelogenesis imperfecta, type IV, MIM# 104510; Trichodontoosseous syndrome, MIM# 190320 to Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093
Publications for gene DLX3 were changed from 9467018; 15666299 to 9467018; 15666299
Rating Changed from Green List (high evidence) to Red List (low evidence)
Skeletal dysplasia v0.334 DLX3 Chirag Patel reviewed gene: DLX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9467018, 18203197, 9783705, 10466415; Phenotypes: Tricho-dento-osseous syndrome MONDO:0008592; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v0.334 DLX3 Chirag Patel Phenotypes for gene: DLX3 were changed from Trichodontoosseous syndrome 190320; Amelogenesis imperfecta, type IV 104510 to Trichodontoosseous syndrome 190320
Hand and foot malformations v0.77 DLX5 Chirag Patel reviewed gene: DLX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22121204, 24496061, 25196357, 20534536, 12112878; Phenotypes: Split-hand/foot malformation 1 with sensorineural hearing loss MIM#220600, Split-hand/foot malformation 1 MIM#183600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v0.333 DLX5 Chirag Patel reviewed gene: DLX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22121204, 24496061, 25196357, 20534536, 12112878; Phenotypes: Split-hand/foot malformation 1 with sensorineural hearing loss MIM#220600, Split-hand/foot malformation 1 MIM#183600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3338 RNF31 Zornitza Stark Marked gene: RNF31 as ready
Mendeliome v1.3338 RNF31 Zornitza Stark Added comment: Comment when marking as ready: Alias: HOIP
Mendeliome v1.3338 RNF31 Zornitza Stark Gene: rnf31 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.343 LEO1 Chirag Patel Classified gene: LEO1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.343 LEO1 Chirag Patel Gene: leo1 has been classified as Green List (High Evidence).
Mendeliome v1.3338 LEO1 Chirag Patel Classified gene: LEO1 as Green List (high evidence)
Mendeliome v1.3338 LEO1 Chirag Patel Gene: leo1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.342 LEO1 Chirag Patel reviewed gene: LEO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40993282, 33004838, 31785789, 40671880, 29674594; Phenotypes: Neurodevelopmental disorder MONDO:0700092, LEO-1 related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3337 LEO1 Chirag Patel reviewed gene: LEO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40993282, 33004838, 31785789, 40671880, 29674594; Phenotypes: Neurodevelopmental disorder MONDO:0700092, LEO-1 related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3337 MDC1 Zornitza Stark Marked gene: MDC1 as ready
Mendeliome v1.3337 MDC1 Zornitza Stark Gene: mdc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3337 MDC1 Zornitza Stark Publications for gene: MDC1 were set to PMID: 40954969, 34089056
Mendeliome v1.3336 MDC1 Zornitza Stark Classified gene: MDC1 as Amber List (moderate evidence)
Mendeliome v1.3336 MDC1 Zornitza Stark Gene: mdc1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.36 MDC1 Zornitza Stark Marked gene: MDC1 as ready
Infertility and Recurrent Pregnancy Loss v1.36 MDC1 Zornitza Stark Gene: mdc1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.36 MDC1 Zornitza Stark Classified gene: MDC1 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.36 MDC1 Zornitza Stark Gene: mdc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3335 SYNE2 Zornitza Stark Phenotypes for gene: SYNE2 were changed from Emery-Dreifuss muscular dystrophy 5, autosomal dominant MIM#612999 to Emery-Dreifuss muscular dystrophy 5, autosomal dominant MIM#612999; Neurodevelopmental disorder, MONDO:0700092, SYNE2 related
Mendeliome v1.3334 SYNE2 Zornitza Stark Publications for gene: SYNE2 were set to 32184094; 17761684; 40757551
Mendeliome v1.3333 SYNE2 Zornitza Stark Mode of inheritance for gene: SYNE2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.99 KLK15 Sangavi Sivagnanasundram gene: KLK15 was added
gene: KLK15 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: KLK15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLK15 were set to 40949095
Phenotypes for gene: KLK15 were set to hypermobile Ehlers-Danlos syndrome MONDO:0007523
Review for gene: KLK15 was set to AMBER
Added comment: Two unrelated families with individuals affected with hEDS
Heterozygous p.Gly226Asp was identified in both families and segregated with disease across other affected individuals and not presented in unaffected family members.
Note: p.Gly226Asp - FAF 0.4970% in gnomAD v4.1

CRISPR-Cas9-generated Klk15G224D/+ knock in mouse model showed a decrease in tendon elasicity, mitral valve prolapse, collagen fibril thinning which is supportive to show the mouse model recapitulated human phenotype.

More evidence is required to support gene-disease association given only one variant in two families and supportive mouse model have been reported.
Sources: Other
Intellectual disability syndromic and non-syndromic v1.342 SYNE2 Zornitza Stark Marked gene: SYNE2 as ready
Intellectual disability syndromic and non-syndromic v1.342 SYNE2 Zornitza Stark Gene: syne2 has been classified as Red List (Low Evidence).
Mendeliome v1.3332 KLK15 Sangavi Sivagnanasundram gene: KLK15 was added
gene: KLK15 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KLK15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLK15 were set to 40949095
Phenotypes for gene: KLK15 were set to hypermobile Ehlers-Danlos syndrome MONDO:0007523
Review for gene: KLK15 was set to AMBER
Added comment: Two unrelated families with individuals affected with hEDS
Heterozygous p.Gly226Asp was identified in both families and segregated with disease across other affected individuals and not presented in unaffected family members.
Note: p.Gly226Asp - FAF 0.4970% in gnomAD v4.1

CRISPR-Cas9-generated Klk15G224D/+ knock in mouse model showed a decrease in tendon elasicity, mitral valve prolapse, collagen fibril thinning which is supportive to show the mouse model recapitulated human phenotype.

More evidence is required to support gene-disease association given only one variant in two families and supportive mouse model have been reported.
Sources: Other
Mendeliome v1.3332 CNTD2 Zornitza Stark Marked gene: CNTD2 as ready
Mendeliome v1.3332 CNTD2 Zornitza Stark Gene: cntd2 has been classified as Green List (High Evidence).
Mendeliome v1.3332 CNTD2 Zornitza Stark Classified gene: CNTD2 as Green List (high evidence)
Mendeliome v1.3332 CNTD2 Zornitza Stark Gene: cntd2 has been classified as Green List (High Evidence).
Mendeliome v1.3331 CNTD2 Zornitza Stark Tag new gene name tag was added to gene: CNTD2.
Infertility and Recurrent Pregnancy Loss v1.35 CNTD2 Zornitza Stark Marked gene: CNTD2 as ready
Infertility and Recurrent Pregnancy Loss v1.35 CNTD2 Zornitza Stark Gene: cntd2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.35 CNTD2 Zornitza Stark Classified gene: CNTD2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.35 CNTD2 Zornitza Stark Gene: cntd2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.34 CNTD2 Zornitza Stark Tag new gene name tag was added to gene: CNTD2.
Deafness_IsolatedAndComplex v1.228 CLIC5 Chirag Patel Classified gene: CLIC5 as Green List (high evidence)
Deafness_IsolatedAndComplex v1.228 CLIC5 Chirag Patel Gene: clic5 has been classified as Green List (High Evidence).
Mendeliome v1.3331 CLIC5 Chirag Patel Classified gene: CLIC5 as Green List (high evidence)
Mendeliome v1.3331 CLIC5 Chirag Patel Gene: clic5 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.227 CLIC5 Chirag Patel reviewed gene: CLIC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40957967, 40928595, 33114113; Phenotypes: Autosomal recessive nonsyndromic hearing loss 103, MONDO:0014469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3330 CLIC5 Chirag Patel reviewed gene: CLIC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40957967, 40928595, 33114113; Phenotypes: Autosomal recessive nonsyndromic hearing loss 103, MONDO:0014469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v1.34 CNTD2 Sangavi Sivagnanasundram gene: CNTD2 was added
gene: CNTD2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Other
Mode of inheritance for gene: CNTD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTD2 were set to 41005306
Phenotypes for gene: CNTD2 were set to Oocyte/zygote/embryo maturation arrest MONDO:0014769
Review for gene: CNTD2 was set to GREEN
Added comment: HGNC approved new gene name: CCNP

3 unrelated women presenting with primary infertility and oocyte/embryo defects in IVF.
Different biallelic variants were identified - all variants were either absent or rare enough in gnomAD v4.1 for AR gene (p.L59Wfs*11, p.Y231N, and c.358-1G>A).

In vivo mouse model showed that the overexpression of mutant CNTD2 mRNA in mouse zygotes led to early embryonic arrest.
Sources: Other
Deafness_IsolatedAndComplex v1.227 CLIC5 Chirag Patel Source Melbourne Genomics Health Alliance Deafness Flagship was removed from CLIC5.
Source Victorian Clinical Genetics Services was removed from CLIC5.
Source Literature was added to CLIC5.
Phenotypes for gene: CLIC5 were changed from Deafness, autosomal recessive 103, MIM# 616042 to Autosomal recessive nonsyndromic hearing loss 103, MONDO:0014469
Mendeliome v1.3330 CLIC5 Chirag Patel Source Victorian Clinical Genetics Services was removed from CLIC5.
Source Literature was added to CLIC5.
Phenotypes for gene: CLIC5 were changed from Deafness, autosomal recessive 103, MIM# 616042 to Autosomal recessive nonsyndromic hearing loss 103, MONDO:0014469
Mendeliome v1.3329 CNTD2 Sangavi Sivagnanasundram gene: CNTD2 was added
gene: CNTD2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CNTD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTD2 were set to 41005306
Phenotypes for gene: CNTD2 were set to Oocyte/zygote/embryo maturation arrest MONDO:0014769
Review for gene: CNTD2 was set to GREEN
Added comment: HGNC approved new gene name: CCNP

3 unrelated women presenting with primary infertility and oocyte/embryo defects in IVF.
Different biallelic variants were identified - all variants were either absent or rare enough in gnomAD v4.1 for AR gene (p.L59Wfs*11, p.Y231N, and c.358-1G>A).

In vivo mouse model showed that the overexpression of mutant CNTD2 mRNA in mouse zygotes led to early embryonic arrest.
Sources: Other
Intellectual disability syndromic and non-syndromic v1.342 SYNE2 Chirag Patel gene: SYNE2 was added
gene: SYNE2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SYNE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYNE2 were set to 34573277
Phenotypes for gene: SYNE2 were set to Neurodevelopmental disorder, MONDO:0700092, SYNE2 related
Review for gene: SYNE2 was set to RED
Added comment: 1 individual with autism spectrum disorder, developmental delay and intellectual disability (from a cohort of 410 trios with neurodevelopmental disorders). Trio WES found compound heterozygous variants in SYNE2 [c.2483T>G; p.(Val828Gly) and c.2362G>A; p.(Glu788Lys)]. Both variants are rare, predicted to be highly damaging using in silico tools, and located in the nesprin-2 giant spectrin repeat domain. Both parents and the healthy brother were heterozygous. Expression and functional testing in patient lymphoblastoid cell lines showed a significant reduction of nesprin-2 giant protein levels, however SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was unaffected as compared to parental control cells.

SYNE 1-4 genes encode for nesprins (nuclear envelope spectrin repeat proteins) which play fundamental roles in nuclear architecture and positioning, directed cell migration, cellular signalling, ciliogenesis, and mechanobiology.
Sources: Literature
Mendeliome v1.3329 SYNE2 Chirag Patel reviewed gene: SYNE2: Rating: RED; Mode of pathogenicity: None; Publications: 34573277; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SYNE2 related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autism v0.221 INTS6 Zornitza Stark Phenotypes for gene: INTS6 were changed from to Neurodevelopmental disorder, MONDO:0700092, INTS6-related
Autism v0.220 INTS6 Zornitza Stark Publications for gene: INTS6 were set to
Autism v0.219 INTS6 Zornitza Stark Mode of inheritance for gene: INTS6 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autism v0.218 INTS6 Zornitza Stark Classified gene: INTS6 as Green List (high evidence)
Autism v0.218 INTS6 Zornitza Stark Gene: ints6 has been classified as Green List (High Evidence).
Autism v0.217 INTS6 Zornitza Stark reviewed gene: INTS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 40966122; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, INTS6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3329 INTS6 Zornitza Stark Phenotypes for gene: INTS6 were changed from to Neurodevelopmental disorder, MONDO:0700092, INTS6-related
Mendeliome v1.3328 INTS6 Zornitza Stark Mode of inheritance for gene: INTS6 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3327 INTS6 Zornitza Stark Classified gene: INTS6 as Green List (high evidence)
Mendeliome v1.3327 INTS6 Zornitza Stark Gene: ints6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.341 INTS6 Zornitza Stark Marked gene: INTS6 as ready
Intellectual disability syndromic and non-syndromic v1.341 INTS6 Zornitza Stark Gene: ints6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.341 INTS6 Zornitza Stark Classified gene: INTS6 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.341 INTS6 Zornitza Stark Gene: ints6 has been classified as Green List (High Evidence).
Mendeliome v1.3326 CCDC188 Zornitza Stark Marked gene: CCDC188 as ready
Mendeliome v1.3326 CCDC188 Zornitza Stark Gene: ccdc188 has been classified as Green List (High Evidence).
Mendeliome v1.3326 CCDC188 Zornitza Stark Classified gene: CCDC188 as Green List (high evidence)
Mendeliome v1.3326 CCDC188 Zornitza Stark Gene: ccdc188 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.34 CCDC188 Zornitza Stark Marked gene: CCDC188 as ready
Infertility and Recurrent Pregnancy Loss v1.34 CCDC188 Zornitza Stark Gene: ccdc188 has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.361 SPDYC Zornitza Stark Marked gene: SPDYC as ready
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.361 SPDYC Zornitza Stark Gene: spdyc has been classified as Green List (High Evidence).
Mendeliome v1.3325 SPDYC Zornitza Stark Marked gene: SPDYC as ready
Mendeliome v1.3325 SPDYC Zornitza Stark Gene: spdyc has been classified as Green List (High Evidence).
Congenital Heart Defect v0.465 PCDHA13 Zornitza Stark Marked gene: PCDHA13 as ready
Congenital Heart Defect v0.465 PCDHA13 Zornitza Stark Gene: pcdha13 has been classified as Red List (Low Evidence).
Mendeliome v1.3325 PCDHA13 Zornitza Stark Marked gene: PCDHA13 as ready
Mendeliome v1.3325 PCDHA13 Zornitza Stark Gene: pcdha13 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.465 PCDHA13 Chirag Patel gene: PCDHA13 was added
gene: PCDHA13 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PCDHA13 was set to Other
Publications for gene: PCDHA13 were set to 40988636
Phenotypes for gene: PCDHA13 were set to Hypoplastic left heart syndrome, MONDO:0004933
Review for gene: PCDHA13 was set to RED
Added comment: WES in 68 subjects with HLHS identified 1 individual with co-occurrence (i.e. digenic) of a SAP130 gene variant (p. S639G) and PCDHA13 gene variant (p. A22V). GnomAD frequencies for variants are: 0.00003% (PCDHA13 variant) and 0.01% with numerous homozygotes (SAP130 variant). The PCDHA13 variant is situated in a region highly conserved across the PCDHA gene family (which is highly homologous), especially PCDHA10 which is the ortholog of mouse Pcdha9.

Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, and Pcdha9 increases penetrance of aortic valve abnormalities. Mutations in Sap130 and Pcdha9 were validated by CRISPR–Cas9 genome editing in mice as being digenic causes of HLHS.
Sources: Literature
Mendeliome v1.3325 PCDHA13 Chirag Patel gene: PCDHA13 was added
gene: PCDHA13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCDHA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCDHA13 were set to 40988636
Phenotypes for gene: PCDHA13 were set to Hypoplastic left heart syndrome, MONDO:0004933
Review for gene: PCDHA13 was set to RED
Added comment: WES in 68 subjects with HLHS identified 1 individual with co-occurrence (i.e. digenic) of a SAP130 gene variant (p. S639G) and PCDHA13 gene variant (p. A22V). GnomAD frequencies for variants are: 0.00003% (PCDHA13 variant) and 0.01% with numerous homozygotes (SAP130 variant). The PCDHA13 variant is situated in a region highly conserved across the PCDHA gene family (which is highly homologous), especially PCDHA10 which is the ortholog of mouse Pcdha9.

Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, and Pcdha9 increases penetrance of aortic valve abnormalities. Mutations in Sap130 and Pcdha9 were validated by CRISPR–Cas9 genome editing in mice as being digenic causes of HLHS.
Sources: Literature
Mendeliome v1.3324 SPDYC Chirag Patel Classified gene: SPDYC as Green List (high evidence)
Mendeliome v1.3324 SPDYC Chirag Patel Gene: spdyc has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.361 SPDYC Chirag Patel Classified gene: SPDYC as Green List (high evidence)
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.361 SPDYC Chirag Patel Gene: spdyc has been classified as Green List (High Evidence).
Mendeliome v1.3323 SPDYC Chirag Patel gene: SPDYC was added
gene: SPDYC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPDYC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPDYC were set to 41005306
Phenotypes for gene: SPDYC were set to Primary ovarian failure, MONDO:0005387
Review for gene: SPDYC was set to GREEN
Added comment: 4 unrelated female patients with primary infertility caused by oocyte/embryo defects, from a large cohort of 3,627 patients. WES identified rare biallelic variants in SPDYC gene (p.R52Vfs∗50, p.R188C, p.P287H). Overexpression of mutant SPDYC mRNA in mouse oocytes caused disruption of the ability of the protein to overcome milrinone-mediated inhibition of meiotic resumption with two of the variants (p.R52Vfs∗50 and p.R188C). SPDYC is involved in crucial processes involving cyclin-dependent kinases during the phase transition of the mitotic cell cycle.
Sources: Literature
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.360 SPDYC Chirag Patel gene: SPDYC was added
gene: SPDYC was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature
Mode of inheritance for gene: SPDYC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPDYC were set to 41005306
Phenotypes for gene: SPDYC were set to Primary ovarian failure, MONDO:0005387
Review for gene: SPDYC was set to GREEN
Added comment: 4 unrelated female patients with primary infertility caused by oocyte/embryo defects, from a large cohort of 3,627 patients. WES identified rare biallelic variants in SPDYC gene (p.R52Vfs∗50, p.R188C, p.P287H). Overexpression of mutant SPDYC mRNA in mouse oocytes caused disruption of the ability of the protein to overcome milrinone-mediated inhibition of meiotic resumption with two of the variants (p.R52Vfs∗50 and p.R188C). SPDYC is involved in crucial processes involving cyclin-dependent kinases during the phase transition of the mitotic cell cycle.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.34 CCDC188 Chirag Patel Classified gene: CCDC188 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.34 CCDC188 Chirag Patel Gene: ccdc188 has been classified as Green List (High Evidence).
Mendeliome v1.3322 CCDC188 Chirag Patel gene: CCDC188 was added
gene: CCDC188 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC188 were set to 41004021
Phenotypes for gene: CCDC188 were set to Male infertility due to acephalic spermatozoa, MONDO:0035153
Review for gene: CCDC188 was set to GREEN
Added comment: 2 patients from 2 unrelated families with acephalic spermatozoa syndrome. WES identified biallelic variants in CCDC188 gene (1 x homozygous, 1 x compound heterozygous). The variants (c.481C > T [p.Gln161*] and c.1022 + 1G > A [p. K325Afs*110]) were rare in gnomAD and segregated in the family with heterozygous carrier parents. Western blotting, RT-PCR, qPCR, and immunofluorescence showed depletion of CCDC188 protein (and SUN5 and PMFBP1 protein) in patient sperm. Mutations in SUN5 and PMFBP1 genes account for 75% patients with acephalic spermatozoa syndrome.
Sources: Literature
Mendeliome v1.3322 CCDC188 Chirag Patel gene: CCDC188 was added
gene: CCDC188 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC188 were set to 41004021
Phenotypes for gene: CCDC188 were set to Male infertility due to acephalic spermatozoa, MONDO:0035153
Review for gene: CCDC188 was set to GREEN
Added comment: 2 patients from 2 unrelated families with acephalic spermatozoa syndrome. WES identified biallelic variants in CCDC188 gene (1 x homozygous, 1 x compound heterozygous). The variants (c.481C > T [p.Gln161*] and c.1022 + 1G > A [p. K325Afs*110]) were rare in gnomAD and segregated in the family with heterozygous carrier parents. Western blotting, RT-PCR, qPCR, and immunofluorescence showed depletion of CCDC188 protein (and SUN5 and PMFBP1 protein) in patient sperm. Mutations in SUN5 and PMFBP1 genes account for 75% patients with acephalic spermatozoa syndrome.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.33 CCDC188 Chirag Patel gene: CCDC188 was added
gene: CCDC188 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CCDC188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC188 were set to 41004021
Phenotypes for gene: CCDC188 were set to Male infertility due to acephalic spermatozoa, MONDO:0035153
Review for gene: CCDC188 was set to GREEN
Added comment: 2 patients from 2 unrelated families with acephalic spermatozoa syndrome. WES identified biallelic variants in CCDC188 gene (1 x homozygous, 1 x compound heterozygous). The variants (c.481C > T [p.Gln161*] and c.1022 + 1G > A [p. K325Afs*110]) were rare in gnomAD and segregated in the family with heterozygous carrier parents. Western blotting, RT-PCR, qPCR, and immunofluorescence showed depletion of CCDC188 protein (and SUN5 and PMFBP1 protein) in patient sperm. Mutations in SUN5 and PMFBP1 genes account for 75% patients with acephalic spermatozoa syndrome.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.340 INTS6 Sarah Milton changed review comment from: INTS6 encodes a member of the integrator complex which plays a role in RNA polymerase II transcription termination and small nuclear RNA processing.

PMID: 40966122 describes 24 affected individuals from 23 families with a variable neurodevelopmental disorder. Variant types included monoallelic missense, nonsense, frameshift and splice site.
Phenotypes included autism, variable language and motor delay, variable ID/developmental delay, sleep disturbances and epilepsy in a small subset.

21 variants were confirmed to be de novo.
All variants either absent in gnomad v4 or had 1 heterozygote only.
pLI for INTS6 is 1 and few overall LOF variants in gnomAD v4 in gene.

Supportive functional studies including biallelic knockout mice demonstrating abnormal brain morphology. Heterozygous knockout mice assessed to have abnormal behaviour and reduced learning efficiency and memory retention. Some variant specific studies performed consistent with loss of function mechanism.
Sources: Literature; to: INTS6 encodes a member of the integrator complex which plays a role in RNA polymerase II transcription termination and small nuclear RNA processing.

PMID: 40966122 describes 24 affected individuals from 23 families with a neurodevelopmental disorder. Variant types included monoallelic missense, nonsense, frameshift and splice site.
Phenotypes included autism, variable language and motor delay, variable ID/developmental delay, sleep disturbances and epilepsy in a small subset.

21 variants were confirmed to be de novo.
All variants either absent in gnomad v4 or had 1 heterozygote only.
pLI for INTS6 is 1 and few overall LOF variants in gnomAD v4 in gene.

Supportive functional studies including biallelic knockout mice demonstrating abnormal brain morphology. Heterozygous knockout mice assessed to have abnormal behaviour and reduced learning efficiency and memory retention. Some variant specific studies performed consistent with loss of function mechanism.
Sources: Literature
Mendeliome v1.3321 INTS6 Sarah Milton changed review comment from: INTS6 encodes a member of the integrator complex which plays a role in RNA polymerase II transcription termination and small nuclear RNA processing.

PMID: 40966122 describes 24 affected individuals from 23 families with a variable neurodevelopmental disorder. Variant types included monoallelic missense, nonsense, frameshift and splice site.
Phenotypes included autism, variable language and motor delay, variable ID/developmental delay, sleep disturbances and epilepsy in a small subset.

21 variants were confirmed to be de novo.
All variants either absent in gnomad v4 or had 1 heterozygote only.
pLI for INTS6 is 1 and few overall LOF variants in gnomAD v4 in gene.

Supportive functional studies including biallelic knockout mice demonstrating abnormal brain morphology. Heterozygous knockout mice assessed to have abnormal behaviour and reduced learning efficiency and memory retention. Some variant specific studies performed consistent with loss of function mechanism.; to: INTS6 encodes a member of the integrator complex which plays a role in RNA polymerase II transcription termination and small nuclear RNA processing.

PMID: 40966122 describes 24 affected individuals from 23 families with a neurodevelopmental disorder. Variant types included monoallelic missense, nonsense, frameshift and splice site.
Phenotypes included autism, variable language and motor delay, variable ID/developmental delay, sleep disturbances and epilepsy in a small subset.

21 variants were confirmed to be de novo.
All variants either absent in gnomad v4 or had 1 heterozygote only.
pLI for INTS6 is 1 and few overall LOF variants in gnomAD v4 in gene.

Supportive functional studies including biallelic knockout mice demonstrating abnormal brain morphology. Heterozygous knockout mice assessed to have abnormal behaviour and reduced learning efficiency and memory retention. Some variant specific studies performed consistent with loss of function mechanism.
Autoinflammatory Disorders v2.28 OAS2 Zornitza Stark Marked gene: OAS2 as ready
Autoinflammatory Disorders v2.28 OAS2 Zornitza Stark Gene: oas2 has been classified as Green List (High Evidence).
Autoinflammatory Disorders v2.28 OAS2 Zornitza Stark Classified gene: OAS2 as Green List (high evidence)
Autoinflammatory Disorders v2.28 OAS2 Zornitza Stark Gene: oas2 has been classified as Green List (High Evidence).
Autoinflammatory Disorders v2.27 OAS2 Zornitza Stark gene: OAS2 was added
gene: OAS2 was added to Autoinflammatory Disorders. Sources: Expert Review
Mode of inheritance for gene: OAS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OAS2 were set to 36538032
Phenotypes for gene: OAS2 were set to Multisystem inflammatory syndrome, MONDO:0035375, OAS2-related
Review for gene: OAS2 was set to GREEN
Added comment: 3x unrelated patients with MIS-C after COVID infection. Patients displayed excessive inflammatory responses to intracellular dsRNA, SARS-CoV-2, SARS-CoV-2–infected cells, and their RNA, providing a plausible mechanism for MIS-C. Similar presentation to OAS1 and RNASEL. Functional data.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v1.340 INTS6 Sarah Milton gene: INTS6 was added
gene: INTS6 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: INTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: INTS6 were set to PMID: 40966122
Phenotypes for gene: INTS6 were set to Neurodevelopmental disorder, MONDO:0700092, INTS6-related
Review for gene: INTS6 was set to GREEN
Added comment: INTS6 encodes a member of the integrator complex which plays a role in RNA polymerase II transcription termination and small nuclear RNA processing.

PMID: 40966122 describes 24 affected individuals from 23 families with a variable neurodevelopmental disorder. Variant types included monoallelic missense, nonsense, frameshift and splice site.
Phenotypes included autism, variable language and motor delay, variable ID/developmental delay, sleep disturbances and epilepsy in a small subset.

21 variants were confirmed to be de novo.
All variants either absent in gnomad v4 or had 1 heterozygote only.
pLI for INTS6 is 1 and few overall LOF variants in gnomAD v4 in gene.

Supportive functional studies including biallelic knockout mice demonstrating abnormal brain morphology. Heterozygous knockout mice assessed to have abnormal behaviour and reduced learning efficiency and memory retention. Some variant specific studies performed consistent with loss of function mechanism.
Sources: Literature
Mendeliome v1.3321 INTS6 Sarah Milton reviewed gene: INTS6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40966122; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, INTS6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Renal Macrocystic Disease v0.90 FLCN Zornitza Stark Marked gene: FLCN as ready
Renal Macrocystic Disease v0.90 FLCN Zornitza Stark Gene: flcn has been classified as Green List (High Evidence).
Renal Macrocystic Disease v0.90 FLCN Zornitza Stark Classified gene: FLCN as Green List (high evidence)
Renal Macrocystic Disease v0.90 FLCN Zornitza Stark Gene: flcn has been classified as Green List (High Evidence).
Renal Macrocystic Disease v0.89 FLCN Zornitza Stark gene: FLCN was added
gene: FLCN was added to Renal Macrocystic Disease. Sources: Expert Review
Mode of inheritance for gene: FLCN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FLCN were set to Birt-Hogg-Dube syndrome, MIM# 135150
Review for gene: FLCN was set to GREEN
Added comment: Renal cysts are part of the phenotype.
Sources: Expert Review
Cardiomyopathy_Paediatric v0.207 DNM1L Zornitza Stark Marked gene: DNM1L as ready
Cardiomyopathy_Paediatric v0.207 DNM1L Zornitza Stark Gene: dnm1l has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.207 DNM1L Zornitza Stark Classified gene: DNM1L as Green List (high evidence)
Cardiomyopathy_Paediatric v0.207 DNM1L Zornitza Stark Gene: dnm1l has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.206 DNM1L Zornitza Stark gene: DNM1L was added
gene: DNM1L was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: DNM1L was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNM1L were set to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388
Review for gene: DNM1L was set to GREEN
Added comment: Cardiomyopathy is a reported feature of this metabolic disorder.
Sources: Literature
Leukodystrophy - paediatric v0.330 ATP7A Zornitza Stark Mode of inheritance for gene: ATP7A was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Leukodystrophy - paediatric v0.329 ATP7A Zornitza Stark reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.347 VHL Zornitza Stark Marked gene: VHL as ready
Incidentalome v0.347 VHL Zornitza Stark Gene: vhl has been classified as Green List (High Evidence).
Incidentalome v0.347 VHL Zornitza Stark Phenotypes for gene: VHL were changed from to von Hippel-Lindau syndrome , MIM#193300
Incidentalome v0.346 VHL Zornitza Stark Mode of inheritance for gene: VHL was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.345 UBQLN2 Zornitza Stark Marked gene: UBQLN2 as ready
Incidentalome v0.345 UBQLN2 Zornitza Stark Gene: ubqln2 has been classified as Green List (High Evidence).
Incidentalome v0.345 UBQLN2 Zornitza Stark Phenotypes for gene: UBQLN2 were changed from to Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (MONDO: 0010459; MIM#300857)
Incidentalome v0.344 UBQLN2 Zornitza Stark Publications for gene: UBQLN2 were set to
Incidentalome v0.343 UBQLN2 Zornitza Stark Mode of inheritance for gene: UBQLN2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.342 TSC2 Zornitza Stark Marked gene: TSC2 as ready
Incidentalome v0.342 TSC2 Zornitza Stark Gene: tsc2 has been classified as Green List (High Evidence).
Incidentalome v0.342 TSC2 Zornitza Stark Phenotypes for gene: TSC2 were changed from to Tuberous sclerosis-2, MIM# 613254
Incidentalome v0.341 TSC2 Zornitza Stark Mode of inheritance for gene: TSC2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.340 TSC1 Zornitza Stark Marked gene: TSC1 as ready
Incidentalome v0.340 TSC1 Zornitza Stark Gene: tsc1 has been classified as Green List (High Evidence).
Incidentalome v0.340 TSC1 Zornitza Stark Phenotypes for gene: TSC1 were changed from to Tuberous sclerosis-1, MIM# 191100
Incidentalome v0.339 TSC1 Zornitza Stark Mode of inheritance for gene: TSC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.338 Zornitza Stark removed gene:TH from the panel
Mendeliome v1.3321 TH Zornitza Stark Marked gene: TH as ready
Mendeliome v1.3321 TH Zornitza Stark Gene: th has been classified as Green List (High Evidence).
Mendeliome v1.3321 TH Zornitza Stark Classified gene: TH as Green List (high evidence)
Mendeliome v1.3321 TH Zornitza Stark Gene: th has been classified as Green List (High Evidence).
Mendeliome v1.3320 TH Zornitza Stark changed review comment from: Well established association with infantile onset DOPA-reponsive dystonia.
Sources: Literature; to: Well established association with infantile onset DOPA-responsive dystonia.
Sources: Literature
Mendeliome v1.3320 TH Zornitza Stark gene: TH was added
gene: TH was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TH were set to Segawa syndrome, recessive MIM#605407
Review for gene: TH was set to GREEN
Added comment: Well established association with infantile onset DOPA-reponsive dystonia.
Sources: Literature
Mendeliome v1.3319 TCIRG1 Zornitza Stark Phenotypes for gene: TCIRG1 were changed from Osteopetrosis, autosomal recessive 1, MIM# 259700 to Osteopetrosis, autosomal recessive 1, MIM# 259700; severe congenital neutropenia, MONDO:0018542, TCIRG1-related
Mendeliome v1.3318 TCIRG1 Zornitza Stark Publications for gene: TCIRG1 were set to 34624559; 34210262; 30084437; 28816234
Infertility and Recurrent Pregnancy Loss v1.32 MDC1 Sarah Milton gene: MDC1 was added
gene: MDC1 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDC1 were set to PMID: 40954969, 34089056
Phenotypes for gene: MDC1 were set to Oligoasthenoteratozoospermia, MONDO:0850098, MDC1-related
Review for gene: MDC1 was set to AMBER
Added comment: MDC1 encodes mediator of DNA damage checkpoint I protein.

PMID: 40954969 describes 2 affected individuals with biallelic loss of function (nonsense and start loss) variants in MDC1 with reduced sperm count, abnormal morphology and poor motility. 1 family consanguineous.
PMID: 34089056 describes 1 similarly affected individual with 2 loss of function variants not confirmed in trans.
All adequately rare in gnomad v4.
No homozygous NMD predicted variants in gnomad v4.

Knockout mice models show meiotic arrest in spermatocytes which subsequently undergo apoptosis.

Functional studies performed in PMID:40954969 showed lack of protein in affected patient cells and lack of colocalization usual partner protein. Didn't demonstrate conclusively loss of downstream function.
Sources: Literature
Mendeliome v1.3317 TCIRG1 Zornitza Stark Mode of inheritance for gene: TCIRG1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3316 TCIRG1 Zornitza Stark edited their review of gene: TCIRG1: Added comment: PMID: 40964614, now total of 6 families with neutropenia and supportive functional data, upgrade mono-allelic association to Green.; Changed publications: 34624559, 34210262, 30084437, 28816234, 40964614
Phagocyte Defects v1.44 TCIRG1 Zornitza Stark Publications for gene: TCIRG1 were set to 24753205; 35573728
Mendeliome v1.3316 MDC1 Sarah Milton gene: MDC1 was added
gene: MDC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDC1 were set to PMID: 40954969, 34089056
Phenotypes for gene: MDC1 were set to Oligoasthenoteratozoospermia, MONDO:0850098, MDC1-related
Review for gene: MDC1 was set to AMBER
Added comment: MDC1 encodes mediator of DNA damage checkpoint I protein.

PMID: 40954969 describes 2 affected individuals with biallelic loss of function (nonsense and start loss) variants in MDC1 with reduced sperm count, abnormal morphology and poor motility. 1 family consanguineous.
PMID: 34089056 describes 1 similarly affected individual with 2 loss of function variants not confirmed in trans.
All adequately rare in gnomad v4.
No homozygous NMD predicted variants in gnomad v4.

Knockout mice models show meiotic arrest in spermatocytes which subsequently undergo apoptosis.

Functional studies performed in PMID:40954969 showed lack of protein in affected patient cells and lack of colocalization usual partner protein. Didn't demonstrate conclusively loss of downstream function.
Sources: Literature
Phagocyte Defects v1.43 TCIRG1 Zornitza Stark Classified gene: TCIRG1 as Green List (high evidence)
Phagocyte Defects v1.43 TCIRG1 Zornitza Stark Gene: tcirg1 has been classified as Green List (High Evidence).
Phagocyte Defects v1.42 TCIRG1 Zornitza Stark edited their review of gene: TCIRG1: Added comment: PMID: 40964614, now total of 6 families and supportive functional data, upgrade to Green.; Changed rating: GREEN; Changed publications: 24753205, 35573728, 40964614
Incidentalome v0.337 STK11 Zornitza Stark Marked gene: STK11 as ready
Incidentalome v0.337 STK11 Zornitza Stark Gene: stk11 has been classified as Green List (High Evidence).
Incidentalome v0.337 STK11 Zornitza Stark Phenotypes for gene: STK11 were changed from to Peutz-Jeghers syndrome, MIM# 175200
Incidentalome v0.336 STK11 Zornitza Stark Mode of inheritance for gene: STK11 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Spastic Paraplegia v1.99 SPAST Zornitza Stark Phenotypes for gene: SPAST were changed from Spastic paraplegia 4, autosomal dominant, MIM# 182601 to Spastic paraplegia 4, autosomal dominant, MIM# 182601; Cerebral Palsy MONDO:0006497, SPAST-related, AR
Hereditary Spastic Paraplegia v1.98 SPAST Zornitza Stark Publications for gene: SPAST were set to
Hereditary Spastic Paraplegia v1.97 SPAST Zornitza Stark Mode of inheritance for gene: SPAST was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary Spastic Paraplegia v1.96 SPAST Zornitza Stark edited their review of gene: SPAST: Added comment: PMID 41000004: 5 individuals from three unrelated families reported with bi-allelic variants and presenting with CP. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient-derived fibroblasts, supporting the pathogenicity of the variants.; Changed publications: 41000004; Changed phenotypes: Spastic paraplegia 4, autosomal dominant, MIM# 182601, Cerebral Palsy MONDO:0006497, SPAST-related, AR; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3316 SPAST Zornitza Stark Phenotypes for gene: SPAST were changed from Spastic paraplegia 4, autosomal dominant (MIM#182601), AD to Spastic paraplegia 4, autosomal dominant (MIM#182601), AD; Cerebral Palsy MONDO:0006497, SPAST-related, AR
Mendeliome v1.3315 SPAST Zornitza Stark Publications for gene: SPAST were set to 30476002; 30006150
Mendeliome v1.3314 SPAST Zornitza Stark Mode of inheritance for gene: SPAST was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3313 SPAST Zornitza Stark reviewed gene: SPAST: Rating: GREEN; Mode of pathogenicity: None; Publications: 41000004; Phenotypes: Cerebral Palsy MONDO:0006497, SPAST-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral Palsy v1.395 SPAST Zornitza Stark Phenotypes for gene: SPAST were changed from Cerebral Palsy (PMID:32989326) to Cerebral Palsy MONDO:0006497, SPAST-related
Cerebral Palsy v1.394 SPAST Zornitza Stark Publications for gene: SPAST were set to 32989326
Cerebral Palsy v1.393 SPAST Zornitza Stark Mode of inheritance for gene: SPAST was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cerebral Palsy v1.392 SPAST Zornitza Stark edited their review of gene: SPAST: Added comment: PMID 41000004: 5 individuals from three unrelated families reported with bi-allelic variants and presenting with CP. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient-derived fibroblasts, supporting the pathogenicity of the variants.; Changed rating: GREEN; Changed publications: 41000004; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.335 SDHC Zornitza Stark Marked gene: SDHC as ready
Incidentalome v0.335 SDHC Zornitza Stark Gene: sdhc has been classified as Green List (High Evidence).
Incidentalome v0.335 SDHC Zornitza Stark Phenotypes for gene: SDHC were changed from to Paragangliomas 3, MIM# 605373
Incidentalome v0.334 SDHC Zornitza Stark Mode of inheritance for gene: SDHC was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.333 SDHB Zornitza Stark Marked gene: SDHB as ready
Incidentalome v0.333 SDHB Zornitza Stark Gene: sdhb has been classified as Green List (High Evidence).
Incidentalome v0.333 SDHB Zornitza Stark Phenotypes for gene: SDHB were changed from to Paragangliomas 4, MIM# 115310
Incidentalome v0.332 SDHB Zornitza Stark Mode of inheritance for gene: SDHB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.340 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679; 40442284
Intellectual disability syndromic and non-syndromic v1.339 RNU2-2P Zornitza Stark Mode of inheritance for gene: RNU2-2P was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.338 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.338 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Added comment: PMID 40950445: reports bi-allelic cases in a cohort of over 100 individuals. One variant frequently de novo in trans with inherited variant.; Changed publications: 40210679, 40442284, 40950445
Genetic Epilepsy v1.237 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679; 40442284
Genetic Epilepsy v1.236 RNU2-2P Zornitza Stark Mode of inheritance for gene: RNU2-2P was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v1.235 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Added comment: PMID 40950445: reports bi-allelic cases in a cohort of over 100 individuals. One variant frequently de novo in trans with inherited variant.; Changed publications: 40210679, 40442284, 40950445; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3313 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679; 40442284
Mendeliome v1.3312 RNU2-2P Zornitza Stark Mode of inheritance for gene: RNU2-2P was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3311 RNU2-2P Zornitza Stark changed review comment from: PMID 40950445: reports bi-alleic cases in a cohort of over 100 individuals. One variant frequently de novo in trans with inherited variant.; to: PMID 40950445: reports bi-allelic cases in a cohort of over 100 individuals. One variant frequently de novo in trans with inherited variant.
Mendeliome v1.3311 RNU2-2P Zornitza Stark changed review comment from: PMID 40950445: reports bi-alleic cases. One variant frequently de novo in trans with inherited variant.; to: PMID 40950445: reports bi-alleic cases in a cohort of over 100 individuals. One variant frequently de novo in trans with inherited variant.
Mendeliome v1.3311 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Added comment: PMID 40950445: reports bi-alleic cases. One variant frequently de novo in trans with inherited variant.; Changed publications: 40210679, 40442284, 40950445; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Renal Macrocystic Disease v0.88 PKD1 Zornitza Stark Mode of inheritance for gene: PKD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Renal Macrocystic Disease v0.87 PKD1 Zornitza Stark reviewed gene: PKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3311 PKD1 Zornitza Stark Mode of inheritance for gene: PKD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3310 PKD1 Zornitza Stark edited their review of gene: PKD1: Added comment: Rare reports of bi-allelic disease presenting antenatally.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.331 PANK2 Zornitza Stark Marked gene: PANK2 as ready
Incidentalome v0.331 PANK2 Zornitza Stark Gene: pank2 has been classified as Green List (High Evidence).
Incidentalome v0.331 PANK2 Zornitza Stark Phenotypes for gene: PANK2 were changed from to Neurodegeneration with brain iron accumulation 1 (MIM#234200)
Incidentalome v0.330 PANK2 Zornitza Stark Publications for gene: PANK2 were set to
Incidentalome v0.329 PANK2 Zornitza Stark Mode of inheritance for gene: PANK2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3310 OSMR Zornitza Stark Phenotypes for gene: OSMR were changed from Amyloidosis, primary localized cutaneous, 1 - MIM#105250 to Amyloidosis, primary localized cutaneous, 1 - MIM#105250; Inborn error of immunity, MONDO:0003778, OSMR-related
Mendeliome v1.3309 OSMR Zornitza Stark Publications for gene: OSMR were set to 19375894; 19528426; 25054142; 20507362; 19690585
Mendeliome v1.3308 OSMR Zornitza Stark Mode of inheritance for gene: OSMR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3307 OSMR Zornitza Stark reviewed gene: OSMR: Rating: GREEN; Mode of pathogenicity: None; Publications: 40970115; Phenotypes: Inborn error of immunity, MONDO:0003778, OSMR-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory Disorders v2.26 OSMR Zornitza Stark Marked gene: OSMR as ready
Autoinflammatory Disorders v2.26 OSMR Zornitza Stark Gene: osmr has been classified as Green List (High Evidence).
Autoinflammatory Disorders v2.26 OSMR Zornitza Stark Classified gene: OSMR as Green List (high evidence)
Autoinflammatory Disorders v2.26 OSMR Zornitza Stark Gene: osmr has been classified as Green List (High Evidence).
Autoinflammatory Disorders v2.25 OSMR Zornitza Stark gene: OSMR was added
gene: OSMR was added to Autoinflammatory Disorders. Sources: Literature
Mode of inheritance for gene: OSMR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSMR were set to 40970115
Phenotypes for gene: OSMR were set to Inborn error of immunity, MONDO:0003778, OSMR-related
Review for gene: OSMR was set to GREEN
Added comment: 4 individuals from 4 unrelated families reported with bi-allelic LoF variants and severe widespread, early-onset atopic dermatitis, peripheral eosinophilia, and elevated serum IgE. Supportive functional data.
Sources: Literature
Mendeliome v1.3307 MAP3K1 Zornitza Stark Publications for gene: MAP3K1 were set to 21129722; 32986312
Mendeliome v1.3306 MAP3K1 Zornitza Stark commented on gene: MAP3K1: PMID 39062623: single family reported with deafness and homozygous missense, but two supportive mouse models. RED for this association and MOI.
Mendeliome v1.3306 ASXL3 Zornitza Stark Publications for gene: ASXL3 were set to 28100473; 27901041; 23383720
Mendeliome v1.3305 ASXL3 Zornitza Stark changed review comment from: PMID 32696347: two families with compound het variants and congenital heart disease, some functional data.; to: PMID 32696347: two families with compound het variants and congenital heart disease, some functional data. RED for this MOI and association.
Mendeliome v1.3305 ASXL3 Zornitza Stark edited their review of gene: ASXL3: Added comment: PMID 32696347: two families with compound het variants and congenital heart disease, some functional data.; Changed publications: 28100473, 27901041, 23383720, 32696347
Congenital Heart Defect v0.464 ASXL3 Zornitza Stark Marked gene: ASXL3 as ready
Congenital Heart Defect v0.464 ASXL3 Zornitza Stark Gene: asxl3 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.464 ASXL3 Zornitza Stark gene: ASXL3 was added
gene: ASXL3 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ASXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASXL3 were set to 32696347
Phenotypes for gene: ASXL3 were set to Congenital heart disease, MONDO:0005453, ASXL3-related
Review for gene: ASXL3 was set to RED
Added comment: Two families reported with compound heterozygous variants and some supportive functional data.
Sources: Literature
Mendeliome v1.3305 MSTO1 Lucy Spencer reviewed gene: MSTO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Microcephaly v1.344 CRNKL1 Zornitza Stark Phenotypes for gene: CRNKL1 were changed from complex neurodevelopmental disorder MONDO:0100038 to complex neurodevelopmental disorder MONDO:0100038 CRNKL1-related
Microcephaly v1.343 CRNKL1 Zornitza Stark Publications for gene: CRNKL1 were set to
Polymicrogyria and Schizencephaly v0.200 CRNKL1 Zornitza Stark Marked gene: CRNKL1 as ready
Polymicrogyria and Schizencephaly v0.200 CRNKL1 Zornitza Stark Gene: crnkl1 has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.200 CRNKL1 Zornitza Stark Phenotypes for gene: CRNKL1 were changed from intellectual disability; epilepsy; simplified gyration; microcephaly to Complex neurodevelopmental disorder, CRNKL1-related - MONDO:0100038
Polymicrogyria and Schizencephaly v0.199 CRNKL1 Zornitza Stark Classified gene: CRNKL1 as Green List (high evidence)
Polymicrogyria and Schizencephaly v0.199 CRNKL1 Zornitza Stark Gene: crnkl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.338 CRNKL1 Zornitza Stark Publications for gene: CRNKL1 were set to
Mendeliome v1.3305 EMB Zornitza Stark Marked gene: EMB as ready
Mendeliome v1.3305 EMB Zornitza Stark Gene: emb has been classified as Red List (Low Evidence).
Hirschsprung disease v0.27 EMB Zornitza Stark Marked gene: EMB as ready
Hirschsprung disease v0.27 EMB Zornitza Stark Gene: emb has been classified as Red List (Low Evidence).
Dystonia - complex v0.288 MRPS36 Zornitza Stark Tag new gene name tag was added to gene: MRPS36.
Genetic Epilepsy v1.235 MRPS36 Zornitza Stark Tag new gene name tag was added to gene: MRPS36.
Mendeliome v1.3305 MRPS36 Zornitza Stark Marked gene: MRPS36 as ready
Mendeliome v1.3305 MRPS36 Zornitza Stark Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3305 MRPS36 Zornitza Stark Tag new gene name tag was added to gene: MRPS36.
Mitochondrial disease v0.1081 MRPS36 Zornitza Stark Tag new gene name tag was added to gene: MRPS36.
Microcephaly v1.342 CRNKL1 Boris Keren reviewed gene: CRNKL1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 40857589; Phenotypes: intellectual disability, epilepsy, simplified gyration, microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Polymicrogyria and Schizencephaly v0.198 CRNKL1 Boris Keren gene: CRNKL1 was added
gene: CRNKL1 was added to Polymicrogyria and Schizencephaly. Sources: Literature
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRNKL1 were set to 40857589
Phenotypes for gene: CRNKL1 were set to intellectual disability; epilepsy; simplified gyration; microcephaly
Penetrance for gene: CRNKL1 were set to Complete
Mode of pathogenicity for gene: CRNKL1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: CRNKL1 was set to GREEN
gene: CRNKL1 was marked as current diagnostic
Added comment: 10 cases with de novo missenses variants PMID: 40857589.
Phenotype : intellectual disability, microcephaly, simplified gyration, epilepsy.
hypothesis : gain-of-function or dominant negative
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.337 CRNKL1 Boris Keren reviewed gene: CRNKL1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 40857589; Phenotypes: microcephaly, intellectual disability, simplified gyration, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.3305 MRC2 Krithika Murali Marked gene: MRC2 as ready
Mendeliome v1.3305 MRC2 Krithika Murali Gene: mrc2 has been classified as Red List (Low Evidence).
Mendeliome v1.3305 MRC2 Krithika Murali gene: MRC2 was added
gene: MRC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRC2 were set to PMID: 38953222
Phenotypes for gene: MRC2 were set to Wolff-Parkinson-White syndrome - MONDO:0008685, MRC2-related
Review for gene: MRC2 was set to RED
Added comment: PMID: 38953222 - Multiple indiviuals from 1 family with het MRC2 variant c.2969A>G; p.Glu990Gly and SVT or WPW reported. In vivo electrophysiological studies/optical mapping in knock-in mice with the E990G variant demonstrated higher incidence of inducible SVT and retrograde conduction through an accessory pathway. Studies in human cardiac fibroblasts revealed enhanced migration in Mrc2-knockdown cells.
Sources: Literature
Cardiac conduction disease v1.3 MRC2 Krithika Murali changed review comment from: Multiple indiviuals from 1 family with het MRC2 variant c.2969A>G; p.Glu990Gly and SVT or WPW reported. In vivo electrophysiological studies/optical mapping in knock-in mice with the E990G variant demonstrated higher incidence of inducible SVT and retrograde conduction through an accessory pathway. Studies in human cardiac fibroblasts revealed enhanced migration in Mrc2-knockdown cells.
Sources: Literature; to: PMID: 38953222 - Multiple indiviuals from 1 family with het MRC2 variant c.2969A>G; p.Glu990Gly and SVT or WPW reported. In vivo electrophysiological studies/optical mapping in knock-in mice with the E990G variant demonstrated higher incidence of inducible SVT and retrograde conduction through an accessory pathway. Studies in human cardiac fibroblasts revealed enhanced migration in Mrc2-knockdown cells.
Sources: Literature
Cardiac conduction disease v1.3 MRC2 Krithika Murali Publications for gene: MRC2 were set to
Cardiac conduction disease v1.2 MRC2 Krithika Murali Marked gene: MRC2 as ready
Cardiac conduction disease v1.2 MRC2 Krithika Murali Gene: mrc2 has been classified as Red List (Low Evidence).
Cardiac conduction disease v1.2 MRC2 Krithika Murali gene: MRC2 was added
gene: MRC2 was added to Cardiac conduction disease. Sources: Literature
Mode of inheritance for gene: MRC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MRC2 were set to Wolff-Parkinson-White syndrome - MONDO:0008685, MRC2-related
Review for gene: MRC2 was set to RED
Added comment: Multiple indiviuals from 1 family with het MRC2 variant c.2969A>G; p.Glu990Gly and SVT or WPW reported. In vivo electrophysiological studies/optical mapping in knock-in mice with the E990G variant demonstrated higher incidence of inducible SVT and retrograde conduction through an accessory pathway. Studies in human cardiac fibroblasts revealed enhanced migration in Mrc2-knockdown cells.
Sources: Literature
Mendeliome v1.3304 EMB Krithika Murali gene: EMB was added
gene: EMB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EMB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMB were set to PMID: 40999499
Phenotypes for gene: EMB were set to Hirschsprung disease - MONDO:0018309, EMB-related
Added comment: Li et al 2025 report enrichment of rare EMB variants in a cohort of patients with Hirschsprung disease. No additional phenotypic or variant information provided. Various in vitro studies and zebrafish/knockout mouse model associate loss of EMB with HSCR phenotype.
Sources: Literature
Hirschsprung disease v0.27 EMB Krithika Murali gene: EMB was added
gene: EMB was added to Hirschsprung disease. Sources: Literature
Mode of inheritance for gene: EMB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMB were set to PMID: 40999499
Phenotypes for gene: EMB were set to Hirschsprung disease - MONDO:0018309, EMB-related
Review for gene: EMB was set to RED
Added comment: Li et al 2025 report enrichment of rare EMB variants in a cohort of patients with Hirschsprung disease. No additional phenotypic or variant information provided. Various in vitro studies and zebrafish/knockout mouse model associate loss of EMB with HSCR phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.337 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.337 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.336 MRPS36 Krithika Murali Marked gene: MRPS36 as ready
Intellectual disability syndromic and non-syndromic v1.336 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.336 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.336 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.335 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. GDD, ID and cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Genetic Epilepsy v1.235 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Genetic Epilepsy v1.235 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.234 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Genetic Epilepsy v1.234 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.233 MRPS36 Krithika Murali Marked gene: MRPS36 as ready
Genetic Epilepsy v1.233 MRPS36 Krithika Murali Gene: mrps36 has been classified as Red List (Low Evidence).
Genetic Epilepsy v1.233 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. Cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Mendeliome v1.3303 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Mendeliome v1.3303 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3302 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. Cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Cardiomyopathy_Paediatric v0.205 MRPS36 Krithika Murali Marked gene: MRPS36 as ready
Cardiomyopathy_Paediatric v0.205 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Cardiomyopathy_Paediatric v0.205 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Cardiomyopathy_Paediatric v0.205 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Cardiomyopathy_Paediatric v0.204 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis.
Cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v1.104 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Muscular dystrophy and myopathy_Paediatric v1.104 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Muscular dystrophy and myopathy_Paediatric v1.103 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. Cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Leukodystrophy - paediatric v0.329 MRPS36 Krithika Murali Marked gene: MRPS36 as ready
Leukodystrophy - paediatric v0.329 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Leukodystrophy - paediatric v0.329 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Leukodystrophy - paediatric v0.329 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Leukodystrophy - paediatric v0.328 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. Cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Dystonia - complex v0.288 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Dystonia - complex v0.288 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Dystonia - complex v0.287 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Dystonia - complex v0.287 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Dystonia - complex v0.286 MRPS36 Krithika Murali Marked gene: MRPS36 as ready
Dystonia - complex v0.286 MRPS36 Krithika Murali Gene: mrps36 has been classified as Red List (Low Evidence).
Dystonia - complex v0.286 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Dystonia - complex. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. Cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Mitochondrial disease v0.1081 MRPS36 Krithika Murali changed review comment from: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis and cardiomyopathy.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature; to: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis.
Cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Mitochondrial disease v0.1081 MRPS36 Krithika Murali changed review comment from: 3 individuals with 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis and cardiomyopathy.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature; to: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis and cardiomyopathy.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Mitochondrial disease v0.1081 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Mitochondrial disease v0.1081 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1080 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Mitochondrial disease v0.1080 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1079 MRPS36 Krithika Murali Marked gene: MRPS36 as ready
Mitochondrial disease v0.1079 MRPS36 Krithika Murali Gene: mrps36 has been classified as Red List (Low Evidence).
Mitochondrial disease v0.1079 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals with 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis and cardiomyopathy.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.157 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.157 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.156 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.156 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3301 CPD Sarah Milton changed review comment from: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature; to: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to assist in function of the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Dilated Cardiomyopathy v1.46 JPH2 Zornitza Stark Classified gene: JPH2 as Green List (high evidence)
Dilated Cardiomyopathy v1.46 JPH2 Zornitza Stark Gene: jph2 has been classified as Green List (High Evidence).
Dilated Cardiomyopathy v1.45 JPH2 Zornitza Stark edited their review of gene: JPH2: Added comment: STRONG by ClinGen.; Changed rating: GREEN
Mendeliome v1.3301 JPH2 Zornitza Stark Classified gene: JPH2 as Green List (high evidence)
Mendeliome v1.3301 JPH2 Zornitza Stark Gene: jph2 has been classified as Green List (High Evidence).
Mendeliome v1.3300 CPD Zornitza Stark Marked gene: CPD as ready
Mendeliome v1.3300 CPD Zornitza Stark Gene: cpd has been classified as Green List (High Evidence).
Mendeliome v1.3300 CPD Zornitza Stark Classified gene: CPD as Green List (high evidence)
Mendeliome v1.3300 CPD Zornitza Stark Gene: cpd has been classified as Green List (High Evidence).
Congenital Heart Defect v0.463 DMRT2 Zornitza Stark Marked gene: DMRT2 as ready
Congenital Heart Defect v0.463 DMRT2 Zornitza Stark Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.463 DMRT2 Zornitza Stark Classified gene: DMRT2 as Amber List (moderate evidence)
Congenital Heart Defect v0.463 DMRT2 Zornitza Stark Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3299 THAP4 Zornitza Stark Marked gene: THAP4 as ready
Mendeliome v1.3299 THAP4 Zornitza Stark Gene: thap4 has been classified as Red List (Low Evidence).
Mendeliome v1.3299 THAP4 Zornitza Stark gene: THAP4 was added
gene: THAP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THAP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THAP4 were set to 40949908
Phenotypes for gene: THAP4 were set to Congenital pulmonary airway malformation, MONDO:0016580, THAP4-related
Review for gene: THAP4 was set to RED
Added comment: Single individual with a missense variant reported in a CPAM cohort.
Sources: Literature
Fetal anomalies v1.433 THAP4 Zornitza Stark Marked gene: THAP4 as ready
Fetal anomalies v1.433 THAP4 Zornitza Stark Gene: thap4 has been classified as Red List (Low Evidence).
Fetal anomalies v1.433 THAP4 Zornitza Stark gene: THAP4 was added
gene: THAP4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: THAP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THAP4 were set to 40949908
Phenotypes for gene: THAP4 were set to Congenital pulmonary airway malformation, MONDO:0016580, THAP4-related
Review for gene: THAP4 was set to RED
Added comment: Single individual reported with missense variant in a CPAM cohort.
Sources: Literature
Mendeliome v1.3298 ALDH1B1 Zornitza Stark Marked gene: ALDH1B1 as ready
Mendeliome v1.3298 ALDH1B1 Zornitza Stark Gene: aldh1b1 has been classified as Red List (Low Evidence).
Mendeliome v1.3298 ALDH1B1 Zornitza Stark gene: ALDH1B1 was added
gene: ALDH1B1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALDH1B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALDH1B1 were set to 40988636
Phenotypes for gene: ALDH1B1 were set to Congenital pulmonary airway malformation, MONDO:0016580, ALDH1B1-related
Review for gene: ALDH1B1 was set to RED
Added comment: Single individual with missense variant reported in a CPAM cohort.
Sources: Literature
Fetal anomalies v1.432 ALDH1B1 Zornitza Stark Marked gene: ALDH1B1 as ready
Fetal anomalies v1.432 ALDH1B1 Zornitza Stark Gene: aldh1b1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.432 ALDH1B1 Zornitza Stark gene: ALDH1B1 was added
gene: ALDH1B1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ALDH1B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALDH1B1 were set to 40988636
Phenotypes for gene: ALDH1B1 were set to Congenital pulmonary airway malformation, MONDO:0016580, ALDH1B1-related
Review for gene: ALDH1B1 was set to RED
Added comment: Missense variant reported in a CPAM cohort.
Sources: Literature
Mendeliome v1.3297 MUC3A Zornitza Stark Marked gene: MUC3A as ready
Mendeliome v1.3297 MUC3A Zornitza Stark Gene: muc3a has been classified as Red List (Low Evidence).
Mendeliome v1.3297 MUC3A Zornitza Stark gene: MUC3A was added
gene: MUC3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MUC3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MUC3A were set to 40949908
Phenotypes for gene: MUC3A were set to Congenital pulmonary airway malformation, MONDO:0016580, MUC3A-related
Review for gene: MUC3A was set to RED
Added comment: Three individuals with LoF variants identified in a CPAM cohort. However, all three variants are present in gnomAD, one of them in over 1500 individuals.
Sources: Literature
Fetal anomalies v1.431 MUC3A Zornitza Stark Publications for gene: MUC3A were set to
Fetal anomalies v1.430 MUC3A Zornitza Stark edited their review of gene: MUC3A: Changed publications: 40949908
Mendeliome v1.3296 GTF2I Zornitza Stark Marked gene: GTF2I as ready
Mendeliome v1.3296 GTF2I Zornitza Stark Gene: gtf2i has been classified as Green List (High Evidence).
Fetal anomalies v1.430 MUC3A Zornitza Stark Marked gene: MUC3A as ready
Fetal anomalies v1.430 MUC3A Zornitza Stark Gene: muc3a has been classified as Red List (Low Evidence).
Fetal anomalies v1.430 MUC3A Zornitza Stark gene: MUC3A was added
gene: MUC3A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MUC3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MUC3A were set to Congenital pulmonary airway malformation, MONDO:0016580, MUC3A-related
Review for gene: MUC3A was set to RED
Added comment: Three individuals with LoF variants identified in a CPAM cohort. However, all three variants are present in gnomAD, one of them in over 1500 individuals.
Sources: Literature
Fetal anomalies v1.429 DMRT2 Krithika Murali Classified gene: DMRT2 as Green List (high evidence)
Fetal anomalies v1.429 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.333 DMRT2 Krithika Murali Classified gene: DMRT2 as Green List (high evidence)
Skeletal dysplasia v0.333 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.332 DMRT2 Krithika Murali edited their review of gene: DMRT2: Added comment: PMID: 29681102 Bouman et al 2018 paper SH3PXD2B reviewed - not coding in canonical transcript, 4 homs in gnomAD v4. In summary, 2 unrelated individuals with severe skeletal dysplasia and other extra-skeletal features and one mouse model with severe skeletal dysplasia supporting Green classification.; Changed rating: GREEN
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.155 DMRT2 Krithika Murali Classified gene: DMRT2 as Green List (high evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.155 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Green List (High Evidence).
Skeletal Dysplasia_Fetal v0.237 DMRT2 Krithika Murali Classified gene: DMRT2 as Green List (high evidence)
Skeletal Dysplasia_Fetal v0.237 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Green List (High Evidence).
Skeletal Dysplasia_Fetal v0.236 DMRT2 Krithika Murali edited their review of gene: DMRT2: Added comment: PMID: 29681102 Bouman et al 2018 paper SH3PXD2B reviewed - not coding in canonical transcript, 4 homs in gnomAD v4. In summary, 2 unrelated individuals with severe skeletal dysplasia and other extra-skeletal features and one mouse model with severe skeletal dysplasia supporting Green classification.; Changed rating: GREEN
Mendeliome v1.3296 DMRT2 Krithika Murali edited their review of gene: DMRT2: Added comment: PMID: 29681102 Bouman et al 2018 paper SH3PXD2B reviewed - not coding in canonical transcript, 4 homs in gnomAD v4. In summary, 2 unrelated individuals with severe skeletal dysplasia and other extra-skeletal features and one mouse model with severe skeletal dysplasia supporting Green classification.; Changed rating: GREEN
Mendeliome v1.3296 DMRT2 Krithika Murali changed review comment from: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature; to: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature
Mendeliome v1.3296 DMRT2 Krithika Murali Classified gene: DMRT2 as Green List (high evidence)
Mendeliome v1.3296 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Green List (High Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.154 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.154 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.153 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.153 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.462 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Review for gene: DMRT2 was set to AMBER
Added comment: Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. Other overlapping features observed in the 2 reported patients include congenital heart defects and CAKUT.
Sources: Literature
Skeletal dysplasia v0.332 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Skeletal dysplasia v0.332 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.152 DMRT2 Krithika Murali Marked gene: DMRT2 as ready
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.152 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.462 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Added comment: Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. Other overlapping features observed in the 2 reported patients include congenital heart defects and CAKUT.
Sources: Literature
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.152 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Review for gene: DMRT2 was set to AMBER
Added comment: Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. Other overlapping features observed in the 2 reported patients include congenital heart defects and CAKUT (non-functioning kidney at birth and bilateral duplicated kidney).
Sources: Literature
Skeletal Dysplasia_Fetal v0.236 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Skeletal Dysplasia_Fetal v0.236 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Skeletal Dysplasia_Fetal v0.235 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Skeletal Dysplasia_Fetal v0.235 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Skeletal Dysplasia_Fetal v0.234 DMRT2 Krithika Murali Marked gene: DMRT2 as ready
Skeletal Dysplasia_Fetal v0.234 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Red List (Low Evidence).
Skeletal Dysplasia_Fetal v0.234 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Skeletal Dysplasia_Fetal. Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Review for gene: DMRT2 was set to AMBER
Added comment: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.
Sources: Literature
Skeletal dysplasia v0.331 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Skeletal dysplasia v0.331 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v0.330 DMRT2 Krithika Murali Marked gene: DMRT2 as ready
Skeletal dysplasia v0.330 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Red List (Low Evidence).
Skeletal dysplasia v0.330 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Review for gene: DMRT2 was set to AMBER
Added comment: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature
Fetal anomalies v1.428 DMRT2 Krithika Murali Marked gene: DMRT2 as ready
Fetal anomalies v1.428 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.428 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Fetal anomalies v1.428 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.427 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Review for gene: DMRT2 was set to AMBER
Added comment: Severe skeletal manifestations with respiratory insufficiency is the overlapping feature between the 2 unrelated patients reported and mouse model.

Prenatal features included severe polyhydramnios, increased nuchal translucency, IUGR, fetal skeletal dysplasia.
Sources: Literature
Mendeliome v1.3295 DMRT2 Krithika Murali changed review comment from: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Fran Ter Haar syndrome which is also known to have skeletal features. The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature; to: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature
Severe Combined Immunodeficiency v1.13 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Severe Combined Immunodeficiency v1.13 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Severe Combined Immunodeficiency v1.12 DMRT2 Krithika Murali Marked gene: DMRT2 as ready
Severe Combined Immunodeficiency v1.12 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Red List (Low Evidence).
Severe Combined Immunodeficiency v1.12 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Severe Combined Immunodeficiency (absent T present B cells). Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Review for gene: DMRT2 was set to AMBER
Added comment: Severe skeletal manifestations is the overlapping feature between the 2 unrelated patients reported and the mouse model. PMID: 41014130 report one of the patients also had absence of TRECs suggestive of SCID on NBS wtih thymic aplasia. Laboratory tests showed profound lyphopenia, near absence of CD3+ T cells, low CD8+ and CD4+ T cells, expansion of B-cells and NK cells with elevation of several immunoglobulins. Patient developed severe CMV pneumonitis and bacterial infections leading to death at 3 months of age.

Have included as Amber rather than Red for immunodeficiency given the rarity of cases overall for this skeletal dysplasia.
Sources: Literature
Mendeliome v1.3295 DMRT2 Krithika Murali Phenotypes for gene: DMRT2 were changed from skeletal dysplasia MONDO:0018230; DMRT2-related to skeletal dysplasia MONDO:0018230,DMRT2-related
Mendeliome v1.3294 DMRT2 Krithika Murali Marked gene: DMRT2 as ready
Mendeliome v1.3294 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3294 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Mendeliome v1.3294 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3293 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Review for gene: DMRT2 was set to AMBER
Added comment: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Fran Ter Haar syndrome which is also known to have skeletal features. The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature
Mendeliome v1.3292 GTF2I Zornitza Stark Classified gene: GTF2I as Green List (high evidence)
Mendeliome v1.3292 GTF2I Zornitza Stark Gene: gtf2i has been classified as Green List (High Evidence).
Mendeliome v1.3291 GTF2I Zornitza Stark gene: GTF2I was added
gene: GTF2I was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GTF2I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GTF2I were set to 40962490
Phenotypes for gene: GTF2I were set to Neurodevelopmental disorder MONDO:0700092, GTF2I-related
Review for gene: GTF2I was set to GREEN
Added comment: 7 individuals reported with de novo variants in this gene and a neurodevelopmental disorder. All but one of the variants are absent from gnomAD v4 (one het present for the indel variant).
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.334 GTF2I Zornitza Stark Phenotypes for gene: GTF2I were changed from to Neurodevelopmental disorder MONDO:0700092, GTF2I-related
Intellectual disability syndromic and non-syndromic v1.333 GTF2I Zornitza Stark Publications for gene: GTF2I were set to
Intellectual disability syndromic and non-syndromic v1.332 GTF2I Zornitza Stark Mode of inheritance for gene: GTF2I was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.331 GTF2I Zornitza Stark Classified gene: GTF2I as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.331 GTF2I Zornitza Stark Gene: gtf2i has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.330 GTF2I Zornitza Stark edited their review of gene: GTF2I: Added comment: 7 individuals reported with de novo variants in this gene and a neurodevelopmental disorder. All but one of the variants are absent from gnomAD v4 (one het present for the indel variant).; Changed rating: GREEN; Changed publications: 40962490; Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, GTF2I-relatedder; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3290 BBOX1 Zornitza Stark Marked gene: BBOX1 as ready
Mendeliome v1.3290 BBOX1 Zornitza Stark Gene: bbox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3290 BBOX1 Zornitza Stark Classified gene: BBOX1 as Amber List (moderate evidence)
Mendeliome v1.3290 BBOX1 Zornitza Stark Gene: bbox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3289 BBOX1 Zornitza Stark gene: BBOX1 was added
gene: BBOX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BBOX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BBOX1 were set to 41022783
Phenotypes for gene: BBOX1 were set to Carnitine deficiency, MONDO:0017716, BBOX1-related
Review for gene: BBOX1 was set to AMBER
Added comment: Three individuals from two unrelated families reported, presenting with myopathy, neurodevelopmental delay, and later-onset psychiatric manifestations. C. elegans knockout and patient-variant models show embryonic lethality rescued by L‑carnitine supplementation
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v1.102 BBOX1 Zornitza Stark Marked gene: BBOX1 as ready
Muscular dystrophy and myopathy_Paediatric v1.102 BBOX1 Zornitza Stark Gene: bbox1 has been classified as Amber List (Moderate Evidence).
Muscular dystrophy and myopathy_Paediatric v1.102 BBOX1 Zornitza Stark Classified gene: BBOX1 as Amber List (moderate evidence)
Muscular dystrophy and myopathy_Paediatric v1.102 BBOX1 Zornitza Stark Gene: bbox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3288 CPD Sarah Milton changed review comment from: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature; to: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v1.101 BBOX1 Zornitza Stark gene: BBOX1 was added
gene: BBOX1 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: BBOX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BBOX1 were set to 41022783
Phenotypes for gene: BBOX1 were set to Carnitine deficiency, MONDO:0017716, BBOX1-related
Review for gene: BBOX1 was set to AMBER
Added comment: Three individuals from two unrelated families reported, presenting with myopathy, neurodevelopmental delay, and later-onset psychiatric manifestations. C. elegans knockout and patient-variant models show embryonic lethality rescued by L‑carnitine supplementation
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.330 BBOX1 Zornitza Stark Marked gene: BBOX1 as ready
Intellectual disability syndromic and non-syndromic v1.330 BBOX1 Zornitza Stark Gene: bbox1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.330 BBOX1 Zornitza Stark Classified gene: BBOX1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.330 BBOX1 Zornitza Stark Gene: bbox1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.329 BBOX1 Zornitza Stark gene: BBOX1 was added
gene: BBOX1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: BBOX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BBOX1 were set to 41022783
Phenotypes for gene: BBOX1 were set to Carnitine deficiency, MONDO:0017716, BBOX1-related
Review for gene: BBOX1 was set to AMBER
Added comment: Three individuals from two unrelated families reported, presenting with myopathy, neurodevelopmental delay, and later-onset psychiatric manifestations. C. elegans knockout and patient-variant models show embryonic lethality rescued by L‑carnitine supplementation
Sources: Literature
Genetic Epilepsy v1.232 NDUFAF8 Elena Savva Classified gene: NDUFAF8 as Amber List (moderate evidence)
Genetic Epilepsy v1.232 NDUFAF8 Elena Savva Gene: ndufaf8 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.231 NDUFAF8 Elena Savva Classified gene: NDUFAF8 as Amber List (moderate evidence)
Genetic Epilepsy v1.231 NDUFAF8 Elena Savva Gene: ndufaf8 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.230 NDUFAF8 Elena Savva Marked gene: NDUFAF8 as ready
Genetic Epilepsy v1.230 NDUFAF8 Elena Savva Gene: ndufaf8 has been removed from the panel.
Genetic Epilepsy v1.230 NDUFAF8 Anissa Johnson gene: NDUFAF8 was added
gene: NDUFAF8 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NDUFAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF8 were set to PMID: 31866046; https://doi.org/10.1212/WNL.000000000021206
Phenotypes for gene: NDUFAF8 were set to Mitochondrial complex I deficiency, nuclear type 34, MIM#618776; Leigh Syndrome MONDO:0009723
Review for gene: NDUFAF8 was set to AMBER
Added comment: - Alston 2020: Reported 1 child (subject 1) with Leigh syndrome, who had hypsarrythmic electroencephalogram (EEG) and "regular fleeting seizures". They were compound heterozygous for c.45_52dup (p.Phe18Serfs*32) and c.195+271C>T (p.?), both inherited.
- Sharma 2025: Abstract only. Aims to evaluate the presentation of infantile epileptic spasms syndrome (IESS) in primary mitochondrial disease (PMD). Mentions a single case of NDUFAF8 but specific patient information was not provided.
- 1 VCGS internal patient who was homozygous for the deep intronic variant, c.195+271C>T, who presented with focal onset seizures and ID, who was also heterozygous for a likely pathogenic variant in SCN8A (paternally inherited).
Sources: Literature
Mendeliome v1.3288 CPD Sarah Milton gene: CPD was added
gene: CPD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CPD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPD were set to PMID: 41026541
Phenotypes for gene: CPD were set to Nonsyndromic genetic hearing loss, MONDO:0019497, CPD-related
Review for gene: CPD was set to GREEN
Added comment: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Mendeliome v1.3288 JPH2 Melanie Marty reviewed gene: JPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30384889, 31227780, 32870709, 35838873, 32879264, 34036930, 23715556, 29540472, 35288587, 37461109, 30847666, 27471098, 23715556; Phenotypes: Cardiomyopathy, hypertrophic, MIM#613873, Cardiomyopathy, dilated, 2E, MIM# 619492; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paroxysmal Dyskinesia v0.143 PDHA1 Zornitza Stark Mode of inheritance for gene: PDHA1 was changed from Other to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Skeletal dysplasia v0.329 LEMD2 Bryony Thompson Classified gene: LEMD2 as Green List (high evidence)
Skeletal dysplasia v0.329 LEMD2 Bryony Thompson Gene: lemd2 has been classified as Green List (High Evidence).
Mendeliome v1.3288 LEMD2 Bryony Thompson Classified gene: LEMD2 as Green List (high evidence)
Mendeliome v1.3288 LEMD2 Bryony Thompson Added comment: Comment on list classification: Biallelic cataract/cardiomyopathy association Amber & Monoallelic recurrent de novo progeroid syndrome association Green.
Mendeliome v1.3288 LEMD2 Bryony Thompson Gene: lemd2 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.328 LEMD2 Bryony Thompson gene: LEMD2 was added
gene: LEMD2 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: LEMD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LEMD2 were set to 38757373; 37867468; 30905398
Phenotypes for gene: LEMD2 were set to Marbach-Rustad progeroid syndrome MONDO:0859147
Review for gene: LEMD2 was set to GREEN
Added comment: 4 unrelated cases with the recurrent de novo missense variant (c.1436C>Tp.Ser479Phe) and a progeroid syndrome phenotype. In vitro functional assays demonstrate abnormalities in the structure of the nuclear envelope in the tested tissues.
Sources: Literature
Mendeliome v1.3287 LEMD2 Bryony Thompson reviewed gene: LEMD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38757373, 37867468, 30905398; Phenotypes: Marbach-Rustad progeroid syndrome MONDO:0859147; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arrhythmogenic Cardiomyopathy v0.71 LEMD2 Bryony Thompson Mode of inheritance for gene: LEMD2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Hereditary Spastic Paraplegia v1.96 INPP4A Zornitza Stark Marked gene: INPP4A as ready
Hereditary Spastic Paraplegia v1.96 INPP4A Zornitza Stark Gene: inpp4a has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia v1.96 INPP4A Zornitza Stark Phenotypes for gene: INPP4A were changed from INPP4A-related neurodevelopmental disorder to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Hereditary Spastic Paraplegia v1.95 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v1.328 INPP4A Zornitza Stark Phenotypes for gene: INPP4A were changed from Intellectual disability to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Intellectual disability syndromic and non-syndromic v1.327 INPP4A Zornitza Stark Publications for gene: INPP4A were set to 31978615; 31938306; 25338135; 20011524
Intellectual disability syndromic and non-syndromic v1.326 INPP4A Zornitza Stark edited their review of gene: INPP4A: Changed phenotypes: Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Genetic Epilepsy v1.230 INPP4A Zornitza Stark Marked gene: INPP4A as ready
Genetic Epilepsy v1.230 INPP4A Zornitza Stark Gene: inpp4a has been classified as Green List (High Evidence).
Genetic Epilepsy v1.230 INPP4A Zornitza Stark Phenotypes for gene: INPP4A were changed from INPP4A-related neurodevelopmental disorder to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Genetic Epilepsy v1.229 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354; Mode of inheritance: None
Muscular dystrophy and myopathy_Paediatric v1.100 INPP4A Zornitza Stark Marked gene: INPP4A as ready
Muscular dystrophy and myopathy_Paediatric v1.100 INPP4A Zornitza Stark Gene: inpp4a has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.100 INPP4A Zornitza Stark Phenotypes for gene: INPP4A were changed from INPP4A-related neurodevelopmental disorder to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Muscular dystrophy and myopathy_Paediatric v1.99 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354; Mode of inheritance: None
Microcephaly v1.342 INPP4A Zornitza Stark Marked gene: INPP4A as ready
Microcephaly v1.342 INPP4A Zornitza Stark Gene: inpp4a has been classified as Green List (High Evidence).
Microcephaly v1.342 INPP4A Zornitza Stark Phenotypes for gene: INPP4A were changed from INPP4A-related neurodevelopmental disorder to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Microcephaly v1.341 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354; Mode of inheritance: None
Mendeliome v1.3287 INPP4A Zornitza Stark Publications for gene: INPP4A were set to 31978615; 31938306; 25338135; 20011524
Mendeliome v1.3286 INPP4A Zornitza Stark Phenotypes for gene: INPP4A were changed from Intellectual disability to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Mendeliome v1.3285 INPP4A Zornitza Stark edited their review of gene: INPP4A: Changed phenotypes: Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Cerebellar and Pontocerebellar Hypoplasia v1.90 INPP4A Zornitza Stark Marked gene: INPP4A as ready
Cerebellar and Pontocerebellar Hypoplasia v1.90 INPP4A Zornitza Stark Gene: inpp4a has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.90 INPP4A Zornitza Stark Phenotypes for gene: INPP4A were changed from INPP4A-related neurodevelopmental disorder to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Cerebellar and Pontocerebellar Hypoplasia v1.89 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354; Mode of inheritance: None
Autoinflammatory Disorders v2.24 PLD4 Zornitza Stark Phenotypes for gene: PLD4 were changed from Systemic lupus erythematosus - MONDO:0007915, PLD4-related to Systemic lupus erythematosus 18, MIM# 621369
Autoinflammatory Disorders v2.23 PLD4 Zornitza Stark reviewed gene: PLD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Systemic lupus erythematosus 18, MIM# 621369; Mode of inheritance: None
Mendeliome v1.3285 PLD4 Zornitza Stark Phenotypes for gene: PLD4 were changed from Systemic lupus erythematosus - MONDO:0007915, PLD4-related to Systemic lupus erythematosus 18, MIM# 621369
Mendeliome v1.3284 PLD4 Zornitza Stark reviewed gene: PLD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Systemic lupus erythematosus 18, MIM# 621369; Mode of inheritance: None
Vasculitis v0.92 PLD4 Zornitza Stark Phenotypes for gene: PLD4 were changed from Systemic lupus erythematosus - MONDO:0007915, PLD4-related to Systemic lupus erythematosus 18, MIM# 621369
Vasculitis v0.91 PLD4 Zornitza Stark reviewed gene: PLD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Systemic lupus erythematosus 18, MIM# 621369; Mode of inheritance: None
Mendeliome v1.3284 IL17RD Bryony Thompson Classified gene: IL17RD as Red List (low evidence)
Mendeliome v1.3284 IL17RD Bryony Thompson Gene: il17rd has been classified as Red List (Low Evidence).
Differences of Sex Development v1.20 IL17RD Bryony Thompson Classified gene: IL17RD as Red List (low evidence)
Differences of Sex Development v1.20 IL17RD Bryony Thompson Gene: il17rd has been classified as Red List (Low Evidence).
Cerebral Palsy v1.392 FBXO31 Bryony Thompson Publications for gene: FBXO31 were set to PMID: 32989326
Mendeliome v1.3283 RHOBTB2 Lucy Spencer reviewed gene: RHOBTB2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Complex neurodevelopmental disorder MONDO:0100038, RHOBTB2-related; Mode of inheritance: None
Mendeliome v1.3283 RHOB Lucy Spencer edited their review of gene: RHOB: Changed phenotypes: Cerebral palsy MONDO:0006497, RHOB-related
Mendeliome v1.3283 RHOB Lucy Spencer changed review comment from: Adding a MONDO term cerebral palsy MONDO:000649, RHOB-related; to: Adding a MONDO term cerebral palsy MONDO:0006497, RHOB-related
Mendeliome v1.3283 RHOB Lucy Spencer reviewed gene: RHOB: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral palsy MONDO:000649, RHOB-related; Mode of inheritance: None
Mendeliome v1.3283 RHBDF2 Lucy Spencer reviewed gene: RHBDF2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency disease MONDO:0021094, RHBDF2-related; Mode of inheritance: None
Mendeliome v1.3283 RHBDF1 Lucy Spencer reviewed gene: RHBDF1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Dilated cardiomyopathy MONDO:0005021, RHBDF1-related; Mode of inheritance: None
Mendeliome v1.3283 RGS9BP Lucy Spencer reviewed gene: RGS9BP: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Prolonged electroretinal response suppression 2 MIM#620344; Mode of inheritance: None
Mendeliome v1.3283 RGS9 Lucy Spencer reviewed gene: RGS9: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Prolonged electroretinal response suppression 1 MIM#608415; Mode of inheritance: None
Mendeliome v1.3283 RGS10 Lucy Spencer reviewed gene: RGS10: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency disease MONDO:0021094, RGS10-related; Mode of inheritance: None
Mendeliome v1.3283 RFXAP Lucy Spencer reviewed gene: RFXAP: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: MHC class II deficiency 4 MIM#620817; Mode of inheritance: None
Mendeliome v1.3283 RFX5 Lucy Spencer reviewed gene: RFX5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: MHC class II deficiency 5 MIM#620818, MHC class II deficiency 3 MIM#620816; Mode of inheritance: None
Mendeliome v1.3283 REV3L Lucy Spencer reviewed gene: REV3L: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Mobius syndrome MONDO:0008006, REV3L-related; Mode of inheritance: None
Mendeliome v1.3283 REN Lucy Spencer reviewed gene: REN: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Tubulointerstitial kidney disease, autosomal dominant, 4 MIM#613092; Mode of inheritance: None
Mendeliome v1.3283 RELA Lucy Spencer reviewed gene: RELA: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory disease, familial, Behcet-like-3 MIM#618287; Mode of inheritance: None
Mendeliome v1.3283 REEP2 Lucy Spencer reviewed gene: REEP2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 72B, autosomal recessive MIM#620606, Spastic paraplegia 72A, autosomal dominant MIM#615625; Mode of inheritance: None
Mendeliome v1.3283 RECQL4 Lucy Spencer reviewed gene: RECQL4: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RECON progeroid syndrome MONDO:0957266, RECQL4-related; Mode of inheritance: None
Mendeliome v1.3283 RECQL Lucy Spencer reviewed gene: RECQL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RECON progeroid syndrome MIM#620370; Mode of inheritance: None
Mendeliome v1.3283 RDH12 Lucy Spencer reviewed gene: RDH12: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RDH12-related recessive retinopathy MONDO:0800099, RDH12-related dominant retinopathy MONDO:0800100; Mode of inheritance: None
Mendeliome v1.3283 RCAN1 Lucy Spencer reviewed gene: RCAN1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Focal segmental glomerulosclerosis MONDO:0100313, RCAN1-related; Mode of inheritance: None
Mendeliome v1.3283 RC3H1 Lucy Spencer reviewed gene: RC3H1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immune dysregulation and systemic hyperinflammation syndrome MIM#618998, Inborn error of immunity, MONDO:0003778, RC3H1-related; Mode of inheritance: None
Mendeliome v1.3283 RBM7 Lucy Spencer reviewed gene: RBM7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy MONDO:0001516, RBM7-related; Mode of inheritance: None
Mendeliome v1.3283 REC8 Lucy Spencer reviewed gene: REC8: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian failure MONDO:0005387, REC8-related; Mode of inheritance: None
Clefting disorders v0.276 DLG1 Zornitza Stark Marked gene: DLG1 as ready
Clefting disorders v0.276 DLG1 Zornitza Stark Gene: dlg1 has been classified as Red List (Low Evidence).
Clefting disorders v0.276 DLG1 Zornitza Stark Mode of inheritance for gene: DLG1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3283 BCL11B Zornitza Stark Publications for gene: BCL11B were set to 29985992
Genetic Epilepsy v1.229 ADGRV1 Zornitza Stark Phenotypes for gene: ADGRV1 were changed from Myoclonic epilepsy; febrile seizures; epilepsy; Rolandic epilepsy to Epilepsy, MONDO:0005027, ADGRV1-related
Mendeliome v1.3282 ADGRV1 Zornitza Stark Phenotypes for gene: ADGRV1 were changed from Febrile seizures, familial, 4 MIM#604352; Usher syndrome, type 2C MIM#60547; Usher syndrome, type 2C, GPR98/PDZD7 digenic MIM#605472 to Epilepsy, MONDO:0005027, ADGRV1-related; Usher syndrome, type 2C MIM#60547; Usher syndrome, type 2C, GPR98/PDZD7 digenic MIM#605472
Mendeliome v1.3281 ADGRV1 Zornitza Stark Publications for gene: ADGRV1 were set to 22147658, 25572244, 14740321
Mendeliome v1.3280 ADGRV1 Zornitza Stark Mode of inheritance for gene: ADGRV1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3279 ADGRV1 Zornitza Stark reviewed gene: ADGRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29266188, 29261713, 32962041, 34160719, 40673693, 40217298, 36399868, 34744978; Phenotypes: Epilepsy, MONDO:0005027, ADGRV1-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v1.228 ADGRV1 Zornitza Stark Mode of inheritance for gene: ADGRV1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v1.227 ADGRV1 Zornitza Stark changed review comment from: PMID 40673693: individual with de novo variant and sleep-related hyper motor epilepsy.
PMID 40217298: individual with de novo variant and ictal asystole.
PMID 36399868: enrichment of rare variants, predicted as LP by in-silico tools in an epilepsy cohort.
PMID 34744978: enrichment of rare variants in a Sudanese epilepsy cohort, one individual with homozygous variant was more severely affected.

AMBER for bi-alleic association with epilepsy.; to: PMID 40673693: individual with de novo variant and sleep-related hyper motor epilepsy.
PMID 40217298: individual with de novo variant and ictal asystole.
PMID 36399868: enrichment of rare variants, predicted as LP by in-silico tools in an epilepsy cohort.
PMID 34744978: enrichment of rare variants in a Sudanese epilepsy cohort, one individual with homozygous variant was more severely affected.

AMBER for bi-allelic association with epilepsy.
Genetic Epilepsy v1.227 ADGRV1 Zornitza Stark edited their review of gene: ADGRV1: Added comment: PMID 40673693: individual with de novo variant and sleep-related hyper motor epilepsy.
PMID 40217298: individual with de novo variant and ictal asystole.
PMID 36399868: enrichment of rare variants, predicted as LP by in-silico tools in an epilepsy cohort.
PMID 34744978: enrichment of rare variants in a Sudanese epilepsy cohort, one individual with homozygous variant was more severely affected.

AMBER for bi-alleic association with epilepsy.; Changed publications: 29266188, 29261713, 32962041, 34160719, 40673693, 40217298, 36399868, 34744978
Prepair 1000+ v2.14 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Joubert syndrome 27, MIM# 617120; Meckel syndrome 9, MIM# 614209 to Ciliopathy, MONDO:0005308, B9D1-related
Prepair 1000+ v2.13 B9D1 Zornitza Stark reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliopathy, MONDO:0005308, B9D1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.426 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Meckel syndrome 9, OMIM:614209; Joubert syndrome 27, MONDO:0014927 to Ciliopathy, MONDO:0005308, B9D1-related
Fetal anomalies v1.425 B9D1 Zornitza Stark edited their review of gene: B9D1: Changed phenotypes: Ciliopathy, MONDO:0005308, B9D1-related
Skeletal dysplasia v0.327 B9D1 Zornitza Stark Marked gene: B9D1 as ready
Skeletal dysplasia v0.327 B9D1 Zornitza Stark Gene: b9d1 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.327 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Meckel syndrome 9 614209 to Ciliopathy, MONDO:0005308, B9D1-related
Skeletal dysplasia v0.326 B9D1 Zornitza Stark Publications for gene: B9D1 were set to 21493627; 24886560
Skeletal dysplasia v0.325 B9D1 Zornitza Stark Classified gene: B9D1 as Green List (high evidence)
Skeletal dysplasia v0.325 B9D1 Zornitza Stark Gene: b9d1 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.324 B9D1 Zornitza Stark edited their review of gene: B9D1: Added comment: Lumped by ClinGen. Additional cases reported.; Changed rating: GREEN; Changed publications: 24886560, 21493627, 25920555, 40565534, 40933483; Changed phenotypes: Ciliopathy, MONDO:0005308, B9D1-related
Intellectual disability syndromic and non-syndromic v1.326 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Joubert syndrome 27, MIM#617120; Meckel syndrome 9, MIM#614209 to Ciliopathy, MONDO:0005308, B9D1-related
Intellectual disability syndromic and non-syndromic v1.325 B9D1 Zornitza Stark Publications for gene: B9D1 were set to 24886560; 21493627
Intellectual disability syndromic and non-syndromic v1.324 B9D1 Zornitza Stark Classified gene: B9D1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.324 B9D1 Zornitza Stark Gene: b9d1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.323 B9D1 Zornitza Stark edited their review of gene: B9D1: Added comment: Lumped by ClinGen. Additional individuals reported, promote to Green.; Changed publications: 24886560, 21493627, 40565534, 40933483; Changed phenotypes: Ciliopathy, MONDO:0005308, B9D1-related
Polydactyly v0.294 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Joubert syndrome 27, MIM#617120; Meckel syndrome 9, MIM#614209 to Ciliopathy, MONDO:0005308, B9D1-related
Polydactyly v0.293 B9D1 Zornitza Stark Publications for gene: B9D1 were set to 24886560; 21493627; 25920555
Polydactyly v0.292 B9D1 Zornitza Stark Classified gene: B9D1 as Green List (high evidence)
Polydactyly v0.292 B9D1 Zornitza Stark Gene: b9d1 has been classified as Green List (High Evidence).
Polydactyly v0.291 B9D1 Zornitza Stark edited their review of gene: B9D1: Added comment: Lumped by ClinGen. Additional cases reported, including some with polydactyly.; Changed rating: GREEN; Changed publications: 24886560, 21493627, 40565534, 40933483; Changed phenotypes: Ciliopathy, MONDO:0005308, B9D1-related
Renal Ciliopathies and Nephronophthisis v1.40 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Meckel syndrome 9, OMIM #614209; Joubert syndrome 27, OMIM #617120 to Ciliopathy, MONDO:0005308, B9D1-related
Renal Ciliopathies and Nephronophthisis v1.39 B9D1 Zornitza Stark Publications for gene: B9D1 were set to
Renal Ciliopathies and Nephronophthisis v1.38 B9D1 Zornitza Stark Classified gene: B9D1 as Green List (high evidence)
Renal Ciliopathies and Nephronophthisis v1.38 B9D1 Zornitza Stark Gene: b9d1 has been classified as Green List (High Evidence).
Renal Ciliopathies and Nephronophthisis v1.37 B9D1 Zornitza Stark edited their review of gene: B9D1: Added comment: Lumped by ClinGen. Additional families reported, upgrade to Green.; Changed rating: GREEN; Changed publications: 24886560, 21493627, 25920555, 40565534, 40933483; Changed phenotypes: Ciliopathy, MONDO:0005308, B9D1-related
Intellectual disability syndromic and non-syndromic v1.323 DNM1 Chirag Patel Source Genetic Health Queensland was removed from DNM1.
Source Literature was added to DNM1.
Publications for gene DNM1 were changed from 25262651; 27066543; 33372033; 34172529; 36553519; 37900685 to 25262651; 27066543; 33372033; 34172529; 36553519; 37900685
Mendeliome v1.3279 DNM1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM1.
Source Literature was added to DNM1.
Publications for gene DNM1 were changed from 25262651; 27066543; 33372033; 34172529; 36553519; 37900685 to 25262651; 27066543; 33372033; 34172529; 36553519; 37900685
Genetic Epilepsy v1.227 DNM1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM1.
Source Australian Genomics Health Alliance Epilepsy Flagship was removed from DNM1.
Source Victorian Clinical Genetics Services was removed from DNM1.
Source Literature was added to DNM1.
Publications for gene DNM1 were changed from 25262651; 27066543; 33372033; 34172529; 36553519; 37900685 to 25262651; 27066543; 33372033; 34172529; 36553519; 37900685
Joubert syndrome and other neurological ciliopathies v1.31 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Meckel syndrome 9, MIM# 614209; Joubert syndrome 27, MIM# 617120 to Ciliopathy, MONDO:0005308, B9D1-related
Joubert syndrome and other neurological ciliopathies v1.30 B9D1 Zornitza Stark Publications for gene: B9D1 were set to 24886560; 21493627; 25920555
Joubert syndrome and other neurological ciliopathies v1.29 B9D1 Zornitza Stark Classified gene: B9D1 as Green List (high evidence)
Joubert syndrome and other neurological ciliopathies v1.29 B9D1 Zornitza Stark Gene: b9d1 has been classified as Green List (High Evidence).
Ciliopathies v1.88 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Meckel syndrome 9, MIM# 614209; Joubert syndrome 27, MIM# 617120 to Ciliopathy, MONDO:0005308, B9D1-related
Ciliopathies v1.87 B9D1 Zornitza Stark Publications for gene: B9D1 were set to 24886560; 21493627; 25920555
Ciliopathies v1.86 B9D1 Zornitza Stark Classified gene: B9D1 as Green List (high evidence)
Ciliopathies v1.86 B9D1 Zornitza Stark Gene: b9d1 has been classified as Green List (High Evidence).
Mendeliome v1.3278 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Joubert syndrome 27, MIM#617120; Meckel syndrome 9, MIM#614209 to Ciliopathy, MONDO:0005308, B9D1-related
Mendeliome v1.3277 B9D1 Zornitza Stark Publications for gene: B9D1 were set to 24886560; 21493627; 25920555; 21763481; 34338422
Combined Immunodeficiency v1.133 RNF31 Zornitza Stark Publications for gene: RNF31 were set to 26008899; 30936877
Mendeliome v1.3276 RNF31 Zornitza Stark Publications for gene: RNF31 were set to 26008899; 30936877
Genetic Epilepsy v1.226 DNAJC5 Chirag Patel Phenotypes for gene: DNAJC5 were changed from adult neuronal ceroid lipofuscinosis (MONDO:0019260) to Ceroid lipofuscinosis, neuronal, 4 (Kufs type), MONDO:0008083
Mendeliome v1.3275 RNF31 Zornitza Stark Classified gene: RNF31 as Green List (high evidence)
Mendeliome v1.3275 RNF31 Zornitza Stark Gene: rnf31 has been classified as Green List (High Evidence).
Mendeliome v1.3274 RNF31 Zornitza Stark edited their review of gene: RNF31: Added comment: Two more families reported.; Changed rating: GREEN; Changed publications: 26008899, 30936877, 39009172, 41026334
Early-onset Dementia v1.44 DNAJC5 Chirag Patel Source Melbourne Genomics Health Alliance Complex Neurology Flagship was removed from DNAJC5.
Source Victorian Clinical Genetics Services was removed from DNAJC5.
Source Expert list was added to DNAJC5.
Mode of inheritance for gene DNAJC5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DNAJC5 were changed from to Ceroid lipofuscinosis, neuronal, 4 (Kufs type), MONDO:0008083
Publications for gene DNAJC5 were changed from 22978711; 21820099; 22235333; 31919451; 26659577 to 22978711; 21820099; 22235333; 31919451; 26659577
Mendeliome v1.3274 DNAJC5 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAJC5.
Source Expert list was added to DNAJC5.
Phenotypes for gene: DNAJC5 were changed from Ceroid lipofuscinosis, neuronal, 4 (Kufs type), autosomal dominant - MIM#162350; ceroid lipofuscinosis, neuronal, 4 (Kufs type) - MONDO:0008083 to Ceroid lipofuscinosis, neuronal, 4 (Kufs type), MONDO:0008083
Combined Immunodeficiency v1.132 RNF31 Zornitza Stark Classified gene: RNF31 as Green List (high evidence)
Combined Immunodeficiency v1.132 RNF31 Zornitza Stark Gene: rnf31 has been classified as Green List (High Evidence).
Combined Immunodeficiency v1.131 RNF31 Zornitza Stark edited their review of gene: RNF31: Added comment: Two more families reported.; Changed rating: GREEN; Changed publications: 26008899, 30936877, 39009172, 41026334
Progressive Myoclonic Epilepsy v0.22 DNAJC5 Chirag Patel Source Royal Melbourne Hospital was removed from DNAJC5.
Source Expert list was added to DNAJC5.
Phenotypes for gene: DNAJC5 were changed from autosomal dominant Kufs disease; generalized tonic clonic seizures; Ceroid lipofuscinosis, neuronal, 4, Parry type, 162350 to Ceroid lipofuscinosis, neuronal, 4 (Kufs type), MONDO:0008083
Autoinflammatory Disorders v2.23 RNF31 Zornitza Stark Publications for gene: RNF31 were set to 26008899; 30936877
Lysosomal Storage Disorder v1.23 DNAJC5 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAJC5.
Source Expert list was added to DNAJC5.
Phenotypes for gene: DNAJC5 were changed from Ceroid lipofuscinosis, neuronal, 4, Parry type, MIM# 162350; MONDO:0008083 to Ceroid lipofuscinosis, neuronal, 4 (Kufs type), MONDO:0008083
Early-onset Parkinson disease v2.40 DNAJC5 Chirag Patel Source Melbourne Genomics Health Alliance Complex Neurology Flagship was removed from DNAJC5.
Source Victorian Clinical Genetics Services was removed from DNAJC5.
Source Expert list was added to DNAJC5.
Phenotypes for gene: DNAJC5 were changed from Ceroid lipofuscinosis, neuronal, 4, Parry type, MIM# 162350 to Ceroid lipofuscinosis, neuronal, 4 (Kufs type), MONDO:0008083
Autoinflammatory Disorders v2.22 RNF31 Zornitza Stark Classified gene: RNF31 as Green List (high evidence)
Autoinflammatory Disorders v2.22 RNF31 Zornitza Stark Gene: rnf31 has been classified as Green List (High Evidence).
Fetal anomalies v1.425 RASA2 Zornitza Stark Phenotypes for gene: RASA2 were changed from Noonan syndrome to Noonan syndrome MONDO:0018997, RASA2-related
Fetal anomalies v1.424 RASA2 Zornitza Stark reviewed gene: RASA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome MONDO:0018997, RASA2-related; Mode of inheritance: None
Cardiomyopathy_Paediatric v0.203 RASA2 Zornitza Stark Marked gene: RASA2 as ready
Cardiomyopathy_Paediatric v0.203 RASA2 Zornitza Stark Gene: rasa2 has been classified as Amber List (Moderate Evidence).
Cardiomyopathy_Paediatric v0.203 RASA2 Zornitza Stark Phenotypes for gene: RASA2 were changed from Noonan syndrome? to Noonan syndrome MONDO:0018997, RASA2-related
Cardiomyopathy_Paediatric v0.202 RASA2 Zornitza Stark reviewed gene: RASA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome MONDO:0018997, RASA2-related; Mode of inheritance: None
Rasopathy v0.108 RASA2 Zornitza Stark Phenotypes for gene: RASA2 were changed from Rasopathy to Noonan syndrome MONDO:0018997, RASA2-related
Rasopathy v0.107 RASA2 Zornitza Stark reviewed gene: RASA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome MONDO:0018997, RASA2-related; Mode of inheritance: None
Mendeliome v1.3273 RASA2 Zornitza Stark Phenotypes for gene: RASA2 were changed from to Noonan syndrome MONDO:0018997, RASA2-related
Autism v0.217 DEAF1 Chirag Patel edited their review of gene: DEAF1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v1.225 DEAF1 Chirag Patel Phenotypes for gene: DEAF1 were changed from Dyskinesia, seizures, and intellectual developmental disorder 617171; autosomal dominant mental retardation 24, MIM# 615828 to Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171; Vulto-van Silfout-de Vries syndrome 615828
Autism v0.217 DEAF1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DEAF1.
Source Expert list was added to DEAF1.
Mode of inheritance for gene DEAF1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: DEAF1 were changed from to Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171; Vulto-van Silfout-de Vries syndrome 615828
Publications for gene DEAF1 were changed from 30923367, 24726472 to 30923367, 24726472
Kabuki syndrome v0.16 RAP1A Zornitza Stark Phenotypes for gene: RAP1A were changed from Kabuki syndrome to Kabuki syndrome MONDO:0016512, RAP1A-related
Autism v0.216 DEAF1 Chirag Patel reviewed gene: DEAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30923367, 24726472; Phenotypes: Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171, Vulto-van Silfout-de Vries syndrome 615828; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Kabuki syndrome v0.15 RAP1A Zornitza Stark edited their review of gene: RAP1A: Changed phenotypes: Kabuki syndrome MONDO:0016512, RAP1A-related
Mendeliome v1.3272 RAP1A Zornitza Stark Phenotypes for gene: RAP1A were changed from Kabuki syndrome to Kabuki syndrome MONDO:0016512, RAP1A-related
Mendeliome v1.3271 RAMP2 Zornitza Stark Phenotypes for gene: RAMP2 were changed from Primary open angle glaucoma to Open angle glaucoma MONDO:0005338, RAMP2-related
Intellectual disability syndromic and non-syndromic v1.322 RALGAPA1 Zornitza Stark Phenotypes for gene: RALGAPA1 were changed from Intellectual disability; hypotonia; infantile spasms. to Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation MIM#618797
Intellectual disability syndromic and non-syndromic v1.321 RALGAPA1 Zornitza Stark edited their review of gene: RALGAPA1: Changed phenotypes: Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation MIM#618797
Genetic Epilepsy v1.224 RALGAPA1 Zornitza Stark Phenotypes for gene: RALGAPA1 were changed from Intellectual disability; hypotonia; infantile spasms. to Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation MIM#618797
Genetic Epilepsy v1.223 RALGAPA1 Zornitza Stark edited their review of gene: RALGAPA1: Changed phenotypes: Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation MIM#618797
Intellectual disability syndromic and non-syndromic v1.321 DDB1 Chirag Patel Source Research was removed from DDB1.
Source Literature was added to DDB1.
Phenotypes for gene: DDB1 were changed from White-Kernohan syndrome, MIM# 619426; Syndromic intellectual disability to White-Kernohan syndrome, MIM# 619426
Mendeliome v1.3270 DDB1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDB1.
Source Literature was added to DDB1.
Phenotypes for gene: DDB1 were changed from White-Kernohan syndrome, MIM# 619426; Syndromic intellectual disability to White-Kernohan syndrome, MIM# 619426
Mendeliome v1.3270 RALGAPA1 Zornitza Stark Phenotypes for gene: RALGAPA1 were changed from Intellectual disability; hypotonia; infantile spasms. to Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation MIM#618797
Atypical Haemolytic Uraemic Syndrome_MPGN v0.54 C1GALT1C1 Michelle Torres reviewed gene: C1GALT1C1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 36599939, 37216524; Phenotypes: Hemolytic uremic syndrome, atypical, 8, with rhizomelic short stature, MIM#301110; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genomic newborn screening: BabyScreen+ v1.139 RAG2 Zornitza Stark Phenotypes for gene: RAG2 were changed from Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457; Combined cellular and humoral immune defects with granulomas MIM# 233650 to Recombinase activating gene 2 deficiency MONDO:0000573
Genomic newborn screening: BabyScreen+ v1.138 RAG2 Zornitza Stark edited their review of gene: RAG2: Changed phenotypes: Recombinase activating gene 2 deficiency MONDO:0000573
Combined Immunodeficiency v1.131 RAG2 Zornitza Stark Phenotypes for gene: RAG2 were changed from Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457; Combined cellular and humoral immune defects with granulomas MIM# 233650 to Recombinase activating gene 2 deficiency MONDO:0000573
Combined Immunodeficiency v1.130 RAG2 Zornitza Stark reviewed gene: RAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Recombinase activating gene 2 deficiency MONDO:0000573; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3269 RAG2 Zornitza Stark Phenotypes for gene: RAG2 were changed from Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457; Combined cellular and humoral immune defects with granulomas MIM# 233650 to Recombinase activating gene 2 deficiency MONDO:0000573
Genomic newborn screening: BabyScreen+ v1.138 RAG1 Zornitza Stark Phenotypes for gene: RAG1 were changed from Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity MIM# 609889; Combined cellular and humoral immune defects with granulomas MIM# 233650; Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457 to Recombinase activating gene 1 deficiency MONDO:0000572
Genomic newborn screening: BabyScreen+ v1.137 RAG1 Zornitza Stark edited their review of gene: RAG1: Changed phenotypes: Recombinase activating gene 1 deficiency MONDO:0000572
Combined Immunodeficiency v1.130 RAG1 Zornitza Stark Phenotypes for gene: RAG1 were changed from Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity MIM# 609889; Combined cellular and humoral immune defects with granulomas MIM# 233650; Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457 to Recombinase activating gene 1 deficiency MONDO:0000572
Combined Immunodeficiency v1.129 RAG1 Zornitza Stark reviewed gene: RAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Recombinase activating gene 1 deficiency MONDO:0000572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3268 RAG1 Zornitza Stark Phenotypes for gene: RAG1 were changed from Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity MIM# 609889; Combined cellular and humoral immune defects with granulomas MIM# 233650; Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457 to Recombinase activating gene 1 deficiency MONDO:0000572
Fetal anomalies v1.424 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48, MIM# 617751 to Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Fetal anomalies v1.423 RAC1 Zornitza Stark edited their review of gene: RAC1: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Intellectual disability syndromic and non-syndromic v1.320 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48, MIM# 617751 to Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Muscular dystrophy and myopathy_Paediatric v1.99 DNM2 Chirag Patel Source Other was removed from DNM2.
Phenotypes for gene: DNM2 were changed from Centronuclear Myopathy 1 (MIM#160150; MONDO:0008048) to Autosomal dominant centronuclear myopathy MONDO:0008048
Intellectual disability syndromic and non-syndromic v1.319 RAC1 Zornitza Stark edited their review of gene: RAC1: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Mendeliome v1.3267 DNM2 Chirag Patel Phenotypes for gene: DNM2 were changed from Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Centronuclear myopathy 1, MIM# 160150; Lethal congenital contracture syndrome 5, MIM# 615368 to Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Autosomal dominant centronuclear myopathy MONDO:0008048; Lethal congenital contracture syndrome 5, MIM# 615368
Microcephaly v1.341 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48, MIM# 617751 to Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Microcephaly v1.340 RAC1 Zornitza Stark edited their review of gene: RAC1: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Polymicrogyria and Schizencephaly v0.198 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48, MIM# 617751 to Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Polymicrogyria and Schizencephaly v0.197 RAC1 Zornitza Stark edited their review of gene: RAC1: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Mendeliome v1.3266 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48, MIM# 617751 to Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Cerebral Palsy v1.391 DNM2 Chirag Patel Phenotypes for gene: DNM2 were changed from Charcot-Marie-Tooth disease, axonal type 2M, MIM#606482 to Cerebral palsy MONDO:0006497
Mendeliome v1.3265 RABL2A Zornitza Stark Phenotypes for gene: RABL2A were changed from male infertility; ciliopathy to Infertility disorder, MONDO:0005047, RABL2A-related
Arthrogryposis v0.426 DNM2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM2.
Source Expert list was added to DNM2.
Phenotypes for gene: DNM2 were changed from to Lethal congenital contracture syndrome 5, MIM# 615368
Intellectual disability syndromic and non-syndromic v1.319 RAB14 Zornitza Stark Phenotypes for gene: RAB14 were changed from Developmental disorders to Neurodevelopmental disorder MONDO:0700092, RAB14-related
Intellectual disability syndromic and non-syndromic v1.318 RAB14 Zornitza Stark edited their review of gene: RAB14: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, RAB14-related
Mendeliome v1.3264 RAB14 Zornitza Stark Phenotypes for gene: RAB14 were changed from Developmental disorders to Neurodevelopmental disorder MONDO:0700092, RAB14-related
Fetal anomalies v1.423 PJA1 Zornitza Stark Phenotypes for gene: PJA1 were changed from Trigonocephaly, intellectual disability to X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148
Fetal anomalies v1.422 PJA1 Zornitza Stark reviewed gene: PJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v1.318 PJA1 Zornitza Stark Phenotypes for gene: PJA1 were changed from Intellectual disability; trigonocephaly to X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148
Intellectual disability syndromic and non-syndromic v1.317 PJA1 Zornitza Stark edited their review of gene: PJA1: Changed phenotypes: X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148
Mendeliome v1.3263 DNM2 Chirag Patel Phenotypes for gene: DNM2 were changed from Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Lethal congenital contracture syndrome 5, MIM# 615368 to Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Centronuclear myopathy 1, MIM# 160150; Lethal congenital contracture syndrome 5, MIM# 615368
Craniosynostosis v1.72 PJA1 Zornitza Stark Phenotypes for gene: PJA1 were changed from Intellectual disability; trigonocephaly to X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148
Craniosynostosis v1.71 PJA1 Zornitza Stark edited their review of gene: PJA1: Changed phenotypes: X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148
Mendeliome v1.3262 DNM2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM2.
Source Expert list was added to DNM2.
Phenotypes for gene: DNM2 were changed from Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674 to Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Lethal congenital contracture syndrome 5, MIM# 615368
Mendeliome v1.3261 PJA1 Zornitza Stark Phenotypes for gene: PJA1 were changed from Intellectual disability; trigonocephaly to X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148
Arthrogryposis v0.425 DNM2 Chirag Patel Classified gene: DNM2 as Red List (low evidence)
Arthrogryposis v0.425 DNM2 Chirag Patel Gene: dnm2 has been classified as Red List (Low Evidence).
Arthrogryposis v0.424 DNM2 Chirag Patel reviewed gene: DNM2: Rating: RED; Mode of pathogenicity: None; Publications: 23092955; Phenotypes: Lethal congenital contracture syndrome 5, MIM# 615368; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.422 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from Lissencephaly 4 (with microcephaly), MIM# 614019; MONDO:0013527; Microhydranencephaly, MIM# 605013; MONDO:0011504 to Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Fetal anomalies v1.421 NDE1 Zornitza Stark edited their review of gene: NDE1: Changed phenotypes: Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Intellectual disability syndromic and non-syndromic v1.317 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from Lissencephaly 4 (with microcephaly), MIM# 614019; MONDO:0013527; Microhydranencephaly, MIM# 605013; MONDO:0011504 to Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Intellectual disability syndromic and non-syndromic v1.316 NDE1 Zornitza Stark edited their review of gene: NDE1: Changed phenotypes: Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Genetic Epilepsy v1.223 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from Microhydranencephaly 605013; Lissencephaly 4 (with microcephaly) 614019 to Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Genetic Epilepsy v1.222 NDE1 Zornitza Stark edited their review of gene: NDE1: Changed rating: GREEN; Changed phenotypes: Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.340 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from Lissencephaly 4 (with microcephaly), MIM# 614019; MONDO:0013527; Microhydranencephaly, MIM# 605013; MONDO:0011504 to Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Skeletal dysplasia v0.324 DNMT3A Chirag Patel Publications for gene DNMT3A were changed from 24614070 to 24614070
Microcephaly v1.339 NDE1 Zornitza Stark edited their review of gene: NDE1: Changed phenotypes: Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Lissencephaly and Band Heterotopia v1.24 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116 to Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Lissencephaly and Band Heterotopia v1.24 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from Microhydranencephaly 605013; Lissencephaly 4 (with microcephaly) 614019 to Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Skeletal dysplasia v0.323 DNMT3A Chirag Patel Source Victorian Clinical Genetics Services was removed from DNMT3A.
Phenotypes for gene: DNMT3A were changed from Tatton-Brown-Rahman syndrome 615879 to Heyn-Sproul-Jackson syndrome, MIM# 618724
Lissencephaly and Band Heterotopia v1.23 NDE1 Zornitza Stark edited their review of gene: NDE1: Changed phenotypes: Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Mendeliome v1.3260 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from Microhydranencephaly 605013; Lissencephaly 4 (with microcephaly) 614019 to Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Skeletal dysplasia v0.322 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from Lethal congenital contracture syndrome 10, MIM# 617022; Skeletal dysplasia to NEK9-related lethal skeletal dysplasia MONDO:0014870
Skeletal dysplasia v0.321 NEK9 Zornitza Stark edited their review of gene: NEK9: Changed phenotypes: NEK9-related lethal skeletal dysplasia MONDO:0014870
Genetic Epilepsy v1.222 DALRD3 Chirag Patel Phenotypes for gene: DALRD3 were changed from Epileptic encephalopathy; Epileptic encephalopathy, early infantile, 86 618910 to Developmental and epileptic encephalopathy, 86 MONDO:0030054
Mendeliome v1.3259 DALRD3 Chirag Patel Phenotypes for gene: DALRD3 were changed from Epileptic encephalopathy; Epileptic encephalopathy, early infantile, 86 618910 to Developmental and epileptic encephalopathy, 86 MONDO:0030054
Mendeliome v1.3258 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262; Skeletal dysplasia to NEK9-related lethal skeletal dysplasia MONDO:0014870; Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262; Skeletal dysplasia
Mendeliome v1.3257 DMGDH Chirag Patel Source Victorian Clinical Genetics Services was removed from DMGDH.
Source Expert list was added to DMGDH.
Phenotypes for gene: DMGDH were changed from Dimethylglycine dehydrogenase deficiency MIM#605850; Disorders and variants of other enzymes that oxidise xenobiotics to Dimethylglycine dehydrogenase deficiency MIM#605850
Miscellaneous Metabolic Disorders v1.53 DMGDH Chirag Patel Phenotypes for gene: DMGDH were changed from Dimethylglycine dehydrogenase deficiency MIM#605850; Disorders and variants of other enzymes that oxidise xenobiotics to Dimethylglycine dehydrogenase deficiency MIM#605850
Mendeliome v1.3256 DMGDH Chirag Patel Classified gene: DMGDH as Red List (low evidence)
Mendeliome v1.3256 DMGDH Chirag Patel Gene: dmgdh has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.52 DMGDH Chirag Patel Classified gene: DMGDH as Red List (low evidence)
Miscellaneous Metabolic Disorders v1.52 DMGDH Chirag Patel Gene: dmgdh has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.51 DMGDH Chirag Patel reviewed gene: DMGDH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dimethylglycine dehydrogenase deficiency MONDO:0011610; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3255 DMGDH Chirag Patel reviewed gene: DMGDH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dimethylglycine dehydrogenase deficiency MONDO:0011610; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia v1.55 DAB1 Chirag Patel Source Literature was removed from DAB1.
Phenotypes for gene: DAB1 were changed from epilepsy; developmental delay; cerebellar ataxia; structural brain abnormalities; oral motor difficulty to Neurodevelopmental disorder, MONDO:0700092, DAB1-related
Genetic Epilepsy v1.221 DAB1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DAB1.
Phenotypes for gene: DAB1 were changed from epilepsy; developmental delay; cerebellar ataxia; structural brain abnormalities; oral motor difficulty to Neurodevelopmental disorder, MONDO:0700092, DAB1-related
Mendeliome v1.3255 DAB1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DAB1.
Phenotypes for gene: DAB1 were changed from Spinocerebellar ataxia 37 MIM#615945; Ataxia and intellectual disability to Spinocerebellar ataxia 37 MIM#615945; Neurodevelopmental disorder, MONDO:0700092, DAB1-related
Mendeliome v1.3254 DMC1 Chirag Patel Phenotypes for gene: DMC1 were changed from Primary ovarian failure, MONDO:0005387,; Azoospermia, MONDO:010045 to Primary ovarian failure, MONDO:0005387, Azoospermia, MONDO:0100459, DMC1-related
Publications for gene DMC1 were changed from 34794894, 18166824, 29331980, 9660954, 9660953 to 34794894, 18166824, 29331980, 9660954, 9660953
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.359 DMC1 Chirag Patel Publications for gene DMC1 were changed from 34794894, 18166824, 29331980, 9660954, 9660953 to 34794894, 18166824, 29331980, 9660954, 9660953
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.358 DMC1 Chirag Patel Phenotypes for gene: DMC1 were changed from Primary ovarian failure, MONDO:0005387,; Azoospermia, MONDO:010045 to Primary ovarian failure, MONDO:0005387, Azoospermia, MONDO:0100459, DMC1-related
Intellectual disability syndromic and non-syndromic v1.316 DNAJA1 Chirag Patel Phenotypes for gene: DNAJA1 were changed from Intellectual disability; seizures to Neurodevelopmental disorder, MONDO:0700092, DNAJA1-related
Mendeliome v1.3253 DNAJA1 Chirag Patel Phenotypes for gene: DNAJA1 were changed from Intellectual disability; seizures to Neurodevelopmental disorder, MONDO:0700092, DNAJA1-related
Fetal anomalies v1.421 DNAH6 Chirag Patel Classified gene: DNAH6 as Red List (low evidence)
Fetal anomalies v1.421 DNAH6 Chirag Patel Gene: dnah6 has been classified as Red List (Low Evidence).
Fetal anomalies v1.420 DNAH6 Chirag Patel reviewed gene: DNAH6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Heterotaxy v1.42 DNAH6 Chirag Patel Classified gene: DNAH6 as Red List (low evidence)
Heterotaxy v1.42 DNAH6 Chirag Patel Gene: dnah6 has been classified as Red List (Low Evidence).
Heterotaxy v1.41 DNAH6 Chirag Patel reviewed gene: DNAH6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ciliary Dyskinesia v1.56 DNAH6 Chirag Patel Phenotypes for gene: DNAH6 were changed from Heterotaxy, Azoospermia to Primary ciliary dyskinesia, MONDO:0016575
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.357 DMC1 Chirag Patel Classified gene: DMC1 as Green List (high evidence)
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.357 DMC1 Chirag Patel Gene: dmc1 has been classified as Green List (High Evidence).
Mendeliome v1.3252 DMC1 Chirag Patel Phenotypes for gene: DMC1 were changed from Primary ovarian insufficiency; non-obstructive azoospermia to Primary ovarian failure, MONDO:0005387,; Azoospermia, MONDO:010045
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.356 DMC1 Chirag Patel Phenotypes for gene: DMC1 were changed from Primary ovarian insufficiency; non-obstructive azoospermia to Primary ovarian failure, MONDO:0005387,; Azoospermia, MONDO:010045
Differences of Sex Development v1.18 DLK1 Chirag Patel Source Literature was removed from DLK1.
Source Expert list was added to DLK1.
Phenotypes for gene: DLK1 were changed from central precocious puberty to central precocious puberty, MONDO:0019165
Mendeliome v1.3251 DLK1 Chirag Patel Phenotypes for gene: DLK1 were changed from central precocious puberty to central precocious puberty, MONDO:0019165
Mendeliome v1.3250 DGCR8 Chirag Patel Phenotypes for gene: DGCR8 were changed from Schwannoma, MONDO:0002546 to Schwannoma, MONDO:0002546; Early-onset multinodular goiter and schwannomatosis, no MIM#
Mendeliome v1.3249 DGCR8 Chirag Patel reviewed gene: DGCR8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwannoma, MONDO:0002546, Early-onset multinodular goiter and schwannomatosis, no MIM#; Mode of inheritance: None
Mendeliome v1.3248 DGCR8 Chirag Patel Source Literature was removed from DGCR8.
Source Expert list was added to DGCR8.
Phenotypes for gene: DGCR8 were changed from Early-onset multinodular goiter and schwannomatosis to Schwannoma, MONDO:0002546
Mendeliome v1.3247 DHX34 Chirag Patel Phenotypes for gene: DHX34 were changed from Intellectual disability; congenital anomalies to Neurodevelopmental disorder, MONDO:0700092, DHX34-related
Clefting disorders v0.275 DLG1 Chirag Patel Phenotypes for gene: DLG1 were changed from Non-syndromic cleft lip with or without cleft palate to cleft lip/palate MONDO:0016044
Mendeliome v1.3245 DLG1 Chirag Patel Phenotypes for gene: DLG1 were changed from Non-syndromic cleft lip and palate to cleft lip/palate MONDO:0016044
Clefting disorders v0.274 DLG1 Chirag Patel reviewed gene: DLG1: Rating: RED; Mode of pathogenicity: None; Publications: 28926086; Phenotypes: Non-syndromic cleft lip and palate; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cataract v0.375 DNMBP Chirag Patel Phenotypes for gene: DNMBP were changed from congenital cataract to Cataract 48, MIM#618415
Mendeliome v1.3244 DNMBP Chirag Patel Phenotypes for gene: DNMBP were changed from congenital cataract to Cataract 48, MIM#618415
Mitochondrial disease v0.1078 DNA2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNA2.
Source Australian Genomics Health Alliance Mitochondrial Flagship was removed from DNA2.
Source Expert list was added to DNA2.
Mode of inheritance for gene DNA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3243 DNAJB11 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAJB11.
Source Expert list was added to DNAJB11.
Publications for gene DNAJB11 were changed from 29706351, 29777155, 32631624, 35664268, 32775842, 33129895, 34177435 to 29706351, 29777155, 32631624, 35664268, 32775842, 33129895, 34177435
Renal Macrocystic Disease v0.86 DNAJB11 Chirag Patel Mode of inheritance for gene DNAJB11 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Renal Macrocystic Disease v0.86 DNAJB11 Chirag Patel Mode of inheritance for gene DNAJB11 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Publications for gene DNAJB11 were changed from 29706351, 29777155, 32631624, 35664268, 32775842, 33129895, 34177435 to 29706351, 29777155, 32631624, 35664268, 32775842, 33129895, 34177435
Mendeliome v1.3242 ACTG1 Chirag Patel Source Victorian Clinical Genetics Services was removed from ACTG1.
Source Expert list was added to ACTG1.
Publications for gene ACTG1 were changed from PMID: 29620237, 22366783, 25052316, 28493397, 26188271, 27240540, 13680526, 14684684, 16773128, 19477959, 19497859 to PMID: 29620237, 22366783, 25052316, 28493397, 26188271, 27240540, 13680526, 14684684, 16773128, 19477959, 19497859
Cardiomyopathy_Paediatric v0.202 ACTN2 Chirag Patel Source London South GLH was removed from ACTN2.
Source South West GLH was removed from ACTN2.
Source Victorian Clinical Genetics Services was removed from ACTN2.
Phenotypes for gene: ACTN2 were changed from Dilated Cardiomyopathy, Dominant to Dilated Cardiomyopathy, Dominant; ACTN2-related cardiac and skeletal myopathy, MONDO:0700349
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.62 ACTN2 Chirag Patel Source Victorian Clinical Genetics Services was removed from ACTN2.
Phenotypes for gene: ACTN2 were changed from Myopathy, distal, 6, adult onset MIM#618655 to Myopathy, distal, 6, adult onset MIM#618655; ACTN2-related cardiac and skeletal myopathy, MONDO:0700349
Muscular dystrophy and myopathy_Paediatric v1.98 ACTN2 Chirag Patel Source Other was removed from ACTN2.
Phenotypes for gene: ACTN2 were changed from Congenital Myopathy 8 (MIM#618654; MONDO: 0032852) to Congenital Myopathy 8 (MIM#618654; MONDO: 0032852); ACTN2-related cardiac and skeletal myopathy, MONDO:0700349
Hypertrophic cardiomyopathy_HCM v1.10 ACTN2 Chirag Patel Source Victorian Clinical Genetics Services was removed from ACTN2.
Source Expert Review was added to ACTN2.
Phenotypes for gene: ACTN2 were changed from Cardiomyopathy, hypertrophic, 23, with or without LVNC, MIM# 612158 to Cardiomyopathy, hypertrophic, 23, with or without LVNC, MIM# 612158; ACTN2-related cardiac and skeletal myopathy, MONDO:0700349
Dilated Cardiomyopathy v1.45 ACTN2 Chirag Patel Source Literature was removed from ACTN2.
Source Expert Review was added to ACTN2.
Phenotypes for gene: ACTN2 were changed from Cardiomyopathy, dilated, 1AA, with or without LVNC, MIM# 612158 to Cardiomyopathy, dilated, 1AA, with or without LVNC, MIM# 612158; ACTN2-related cardiac and skeletal myopathy, MONDO:0700349
Mendeliome v1.3241 BCL11B Sarah Milton reviewed gene: BCL11B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40033098, 37860968, 37337996; Phenotypes: Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities, MONDO:0060763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v1.220 ADGRV1 Chirag Patel Mode of inheritance for gene ADGRV1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Mendeliome v1.3241 ADGRV1 Chirag Patel Source Victorian Clinical Genetics Services was removed from ADGRV1.
Source Expert list was added to ADGRV1.
Publications for gene ADGRV1 were changed from 22147658, 25572244, 14740321 to 22147658, 25572244, 14740321
Mendeliome v1.3240 AFP Chirag Patel Publications for gene AFP were changed from 15280901; 18854864, 14699509, 7684942 to 15280901; 18854864, 14699509, 7684942
Mendeliome v1.3239 AFP Chirag Patel Source Victorian Clinical Genetics Services was removed from AFP.
Source Literature was added to AFP.
Mode of inheritance for gene AFP was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3238 AFP Chirag Patel reviewed gene: AFP: Rating: AMBER; Mode of pathogenicity: None; Publications: PubMed: 14699509, 7684942; Phenotypes: [Hereditary persistence of alpha-fetoprotein] MIM#615970; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Joubert syndrome and other neurological ciliopathies v1.28 B9D1 Sarah Milton reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40565534, 40933483; Phenotypes: Ciliopathy, MONDO:0005308, B9D1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliopathies v1.85 B9D1 Sarah Milton reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40565534, 40933483; Phenotypes: Ciliopathy, MONDO:0005308, B9D1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3238 B9D1 Sarah Milton reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40565534, 40933483; Phenotypes: Ciliopathy, MONDO:0005308, B9D1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3238 B9D1 Sarah Milton Deleted their review
Mendeliome v1.3238 B9D1 Sarah Milton reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40565534, 40933483; Phenotypes: Ciliopathy, MONDO:0005308, B9D1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory Disorders v2.21 RNF31 Peter McNaughton reviewed gene: RNF31: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39009172, PMID: 41026334; Phenotypes: Immunodeficiency 115 with autoinflammation, MIM# 620632; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Vascular Malformations_Somatic v1.15 AKT1 Chirag Patel Publications for gene AKT1 were changed from 23246288, 21793738, 33030203 to 23246288, 21793738, 33030203
Vascular Malformations_Somatic v1.14 AKT1 Chirag Patel Deleted their review
Vascular Malformations_Somatic v1.14 AKT1 Chirag Patel reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: PMID: 21793738, 33030203; Phenotypes: ; Mode of inheritance: None
Macrocephaly_Megalencephaly v0.151 AKT1 Chirag Patel Classified gene: AKT1 as Red List (low evidence)
Macrocephaly_Megalencephaly v0.151 AKT1 Chirag Patel Gene: akt1 has been classified as Red List (Low Evidence).
Macrocephaly_Megalencephaly v0.150 AKT1 Chirag Patel reviewed gene: AKT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hyperinsulinism v1.49 AKT2 Chirag Patel Phenotypes for gene: AKT2 were changed from Diabetes mellitus, type II MIM#125853; Hypoinsulinemic hypoglycemia with hemihypertrophy MIM#240900 to Hypoinsulinemic hypoglycemia with hemihypertrophy MIM#240900
Mendeliome v1.3238 AKT2 Chirag Patel Source Victorian Clinical Genetics Services was removed from AKT2.
Source Literature was added to AKT2.
Phenotypes for gene: AKT2 were changed from Hypoinsulinemic hypoglycemia and body hemihypertrophy, MONDO:0009416; Hypoinsulinemic hypoglycemia with hemihypertrophy, OMIM:240900; Diabetes mellitus, type II , MIM#125853 to Hypoinsulinemic hypoglycemia and body hemihypertrophy, MONDO:0009416; AKT2-related familial partial lipodystrophy MONDO:0019192
Lipodystrophy_Lipoatrophy v1.25 AKT2 Chirag Patel Source Victorian Clinical Genetics Services was removed from AKT2.
Source Literature was added to AKT2.
Phenotypes for gene: AKT2 were changed from Hypoinsulinemic hypoglycemia with hemihypertrophy 240900 to AKT2-related familial partial lipodystrophy MONDO:0019192
Lipodystrophy_Lipoatrophy v1.24 AKT2 Chirag Patel reviewed gene: AKT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: AKT2-related familial partial lipodystrophy MONDO:0019192; Mode of inheritance: None
Overgrowth v1.16 AKT2 Chirag Patel Classified gene: AKT2 as Green List (high evidence)
Overgrowth v1.16 AKT2 Chirag Patel Gene: akt2 has been classified as Green List (High Evidence).
Overgrowth v1.16 AKT2 Chirag Patel Classified gene: AKT2 as Green List (high evidence)
Overgrowth v1.16 AKT2 Chirag Patel Gene: akt2 has been classified as Green List (High Evidence).
Overgrowth v1.15 AKT2 Chirag Patel Deleted their review
Overgrowth v1.15 AKT2 Chirag Patel Classified gene: AKT2 as Red List (low evidence)
Overgrowth v1.15 AKT2 Chirag Patel Gene: akt2 has been classified as Red List (Low Evidence).
Overgrowth v1.14 AKT2 Chirag Patel reviewed gene: AKT2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital Myasthenia v1.14 ALG2 Chirag Patel Classified gene: ALG2 as Green List (high evidence)
Congenital Myasthenia v1.14 ALG2 Chirag Patel Gene: alg2 has been classified as Green List (High Evidence).
Congenital Myasthenia v1.13 ALG2 Chirag Patel reviewed gene: ALG2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12684507, 34980536, 23404334, 30397276, 33644825; Phenotypes: Congenital disorder of glycosylation, type Ii, MIM# 607906; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.315 ALG2 Chirag Patel Classified gene: ALG2 as Green List (high evidence)
Genetic Epilepsy v1.219 ALG2 Chirag Patel Classified gene: ALG2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.315 ALG2 Chirag Patel Gene: alg2 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.219 ALG2 Chirag Patel Gene: alg2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.315 ALG2 Chirag Patel Classified gene: ALG2 as Green List (high evidence)
Genetic Epilepsy v1.219 ALG2 Chirag Patel Classified gene: ALG2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.315 ALG2 Chirag Patel Gene: alg2 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.219 ALG2 Chirag Patel Gene: alg2 has been classified as Green List (High Evidence).
Mendeliome v1.3237 ALG2 Chirag Patel Classified gene: ALG2 as Green List (high evidence)
Mendeliome v1.3237 ALG2 Chirag Patel Gene: alg2 has been classified as Green List (High Evidence).
Congenital Disorders of Glycosylation v1.74 ALG2 Chirag Patel Classified gene: ALG2 as Green List (high evidence)
Congenital Disorders of Glycosylation v1.74 ALG2 Chirag Patel Gene: alg2 has been classified as Green List (High Evidence).
Congenital Disorders of Glycosylation v1.73 ALG2 Chirag Patel reviewed gene: ALG2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12684507, 34980536, 23404334, 30397276, 33644825; Phenotypes: Congenital disorder of glycosylation, type Ii, MIM# 607906; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.218 ALG2 Chirag Patel reviewed gene: ALG2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12684507, 34980536, 23404334, 30397276, 33644825; Phenotypes: Congenital disorder of glycosylation, type Ii, MIM# 607906; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.314 ALG2 Chirag Patel reviewed gene: ALG2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12684507, 34980536, 23404334, 30397276, 33644825; Phenotypes: Congenital disorder of glycosylation, type Ii, MIM# 607906; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3236 ALG2 Chirag Patel reviewed gene: ALG2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12684507, 34980536, 23404334, 30397276, 33644825; Phenotypes: Congenital disorder of glycosylation, type Ii, MIM# 607906; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3236 RASA2 Lucy Spencer reviewed gene: RASA2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome MONDO:0018997, RASA2-related; Mode of inheritance: None
Mendeliome v1.3236 RAP1A Lucy Spencer reviewed gene: RAP1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Kabuki syndrome MONDO:0016512, RAP1A-related; Mode of inheritance: None
Mendeliome v1.3236 RAMP2 Lucy Spencer reviewed gene: RAMP2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Open angle glaucoma MONDO:0005338, RAMP2-related; Mode of inheritance: None
Mendeliome v1.3236 RALGAPA1 Lucy Spencer reviewed gene: RALGAPA1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation MIM#618797; Mode of inheritance: None
Mendeliome v1.3236 RAG2 Lucy Spencer reviewed gene: RAG2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Recombinase activating gene 2 deficiency MONDO:0000573; Mode of inheritance: None
Mendeliome v1.3236 RAG1 Lucy Spencer reviewed gene: RAG1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Recombinase activating gene 1 deficiency MONDO:0000572; Mode of inheritance: None
Mendeliome v1.3236 RAC1 Lucy Spencer reviewed gene: RAC1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 48 MIM#617751; Mode of inheritance: None
Mendeliome v1.3236 RABL2A Lucy Spencer reviewed gene: RABL2A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Infertility disorder, MONDO:0005047, RABL2A-related; Mode of inheritance: None
Mendeliome v1.3236 RAB14 Lucy Spencer reviewed gene: RAB14: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, RAB14-related; Mode of inheritance: None
Hereditary Pigmentary Disorders v1.3 ABCB6 Chirag Patel commented on gene: ABCB6
Mendeliome v1.3236 NDP Zornitza Stark Phenotypes for gene: NDP were changed from Exudative vitreoretinopathy 2, X-linked, MIM 305390; Norrie disease, MIM 310600 to Norrie disease MONDO:0010691; Exudative vitreoretinopathy 2, X-linked, MIM 305390; Norrie disease, MIM 310600
Genetic Epilepsy v1.217 AP2S1 Zornitza Stark Marked gene: AP2S1 as ready
Genetic Epilepsy v1.217 AP2S1 Zornitza Stark Gene: ap2s1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.217 AP2S1 Zornitza Stark Classified gene: AP2S1 as Green List (high evidence)
Genetic Epilepsy v1.217 AP2S1 Zornitza Stark Gene: ap2s1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.216 AP2S1 Zornitza Stark gene: AP2S1 was added
gene: AP2S1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: AP2S1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AP2S1 were set to 31981491; 33057194; 35982160; 35982159
Phenotypes for gene: AP2S1 were set to Neurodevelopmental disorder, MONDO:0700092, AP2S1-related
Review for gene: AP2S1 was set to GREEN
Added comment: Several isolated cases with de novo missense variants in large NDD cohorts PMID: 31981491;33057194;35982160;35982159.

26 unrelated NDD in a preprint with 5 recurring de novo missenses p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His https://doi.org/10.1101/2024.07.22.24310683. 70% had epilepsy, 50% brain anomalies.
Sources: Literature
Mendeliome v1.3235 AP2S1 Zornitza Stark Phenotypes for gene: AP2S1 were changed from Hypocalciuric hypercalcaemia, type III, MIM# 600740; MONDO:0010926; Developmental disorder to Hypocalciuric hypercalcaemia, type III, MIM# 600740; MONDO:0010926; Neurodevelopmental disorder, MONDO:0700092, AP2S1-related
Mendeliome v1.3234 AP2S1 Zornitza Stark Publications for gene: AP2S1 were set to 33057194; 23222959; 33729479; 33168530; 3204769; 31723423; 29479578
Mendeliome v1.3233 AP2S1 Zornitza Stark edited their review of gene: AP2S1: Added comment: Association with NDD: Several isolated cases with de novo missense variants in large NDD cohorts PMID: 31981491;33057194;35982160;35982159.

26 unrelated NDD in a preprint with 5 recurring de novo missenses p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His https://doi.org/10.1101/2024.07.22.24310683. 70% had epilepsy, 50% brain anomalies.; Changed publications: 23222959, 33729479, 33168530, 3204769, 31723423, 29479578, 31981491, 33057194, 35982160, 35982159; Changed phenotypes: Hypocalciuric hypercalcaemia, type III, MIM# 600740, MONDO:0010926, Neurodevelopmental disorder, MONDO:0700092, AP2S1-related
Intellectual disability syndromic and non-syndromic v1.314 AP2S1 Zornitza Stark Phenotypes for gene: AP2S1 were changed from Developmental disorder to Neurodevelopmental disorder, MONDO:0700092, AP2S1-related
Intellectual disability syndromic and non-syndromic v1.313 AP2S1 Zornitza Stark Publications for gene: AP2S1 were set to 33057194
Intellectual disability syndromic and non-syndromic v1.312 AP2S1 Zornitza Stark Classified gene: AP2S1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.312 AP2S1 Zornitza Stark Gene: ap2s1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.215 TRAF7 Zornitza Stark Publications for gene: TRAF7 were set to 29961569; 27479843; 28135719; 25363760; 25961944
Genetic Epilepsy v1.214 TRAF7 Zornitza Stark Classified gene: TRAF7 as Green List (high evidence)
Genetic Epilepsy v1.214 TRAF7 Zornitza Stark Gene: traf7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.311 AP2S1 Boris Keren reviewed gene: AP2S1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 31981491, 33057194, 35982160, 35982159; Phenotypes: intellectual disability, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Incidentalome v0.328 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Genetic Epilepsy v1.213 TRAF7 Leah Frajman reviewed gene: TRAF7: Rating: GREEN; Mode of pathogenicity: None; Publications: 38569228; Phenotypes: Cardiac, facial, and digital anomalies with developmental delay, MIM#618164; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.311 GPHN Bryony Thompson Classified gene: GPHN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.311 GPHN Bryony Thompson Gene: gphn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.310 GPHN Bryony Thompson reviewed gene: GPHN: Rating: GREEN; Mode of pathogenicity: None; Publications: 22040219, 11095995, 9812897, 34617111; Phenotypes: sulfite oxidase deficiency due to molybdenum cofactor deficiency type C MONDO:0014212; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3232 GPHN Bryony Thompson Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C, MIM# 615501; Epilepsy; Autism; Intellectual disability to sulfite oxidase deficiency due to molybdenum cofactor deficiency type C MONDO:0014212; complex neurodevelopmental disorder MONDO:0100038
Mendeliome v1.3231 GPHN Bryony Thompson Publications for gene: GPHN were set to 22040219; 11095995; 26613940; 24561070; 23393157; 27604308; 9812897
Mendeliome v1.3230 GPHN Bryony Thompson edited their review of gene: GPHN: Added comment: High evidence - AR Molybdenum cofactor deficiency C - PMID: 22040219, 11095995, 9812897, 34617111 - now 3 unrelated families and a mouse model. LoF is the mechanism of disease.

Amber - AD complex neurodevelopmental disorder - PMID: 26613940, 24561070, 23393157 - de novo missense and de novo/inherited deletions with supporting functional assays. However, incomplete penetrance has been reported for some of the CNVs.; Changed publications: 11095995, 22040219, 9812897, 34617111, 26613940, 24561070, 23393157; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3229 MT-ATP6 Zornitza Stark Publications for gene: MT-ATP6 were set to 40112238
Mendeliome v1.3228 MT-ATP6 Zornitza Stark edited their review of gene: MT-ATP6: Added comment: DEFINITIVE by ClinGen.; Changed publications: 40112238, 1550128, 8554662, 23206802, 1456751, 9270604, 9501263, 10604142, 17352390, 11245730, 16217706, 11731285, 27812026, 25037980, 19747204, 2137962
Mitochondrial disease v0.1077 MT-TY Zornitza Stark Phenotypes for gene: MT-TY were changed from Progressive external ophthalmoplegia; Cardiomyopathy; Myopathy to Mitochondrial disease (MONDO:0044970), MT-TY-related
Mitochondrial disease v0.1076 MT-TY Zornitza Stark Publications for gene: MT-TY were set to
Mitochondrial disease v0.1075 MT-TY Zornitza Stark edited their review of gene: MT-TY: Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported. Age of onset in affected individuals is variable and clinical features seen include myopathy with or without ophthalmoplegia. There is at least one case report with a more severe phenotype with neuropathy, ataxia, seizures, myoclonus, sensorineural hearing loss, and pigmentary retinopathy. Muscle biopsy in affected individuals has shown COX-negative and ragged red fibers, with variable mitochondrial respiratory chain enzyme deficiencies. The variants in affected individuals are often present at highest heteroplasmy levels in muscle and may be undetectable in other tissues such as blood and buccal tissue. Multiple single fiber studies were performed in these patients and supportive of variant pathogenicity; Changed publications: 11071502, 11756614, 11594340, 33279411, 30643656, 32684384, 32485333, 33279411; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TY-related
Mendeliome v1.3228 MT-TY Zornitza Stark Marked gene: MT-TY as ready
Mendeliome v1.3228 MT-TY Zornitza Stark Gene: mt-ty has been classified as Green List (High Evidence).
Mendeliome v1.3228 MT-TY Zornitza Stark Classified gene: MT-TY as Green List (high evidence)
Mendeliome v1.3228 MT-TY Zornitza Stark Gene: mt-ty has been classified as Green List (High Evidence).
Mendeliome v1.3227 MT-TY Zornitza Stark gene: MT-TY was added
gene: MT-TY was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TY.
Mode of inheritance for gene gene: MT-TY was set to MITOCHONDRIAL
Publications for gene: MT-TY were set to 11071502; 11756614; 11594340; 33279411; 30643656; 32684384; 32485333; 33279411
Phenotypes for gene: MT-TY were set to Mitochondrial disease (MONDO:0044970), MT-TY-related
Review for gene: MT-TY was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported. Age of onset in affected individuals is variable and clinical features seen include myopathy with or without ophthalmoplegia. There is at least one case report with a more severe phenotype with neuropathy, ataxia, seizures, myoclonus, sensorineural hearing loss, and pigmentary retinopathy. Muscle biopsy in affected individuals has shown COX-negative and ragged red fibers, with variable mitochondrial respiratory chain enzyme deficiencies. The variants in affected individuals are often present at highest heteroplasmy levels in muscle and may be undetectable in other tissues such as blood and buccal tissue. Multiple single fiber studies were performed in these patients and supportive of variant pathogenicity
Sources: Expert list
Mitochondrial disease v0.1075 MT-TW Zornitza Stark Phenotypes for gene: MT-TW were changed from Encephalomyopathy to Mitochondrial disease (MONDO:0044970), MT-TW-related
Mitochondrial disease v0.1074 MT-TW Zornitza Stark Publications for gene: MT-TW were set to
Mitochondrial disease v0.1073 MT-TW Zornitza Stark edited their review of gene: MT-TW: Added comment: DEFINITIVE by ClinGen.

At least 10 individuals reported. Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, microcephaly, developmental delay and regression, cognitive decline, fatigue, seizures, ataxia, chorea, muscle wasting, axonal neuropathy, diabetes, liver steatosis and fibrosis, constipation, recurrent vomiting, failure to thrive, pigmentary retinopathy, ptosis, optic atrophy, ophthalmoplegia, sensorineural hearing loss, and hypertrophic and dilated cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS to generalized atrophy and white matter involvement.

Muscle biopsies showed ragged red fibers, COX-deficient fibers, and decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated blood and cerebrospinal fluid lactate. Heteroplasmy levels in affected individuals were highest in muscle and/or liver when multiple tissues were assessed (25 - >95 % in muscle, 1 to >95% in blood, >95% in liver, 1-92% in skin fibroblasts, and 5% in urine when assessed). Functional studies to support variant pathogenicity.; Changed publications: 7695240, 9266739, 9673981, 12776230, 15054399, 18337306, 19809478, 26524491, 23841600, 30937556; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TW-related
Mendeliome v1.3226 MT-TW Zornitza Stark Marked gene: MT-TW as ready
Mendeliome v1.3226 MT-TW Zornitza Stark Gene: mt-tw has been classified as Green List (High Evidence).
Mendeliome v1.3226 MT-TW Zornitza Stark Classified gene: MT-TW as Green List (high evidence)
Mendeliome v1.3226 MT-TW Zornitza Stark Gene: mt-tw has been classified as Green List (High Evidence).
Mendeliome v1.3225 MT-TW Zornitza Stark gene: MT-TW was added
gene: MT-TW was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TW.
Mode of inheritance for gene gene: MT-TW was set to MITOCHONDRIAL
Publications for gene: MT-TW were set to 7695240; 9266739; 9673981; 12776230; 15054399; 18337306; 19809478; 26524491; 23841600; 30937556
Phenotypes for gene: MT-TW were set to Mitochondrial disease (MONDO:0044970), MT-TW-related
Review for gene: MT-TW was set to GREEN
Added comment: DEFINITIVE by ClinGen.

At least 10 individuals reported. Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, microcephaly, developmental delay and regression, cognitive decline, fatigue, seizures, ataxia, chorea, muscle wasting, axonal neuropathy, diabetes, liver steatosis and fibrosis, constipation, recurrent vomiting, failure to thrive, pigmentary retinopathy, ptosis, optic atrophy, ophthalmoplegia, sensorineural hearing loss, and hypertrophic and dilated cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS to generalized atrophy and white matter involvement.

Muscle biopsies showed ragged red fibers, COX-deficient fibers, and decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated blood and cerebrospinal fluid lactate. Heteroplasmy levels in affected individuals were highest in muscle and/or liver when multiple tissues were assessed (25 - >95 % in muscle, 1 to >95% in blood, >95% in liver, 1-92% in skin fibroblasts, and 5% in urine when assessed). Functional studies to support variant pathogenicity.
Sources: Expert list
Mitochondrial disease v0.1073 MT-TV Zornitza Stark Phenotypes for gene: MT-TV were changed from Ataxia; Seizures; Deafness to Mitochondrial disease (MONDO:0044970), MT-TV-related
Mitochondrial disease v0.1072 MT-TV Zornitza Stark Publications for gene: MT-TV were set to
Mitochondrial disease v0.1071 MT-TV Zornitza Stark edited their review of gene: MT-TV: Changed publications: 9450773, 12056939, 19252805, 15320572, 18314141, 24691472, 39468830
Mitochondrial disease v0.1071 MT-TV Zornitza Stark edited their review of gene: MT-TV: Added comment: DEFINITIVE by ClinGen.

At least 8 individuals reported. Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, cognitive decline, fatigue, migraines, seizures, myoclonic jerks, ataxia, dystonia, dysarthria, imbalance, muscle weakness, axonal sensorimotor polyneuropathy, diabetes, gastrointestinal dysmotility, cataracts, retinitis pigmentosa, sensorineural hearing loss, and hypertrophic cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS, cerebellar and cerebral atrophy, brainstem atrophy, and basal ganglia calcifications. Muscle biopsies showed ragged red fibers, COX-deficient fibers, and normal to decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated lactate.

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (67% to homoplasmic in muscle, 70% to homoplasmic in blood, and homoplasmic in skin fibroblasts).; Changed publications: 9450773, 12056939, 19252805, 15320572, 18314141, 24691472; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TV-related
Mendeliome v1.3224 MT-TV Zornitza Stark Marked gene: MT-TV as ready
Mendeliome v1.3224 MT-TV Zornitza Stark Gene: mt-tv has been classified as Green List (High Evidence).
Mendeliome v1.3224 MT-TV Zornitza Stark Classified gene: MT-TV as Green List (high evidence)
Mendeliome v1.3224 MT-TV Zornitza Stark Gene: mt-tv has been classified as Green List (High Evidence).
Mendeliome v1.3223 MT-TV Zornitza Stark gene: MT-TV was added
gene: MT-TV was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TV.
Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL
Publications for gene: MT-TV were set to 9450773; 12056939; 19252805; 15320572; 18314141; 24691472
Phenotypes for gene: MT-TV were set to Mitochondrial disease (MONDO:0044970), MT-TV-related
Review for gene: MT-TV was set to GREEN
Added comment: DEFINITIVE by ClinGen.

At least 8 individuals reported. Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, cognitive decline, fatigue, migraines, seizures, myoclonic jerks, ataxia, dystonia, dysarthria, imbalance, muscle weakness, axonal sensorimotor polyneuropathy, diabetes, gastrointestinal dysmotility, cataracts, retinitis pigmentosa, sensorineural hearing loss, and hypertrophic cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS, cerebellar and cerebral atrophy, brainstem atrophy, and basal ganglia calcifications. Muscle biopsies showed ragged red fibers, COX-deficient fibers, and normal to decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated lactate.

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (67% to homoplasmic in muscle, 70% to homoplasmic in blood, and homoplasmic in skin fibroblasts).
Sources: Expert list
Mitochondrial disease v0.1071 MT-TT Zornitza Stark Publications for gene: MT-TT were set to
Mitochondrial disease v0.1070 MT-TT Zornitza Stark Classified gene: MT-TT as Green List (high evidence)
Mitochondrial disease v0.1070 MT-TT Zornitza Stark Gene: mt-tt has been classified as Green List (High Evidence).
Mitochondrial disease v0.1069 MT-TT Zornitza Stark edited their review of gene: MT-TT: Added comment: MODERATE by ClinGen.

At least 10 probands reported with 5 unique variants. Age of onset in affected individuals varied from the neonatal period to more than 50 years. Clinical features in affected individuals included neonatal lactic acidosis; myoclonic epilepsy and ragged red fibers (MERRF); Leber Hereditary Optic Neuropathy (LHON); myopathy, seizures, migraines, pigmentary retinopathy, hearing loss, and diabetes. Brain imaging findings were variable. Muscle biopsies showed ragged red fibers and COX-deficient fibers. Lab investigations showed elevated lactate. Heteroplasmy levels were highest in muscle when multiple tissues were assessed, and ranged from 33% to homoplasmy in muscle.; Changed rating: GREEN; Changed publications: 32083134, 8769114, 9367299, 1645537, 8511015, 22638997, 29760464, 30236074, 28187756, 35808913; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TT-related
Mendeliome v1.3222 MT-TT Zornitza Stark Marked gene: MT-TT as ready
Mendeliome v1.3222 MT-TT Zornitza Stark Gene: mt-tt has been classified as Green List (High Evidence).
Mendeliome v1.3222 MT-TT Zornitza Stark Classified gene: MT-TT as Green List (high evidence)
Mendeliome v1.3222 MT-TT Zornitza Stark Gene: mt-tt has been classified as Green List (High Evidence).
Mendeliome v1.3221 MT-TT Zornitza Stark gene: MT-TT was added
gene: MT-TT was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TT.
Mode of inheritance for gene gene: MT-TT was set to MITOCHONDRIAL
Publications for gene: MT-TT were set to 32083134; 8769114; 9367299; 1645537; 8511015; 22638997; 29760464; 30236074; 28187756; 35808913
Phenotypes for gene: MT-TT were set to Mitochondrial disease (MONDO:0044970), MT-TT-related
Review for gene: MT-TT was set to GREEN
Added comment: MODERATE by ClinGen.

At least 10 probands reported with 5 unique variants. Age of onset in affected individuals varied from the neonatal period to more than 50 years. Clinical features in affected individuals included neonatal lactic acidosis; myoclonic epilepsy and ragged red fibers (MERRF); Leber Hereditary Optic Neuropathy (LHON); myopathy, seizures, migraines, pigmentary retinopathy, hearing loss, and diabetes. Brain imaging findings were variable. Muscle biopsies showed ragged red fibers and COX-deficient fibers. Lab investigations showed elevated lactate. Heteroplasmy levels were highest in muscle when multiple tissues were assessed, and ranged from 33% to homoplasmy in muscle.
Sources: Expert list
Mitochondrial disease v0.1069 MT-TS2 Zornitza Stark Phenotypes for gene: MT-TS2 were changed from MERRF; MELAS; Cerebellar ataxia to Mitochondrial disease (MONDO:0044970), MT-TS2-related
Mitochondrial disease v0.1068 MT-TS2 Zornitza Stark Publications for gene: MT-TS2 were set to
Mitochondrial disease v0.1067 MT-TS2 Zornitza Stark edited their review of gene: MT-TS2: Added comment: MODERATE by ClinGen.

At least 7 individuals reported. Affected individuals had varying clinical features including cataracts, retinal dystrophy, hearing loss, myopathy, ataxia, seizures, global developmental delay, diabetes, Wolff-Parkinson-White arrhythmia, hypertrophic cardiomyopathy, and hypogonadotropic hypogonadism. Lab investigations revealed elevated blood lactate and elevated creatine kinase. Muscle biopsy, when performed, generally showed reduced activities of complexes I, I+III, III, and/or IV. Brain imaging was normal in some cases. In one individual brain imaging revealed changes in the basal ganglia and diffuse atrophy with an enlarged cisterna magna and in another showed changes in the cerebral white matter.

Heteroplasmy levels were variable – some individuals had the highest levels in muscle with the variant being undetectable in other tissues while others had the variant present at homoplasmy in multiple tissues. Northern blotting and single fiber testing further supported variant pathogenicity.; Changed publications: 9792552, 10090882, 16950817, 21257182, 22369973, 22378285; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TS2-related
Mendeliome v1.3220 MT-TS2 Zornitza Stark Marked gene: MT-TS2 as ready
Mendeliome v1.3220 MT-TS2 Zornitza Stark Gene: mt-ts2 has been classified as Green List (High Evidence).
Mendeliome v1.3220 MT-TS2 Zornitza Stark Classified gene: MT-TS2 as Green List (high evidence)
Mendeliome v1.3220 MT-TS2 Zornitza Stark Gene: mt-ts2 has been classified as Green List (High Evidence).
Mendeliome v1.3219 MT-TS2 Zornitza Stark gene: MT-TS2 was added
gene: MT-TS2 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TS2.
Mode of inheritance for gene gene: MT-TS2 was set to MITOCHONDRIAL
Publications for gene: MT-TS2 were set to 9792552; 10090882; 16950817; 21257182; 22369973; 22378285
Phenotypes for gene: MT-TS2 were set to Mitochondrial disease (MONDO:0044970), MT-TS2-related
Review for gene: MT-TS2 was set to GREEN
Added comment: MODERATE by ClinGen.

At least 7 individuals reported. Affected individuals had varying clinical features including cataracts, retinal dystrophy, hearing loss, myopathy, ataxia, seizures, global developmental delay, diabetes, Wolff-Parkinson-White arrhythmia, hypertrophic cardiomyopathy, and hypogonadotropic hypogonadism. Lab investigations revealed elevated blood lactate and elevated creatine kinase. Muscle biopsy, when performed, generally showed reduced activities of complexes I, I+III, III, and/or IV. Brain imaging was normal in some cases. In one individual brain imaging revealed changes in the basal ganglia and diffuse atrophy with an enlarged cisterna magna and in another showed changes in the cerebral white matter.

Heteroplasmy levels were variable – some individuals had the highest levels in muscle with the variant being undetectable in other tissues while others had the variant present at homoplasmy in multiple tissues. Northern blotting and single fiber testing further supported variant pathogenicity.
Sources: Expert list
Mitochondrial disease v0.1067 MT-TS1 Zornitza Stark Phenotypes for gene: MT-TS1 were changed from MERRF; MELAS; Deafness to Mitochondrial disease (MONDO:0044970), MT-TS1-related
Mitochondrial disease v0.1066 MT-TS1 Zornitza Stark Publications for gene: MT-TS1 were set to
Mitochondrial disease v0.1065 MT-TS1 Zornitza Stark edited their review of gene: MT-TS1: Added comment: DEFINITIVE by ClinGen.

At least 8 individuals reported. Clinical features seen in affected individuals range from isolated hearing loss to mitochondrial myopathy to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and myoclonus epilepsy, ragged red fibers (MERRF). One case of fatal neonatal lactic acidosis has been reported. Intrafamilial variability has been observed.

Muscle biopsy often shows COX-negative fibers and/or ragged red fibers. A combined mitochondrial chain respiratory deficiency (commonly involving complexes I and IV) may also be observed in muscle biopsies. Heteroplasmy levels in affected individuals are often near homoplasmy in muscle and lower in tissues such as blood and urine, although homoplasmy across multiple tissues has also been seen. One individual had mitochondrial myopathy with heteroplasmy levels as low as 37% heteroplasmy in muscle.

Multiple single fiber studies and cybrid analyses were performed in these patients and are supportive of variant pathogenicity.; Changed publications: 7669057, 9778262, 14605505, 23696415, 33279600, 7581383; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TS1-related
Mendeliome v1.3218 MT-TS1 Zornitza Stark Marked gene: MT-TS1 as ready
Mendeliome v1.3218 MT-TS1 Zornitza Stark Gene: mt-ts1 has been classified as Green List (High Evidence).
Mendeliome v1.3218 MT-TS1 Zornitza Stark Classified gene: MT-TS1 as Green List (high evidence)
Mendeliome v1.3218 MT-TS1 Zornitza Stark Gene: mt-ts1 has been classified as Green List (High Evidence).
Mendeliome v1.3217 MT-TS1 Zornitza Stark gene: MT-TS1 was added
gene: MT-TS1 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TS1.
Mode of inheritance for gene gene: MT-TS1 was set to MITOCHONDRIAL
Publications for gene: MT-TS1 were set to 7669057; 9778262; 14605505; 23696415; 33279600; 7581383
Phenotypes for gene: MT-TS1 were set to Mitochondrial disease (MONDO:0044970), MT-TS1-related
Review for gene: MT-TS1 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

At least 8 individuals reported. Clinical features seen in affected individuals range from isolated hearing loss to mitochondrial myopathy to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and myoclonus epilepsy, ragged red fibers (MERRF). One case of fatal neonatal lactic acidosis has been reported. Intrafamilial variability has been observed.

Muscle biopsy often shows COX-negative fibers and/or ragged red fibers. A combined mitochondrial chain respiratory deficiency (commonly involving complexes I and IV) may also be observed in muscle biopsies. Heteroplasmy levels in affected individuals are often near homoplasmy in muscle and lower in tissues such as blood and urine, although homoplasmy across multiple tissues has also been seen. One individual had mitochondrial myopathy with heteroplasmy levels as low as 37% heteroplasmy in muscle.

Multiple single fiber studies and cybrid analyses were performed in these patients and are supportive of variant pathogenicity.
Sources: Expert list
Mitochondrial disease v0.1065 MT-TR Zornitza Stark Phenotypes for gene: MT-TR were changed from Encephalomyopathy to mitochondrial disease (MONDO:0044970), MT-TR-related
Mitochondrial disease v0.1064 MT-TR Zornitza Stark Publications for gene: MT-TR were set to
Mitochondrial disease v0.1063 MT-TR Zornitza Stark edited their review of gene: MT-TR: Added comment: MODERATE by ClinGen.

At least 4 individuals reported. Cybrid studies and single fiber testing further supported the pathogenicity of several of the reported variants. Age of onset was in childhood and features seen in affected individuals included muscle weakness, ataxia, hypotonia, epilepsy, global developmental delay and regression, pigmentary retinopathy, optic atrophy, renal insufficiency, and hypertrophic cardiomyopathy. Muscle biopsies showed ragged red fibers and COX-negative fibers and variable respiratory chain enzyme deficiencies.; Changed publications: 15286228, 17588757, 19809478, 22781096; Changed phenotypes: mitochondrial disease (MONDO:0044970), MT-TR-related
Mendeliome v1.3216 MT-TR Zornitza Stark Marked gene: MT-TR as ready
Mendeliome v1.3216 MT-TR Zornitza Stark Gene: mt-tr has been classified as Green List (High Evidence).
Mendeliome v1.3216 MT-TR Zornitza Stark Classified gene: MT-TR as Green List (high evidence)
Mendeliome v1.3216 MT-TR Zornitza Stark Gene: mt-tr has been classified as Green List (High Evidence).
Mendeliome v1.3215 MT-TR Zornitza Stark gene: MT-TR was added
gene: MT-TR was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TR.
Mode of inheritance for gene gene: MT-TR was set to MITOCHONDRIAL
Publications for gene: MT-TR were set to 15286228; 17588757; 19809478; 22781096
Phenotypes for gene: MT-TR were set to mitochondrial disease (MONDO:0044970), MT-TR-related
Review for gene: MT-TR was set to GREEN
Added comment: MODERATE by ClinGen.

At least 4 individuals reported. Cybrid studies and single fiber testing further supported the pathogenicity of several of the reported variants. Age of onset was in childhood and features seen in affected individuals included muscle weakness, ataxia, hypotonia, epilepsy, global developmental delay and regression, pigmentary retinopathy, optic atrophy, renal insufficiency, and hypertrophic cardiomyopathy. Muscle biopsies showed ragged red fibers and COX-negative fibers and variable respiratory chain enzyme deficiencies.
Sources: Expert list
Mitochondrial disease v0.1063 MT-TQ Zornitza Stark Phenotypes for gene: MT-TQ were changed from MELAS; deafness; mitochondrial myopathy to Mitochondrial disease (MONDO:0044970), MT-TQ-related
Mitochondrial disease v0.1062 MT-TQ Zornitza Stark Publications for gene: MT-TQ were set to
Mitochondrial disease v0.1061 MT-TQ Zornitza Stark Classified gene: MT-TQ as Amber List (moderate evidence)
Mitochondrial disease v0.1061 MT-TQ Zornitza Stark Gene: mt-tq has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1060 MT-TQ Zornitza Stark edited their review of gene: MT-TQ: Added comment: LIMITED by ClinGen.

Three unique variants (m.4332G>A, m.4369_4370insA, m.4381A>G) reported in three probands across 3 publications. Single fiber testing further supported the pathogenicity of several of these variants. Age of onset in affected individuals was five years old, teens, and 20 years old. Clinical features in affected individuals included stroke-like episodes, hearing loss, myopathy, and Leber Hereditary Optic Neuropathy (LHON). Brain imaging was variable. Muscle biopsies showed ragged red fibers and COX-negative fibers. Metabolic screening investigations were only reported in one individual and showed high cerebrospinal fluid (CSF) lactate with normal blood lactate. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (61-87% in muscle).; Changed rating: AMBER; Changed publications: 11171912, 10996779, 17003408, 11335700; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TQ-related
Mendeliome v1.3214 MT-TQ Zornitza Stark Phenotypes for gene: MT-TQ were changed from to Mitochondrial disease (MONDO:0044970), MT-TQ-related
Mendeliome v1.3213 MT-TQ Zornitza Stark edited their review of gene: MT-TQ: Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TQ-related
Mendeliome v1.3213 MT-TQ Zornitza Stark Classified gene: MT-TQ as Amber List (moderate evidence)
Mendeliome v1.3213 MT-TQ Zornitza Stark Gene: mt-tq has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3212 MT-TQ Zornitza Stark gene: MT-TQ was added
gene: MT-TQ was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TQ.
Mode of inheritance for gene gene: MT-TQ was set to MITOCHONDRIAL
Publications for gene: MT-TQ were set to 11171912; 10996779; 17003408; 11335700
Review for gene: MT-TQ was set to AMBER
Added comment: LIMITED by ClinGen.

Three unique variants (m.4332G>A, m.4369_4370insA, m.4381A>G) reported in three probands across 3 publications. Single fiber testing further supported the pathogenicity of several of these variants. Age of onset in affected individuals was five years old, teens, and 20 years old. Clinical features in affected individuals included stroke-like episodes, hearing loss, myopathy, and Leber Hereditary Optic Neuropathy (LHON). Brain imaging was variable. Muscle biopsies showed ragged red fibers and COX-negative fibers. Metabolic screening investigations were only reported in one individual and showed high cerebrospinal fluid (CSF) lactate with normal blood lactate. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (61-87% in muscle).
Sources: Expert list
Mitochondrial disease v0.1060 MT-TP Zornitza Stark Phenotypes for gene: MT-TP were changed from MERRF; myopathy to Mitochondrial disease (MONDO:0044970), MT-TP-related
Mitochondrial disease v0.1059 MT-TP Zornitza Stark Publications for gene: MT-TP were set to
Mitochondrial disease v0.1058 MT-TP Zornitza Stark edited their review of gene: MT-TP: Added comment: DEFINITIVE by ClinGen.

At least 9 individuals reported. Age of onset of affected individual is variable. Clinical features reported include myopathy, chronic progressive external ophthalmoplegia (CPEO), retinal dystrophy, and lactic acidosis. Muscle biopsy often shows classic findings of mitochondrial myopathy with COX-negative and ragged red fibers. Respiratory chain enzyme deficiencies may also be observed in muscle biopsies. The pathogenic variants were present at high levels of heteroplasmy in muscle tissue and, frequently, other tissues such as blood, saliva, buccal samples, urine, and fibroblasts harbored the variant at substantially lower heteroplasmy levels, including being undetectable. Affected individuals have been reported with heteroplasmy levels as low as 25-40% in muscle tissue. Single fiber studies were performed in several probands further supporting variant pathogenicity.; Changed publications: 7689388, 11196116, 19223931, 23696415, 19273760, 27536729, 27816331, 32305257, 32419253; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TP-related
Mendeliome v1.3211 MT-TP Zornitza Stark Phenotypes for gene: MT-TP were changed from to Mitochondrial disease (MONDO:0044970), MT-TP-related
Mendeliome v1.3210 MT-TP Zornitza Stark Publications for gene: MT-TP were set to
Mendeliome v1.3209 MT-TP Zornitza Stark Tag mtDNA tag was added to gene: MT-TP.
Mendeliome v1.3209 MT-TP Zornitza Stark Classified gene: MT-TP as Green List (high evidence)
Mendeliome v1.3209 MT-TP Zornitza Stark Gene: mt-tp has been classified as Green List (High Evidence).
Mendeliome v1.3208 MT-TP Zornitza Stark reviewed gene: MT-TP: Rating: GREEN; Mode of pathogenicity: None; Publications: 7689388, 11196116, 19223931, 23696415, 19273760, 27536729, 27816331, 32305257, 32419253; Phenotypes: Mitochondrial disease (MONDO:0044970), MT-TP-related; Mode of inheritance: MITOCHONDRIAL
Mitochondrial disease v0.1058 MT-TM Zornitza Stark Phenotypes for gene: MT-TM were changed from mitochondrial disease (MONDO:0044970), MT-TM-related to mitochondrial disease (MONDO:0044970), MT-TM-related
Mitochondrial disease v0.1058 MT-TM Zornitza Stark Phenotypes for gene: MT-TM were changed from mitochondrial disease (MONDO:0044970), MT-TM-related to mitochondrial disease (MONDO:0044970), MT-TM-related
Mitochondrial disease v0.1057 MT-TM Zornitza Stark Phenotypes for gene: MT-TM were changed from Mitochondrial myopathy to mitochondrial disease (MONDO:0044970), MT-TM-related
Mitochondrial disease v0.1057 MT-TM Zornitza Stark Publications for gene: MT-TM were set to
Mitochondrial disease v0.1056 MT-TM Zornitza Stark edited their review of gene: MT-TM: Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported. The condition was first described in a 10-year-old girl with exercise intolerance, myopathy, and short stature with mildly elevated serum lactate. Subsequent publications have shown a consistent phenotype involving a mitochondrial myopathy (typically childhood onset) with elevated lactate. Chronic external progressive ophthalmoplegia (CPEO) is not common but has been reported. Basal ganglia lesions and Leigh syndrome spectrum/mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) overlap have also been reported in one patient. Retinitis pigmentosa has also been reported. Muscle biopsy often shows classic findings of mitochondrial myopathy with COX-negative and ragged red (or blue) fibers. Combined OXPHOS deficiencies in muscle are also observed.; Changed publications: 9633749, 24711008, 25468263, 30739820, 11335700, 31488384, 31022467, 29174468; Changed phenotypes: mitochondrial disease (MONDO:0044970), MT-TM-related
Mendeliome v1.3208 MT-TM Zornitza Stark Marked gene: MT-TM as ready
Mendeliome v1.3208 MT-TM Zornitza Stark Gene: mt-tm has been classified as Green List (High Evidence).
Mendeliome v1.3208 MT-TM Zornitza Stark Classified gene: MT-TM as Green List (high evidence)
Mendeliome v1.3208 MT-TM Zornitza Stark Gene: mt-tm has been classified as Green List (High Evidence).
Mendeliome v1.3207 MT-TM Zornitza Stark gene: MT-TM was added
gene: MT-TM was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TM.
Mode of inheritance for gene gene: MT-TM was set to MITOCHONDRIAL
Publications for gene: MT-TM were set to 9633749; 24711008; 25468263; 30739820; 11335700; 31488384; 31022467; 29174468
Phenotypes for gene: MT-TM were set to mitochondrial disease (MONDO:0044970), MT-TM-related
Review for gene: MT-TM was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported. The condition was first described in a 10-year-old girl with exercise intolerance, myopathy, and short stature with mildly elevated serum lactate. Subsequent publications have shown a consistent phenotype involving a mitochondrial myopathy (typically childhood onset) with elevated lactate. Chronic external progressive ophthalmoplegia (CPEO) is not common but has been reported. Basal ganglia lesions and Leigh syndrome spectrum/mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) overlap have also been reported in one patient. Retinitis pigmentosa has also been reported. Muscle biopsy often shows classic findings of mitochondrial myopathy with COX-negative and ragged red (or blue) fibers. Combined OXPHOS deficiencies in muscle are also observed.
Sources: Expert list
Mitochondrial disease v0.1056 MT-TL2 Zornitza Stark Publications for gene: MT-TL2 were set to
Mitochondrial disease v0.1055 MT-TL2 Zornitza Stark Phenotypes for gene: MT-TL2 were changed from Myopathy; Cardiomyopathy; Encephalomyopathy to Mitochondrial disease (MONDO:0044970), MT-TL2-related
Mitochondrial disease v0.1054 MT-TL2 Zornitza Stark edited their review of gene: MT-TL2: Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with a range of clinical phenotypes, including CPEO, retinopathy, hearing loss, myopathy, exercise intolerance, and peripheral neuropathy. There is a substantial amount of functional evidence for the reported variants, including numerous single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects; Changed publications: 8923013, 12398839, 19718780, 18977334, 21819490, 15649400, 15591266, 23847141, 20022607, 29052516; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TL2-related
Mendeliome v1.3206 MT-TL2 Zornitza Stark Marked gene: MT-TL2 as ready
Mendeliome v1.3206 MT-TL2 Zornitza Stark Gene: mt-tl2 has been classified as Green List (High Evidence).
Mendeliome v1.3206 MT-TL2 Zornitza Stark Classified gene: MT-TL2 as Green List (high evidence)
Mendeliome v1.3206 MT-TL2 Zornitza Stark Gene: mt-tl2 has been classified as Green List (High Evidence).
Mendeliome v1.3205 MT-TL2 Zornitza Stark gene: MT-TL2 was added
gene: MT-TL2 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TL2.
Mode of inheritance for gene gene: MT-TL2 was set to MITOCHONDRIAL
Publications for gene: MT-TL2 were set to 8923013; 12398839; 19718780; 18977334; 21819490; 15649400; 15591266; 23847141; 20022607; 29052516
Phenotypes for gene: MT-TL2 were set to Mitochondrial disease (MONDO:0044970), MT-TL2-related
Review for gene: MT-TL2 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with a range of clinical phenotypes, including CPEO, retinopathy, hearing loss, myopathy, exercise intolerance, and peripheral neuropathy. There is a substantial amount of functional evidence for the reported variants, including numerous single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects
Sources: Expert list
Mitochondrial disease v0.1054 MT-TL1 Zornitza Stark Phenotypes for gene: MT-TL1 were changed from MELAS to Mitochondrial disease (MONDO:0044970), MT-TL1-related
Mitochondrial disease v0.1053 MT-TL1 Zornitza Stark Publications for gene: MT-TL1 were set to
Mitochondrial disease v0.1052 MT-TL1 Zornitza Stark edited their review of gene: MT-TL1: Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with a range of clinical presentations, including MELAS, myoclonus epilepsy, ragged red fibers (MERRF), Leigh syndrome spectrum, progressive external ophthalmoplegia (PEO), and maternally inherited deafness and diabetes (MIDD), as well as myopathy, hypertrophic cardiomyopathy, and renal disease. At least 7 unique variants reported with a substantial amount of functional evidence, including numerous cybrid analyses, single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects.; Changed publications: 9323566, 12221518, 20471262, 23220830, 23273904, 24338029, 23582502, 11271374, 23258140; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TL1-related
Mendeliome v1.3204 MT-TL1 Zornitza Stark Marked gene: MT-TL1 as ready
Mendeliome v1.3204 MT-TL1 Zornitza Stark Gene: mt-tl1 has been classified as Green List (High Evidence).
Mendeliome v1.3204 MT-TL1 Zornitza Stark Classified gene: MT-TL1 as Green List (high evidence)
Mendeliome v1.3204 MT-TL1 Zornitza Stark Gene: mt-tl1 has been classified as Green List (High Evidence).
Mendeliome v1.3203 MT-TL1 Zornitza Stark gene: MT-TL1 was added
gene: MT-TL1 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TL1.
Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL
Publications for gene: MT-TL1 were set to 9323566; 12221518; 20471262; 23220830; 23273904; 24338029; 23582502; 11271374; 23258140
Phenotypes for gene: MT-TL1 were set to Mitochondrial disease (MONDO:0044970), MT-TL1-related
Review for gene: MT-TL1 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with a range of clinical presentations, including MELAS, myoclonus epilepsy, ragged red fibers (MERRF), Leigh syndrome spectrum, progressive external ophthalmoplegia (PEO), and maternally inherited deafness and diabetes (MIDD), as well as myopathy, hypertrophic cardiomyopathy, and renal disease. At least 7 unique variants reported with a substantial amount of functional evidence, including numerous cybrid analyses, single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects.
Sources: Expert list
Mendeliome v1.3202 MT-TK Zornitza Stark edited their review of gene: MT-TK: Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TK-related
Mitochondrial disease v0.1052 MT-TK Zornitza Stark edited their review of gene: MT-TK: Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with wide spectrum of clinical presentations including MERRF, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome spectrum, and mitochondrial neurogastrointestinal encephalopathy (MNGIE), as well as lipomas, myopathy, hypertrophic cardiomyopathy, hearing loss, diabetes, and episodic ataxia. Variant pathogenicity is supported by cybrid analyses, single fiber studies, and respiratory chain studies showing clear evidence of OXPHOS defects.; Changed publications: 9380435, 19618438, 17410322, 25559684, 1361099, 10868777, 35821181, 36675808; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TK-related
Mendeliome v1.3202 MT-TK Zornitza Stark Phenotypes for gene: MT-TK were changed from Mitochondrial disease (MONDO:0044970), MT-TK-relatednd to Mitochondrial disease (MONDO:0044970), MT-TK-related
Mendeliome v1.3201 MT-TK Zornitza Stark Marked gene: MT-TK as ready
Mendeliome v1.3201 MT-TK Zornitza Stark Gene: mt-tk has been classified as Green List (High Evidence).
Mendeliome v1.3201 MT-TK Zornitza Stark Classified gene: MT-TK as Green List (high evidence)
Mendeliome v1.3201 MT-TK Zornitza Stark Gene: mt-tk has been classified as Green List (High Evidence).
Mendeliome v1.3200 MT-TK Zornitza Stark gene: MT-TK was added
gene: MT-TK was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TK.
Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL
Publications for gene: MT-TK were set to 9380435; 19618438; 17410322; 25559684; 1361099; 10868777; 35821181; 36675808
Phenotypes for gene: MT-TK were set to Mitochondrial disease (MONDO:0044970), MT-TK-relatednd
Review for gene: MT-TK was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with wide spectrum of clinical presentations including MERRF, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome spectrum, and mitochondrial neurogastrointestinal encephalopathy (MNGIE), as well as lipomas, myopathy, hypertrophic cardiomyopathy, hearing loss, diabetes, and episodic ataxia. Variant pathogenicity is supported by cybrid analyses, single fiber studies, and respiratory chain studies showing clear evidence of OXPHOS defects.
Sources: Expert list
Mitochondrial disease v0.1052 MT-TI Zornitza Stark Phenotypes for gene: MT-TI were changed from Mitochondrial myopathy; Encephalopathy to Mitochondrial disease (MONDO:0044970), MT-TI-related
Mitochondrial disease v0.1051 MT-TI Zornitza Stark Publications for gene: MT-TI were set to
Mitochondrial disease v0.1050 MT-TI Zornitza Stark edited their review of gene: MT-TI: Added comment: DEFINITIVE by ClinGen.

More than 10 individuals reported. Clinical presentations included LSS, myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), in addition to rhabdomyolysis, cardiomyopathy, encephalopathy, exercise intolerance, muscle weakness, hypertension2, hypercholesterolaemia, and hypomagnesaemia. Heteroplasmy levels of MT-TI can be variable in tissues from the same individual. In general, variants tend to be lower in tissues such as blood, saliva, and buccal swab and urine and muscle heteroplasmy levels tend to be higher.; Changed publications: 15121771, 21982779, 23395828, 16120360, 9473477, 12767666, 10065021, 7646516, 20884012, 21292040, 1632786, 23696415, 34607911; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TI-related
Mendeliome v1.3199 MT-TI Zornitza Stark Marked gene: MT-TI as ready
Mendeliome v1.3199 MT-TI Zornitza Stark Gene: mt-ti has been classified as Green List (High Evidence).
Mendeliome v1.3199 MT-TI Zornitza Stark Classified gene: MT-TI as Green List (high evidence)
Mendeliome v1.3199 MT-TI Zornitza Stark Gene: mt-ti has been classified as Green List (High Evidence).
Mendeliome v1.3198 MT-TI Zornitza Stark gene: MT-TI was added
gene: MT-TI was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TI.
Mode of inheritance for gene gene: MT-TI was set to MITOCHONDRIAL
Publications for gene: MT-TI were set to 15121771; 21982779; 23395828; 16120360; 9473477; 12767666; 10065021; 7646516; 20884012; 21292040; 1632786; 23696415; 34607911
Phenotypes for gene: MT-TI were set to Mitochondrial disease (MONDO:0044970), MT-TI-related
Review for gene: MT-TI was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 10 individuals reported. Clinical presentations included LSS, myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), in addition to rhabdomyolysis, cardiomyopathy, encephalopathy, exercise intolerance, muscle weakness, hypertension2, hypercholesterolaemia, and hypomagnesaemia. Heteroplasmy levels of MT-TI can be variable in tissues from the same individual. In general, variants tend to be lower in tissues such as blood, saliva, and buccal swab and urine and muscle heteroplasmy levels tend to be higher.
Sources: Expert list
Mendeliome v1.3197 NEK9 Sangavi Sivagnanasundram reviewed gene: NEK9: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: NEK9-related lethal skeletal dysplasia MONDO:0014870; Mode of inheritance: None
Mitochondrial disease v0.1050 MT-TH Zornitza Stark Phenotypes for gene: MT-TH were changed from Dilated cardiomyopathy; Retinopathy; Deafness; MELAS; MERFF to Mitochondrial disease (MONDO:0044970), MT-TH-related
Mitochondrial disease v0.1049 MT-TH Zornitza Stark Publications for gene: MT-TH were set to
Mitochondrial disease v0.1048 MT-TH Zornitza Stark edited their review of gene: MT-TH: Added comment: DEFINITIVE by ClinGen.

More than 5 individuals reported. Age of onset in affected individuals varied from adolescence to the 40s. Clinical features included stroke-like episodes, seizures, myoclonus, ataxia, optic atrophy, retinal dystrophy, cataracts, hearing loss, hypogonadism, and mood disorder. Cerebellar vermis hypoplasia and signal changes in the basal ganglia, dentate nuclei, temporal lobes, and occipital lobes were seen on brain imaging.

Tissue biopsies identified ragged red fibers and COX-negative fibers. Laboratory investigations showed increased blood and cerebrospinal fluid lactate. Decreased activities of complexes I and IV were variably seen in muscle. Heteroplasmy levels of the variants in affected individuals ranged from 81% to homoplasmic in muscle, 33-87% in urine, 1-60% in blood, and undetectable to homoplasmic in fibroblasts. Single fiber testing, cybrid analysis, and Northern blot analysis further supported variant pathogenicity.

This gene-disease relationship is also supported by known biochemical function and functional alteration in patient and non-patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in MT-TH; PMID: 24920829, 21704194).; Changed publications: 12682337, 14967777, 15111688, 21704194, 21931169, 23696415, 35092007, 24920829, 21704194; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TH-related
Mendeliome v1.3197 MT-TH Zornitza Stark Marked gene: MT-TH as ready
Mendeliome v1.3197 MT-TH Zornitza Stark Gene: mt-th has been classified as Green List (High Evidence).
Mendeliome v1.3197 MT-TH Zornitza Stark Classified gene: MT-TH as Green List (high evidence)
Mendeliome v1.3197 MT-TH Zornitza Stark Gene: mt-th has been classified as Green List (High Evidence).
Mendeliome v1.3196 MT-TH Zornitza Stark gene: MT-TH was added
gene: MT-TH was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TH.
Mode of inheritance for gene gene: MT-TH was set to MITOCHONDRIAL
Publications for gene: MT-TH were set to 12682337; 14967777; 15111688; 21704194; 21931169; 23696415; 35092007; 24920829; 21704194
Phenotypes for gene: MT-TH were set to Mitochondrial disease (MONDO:0044970), MT-TH-related
Review for gene: MT-TH was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 5 individuals reported. Age of onset in affected individuals varied from adolescence to the 40s. Clinical features included stroke-like episodes, seizures, myoclonus, ataxia, optic atrophy, retinal dystrophy, cataracts, hearing loss, hypogonadism, and mood disorder. Cerebellar vermis hypoplasia and signal changes in the basal ganglia, dentate nuclei, temporal lobes, and occipital lobes were seen on brain imaging.

Tissue biopsies identified ragged red fibers and COX-negative fibers. Laboratory investigations showed increased blood and cerebrospinal fluid lactate. Decreased activities of complexes I and IV were variably seen in muscle. Heteroplasmy levels of the variants in affected individuals ranged from 81% to homoplasmic in muscle, 33-87% in urine, 1-60% in blood, and undetectable to homoplasmic in fibroblasts. Single fiber testing, cybrid analysis, and Northern blot analysis further supported variant pathogenicity.

This gene-disease relationship is also supported by known biochemical function and functional alteration in patient and non-patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in MT-TH; PMID: 24920829, 21704194).
Sources: Expert list
Mitochondrial disease v0.1048 MT-TG Zornitza Stark Phenotypes for gene: MT-TG were changed from Cardiomyopathy to Mitochondrial disease (MONDO:0044970), MT-TG-related
Mitochondrial disease v0.1047 MT-TG Zornitza Stark Publications for gene: MT-TG were set to
Mitochondrial disease v0.1046 MT-TG Zornitza Stark edited their review of gene: MT-TG: Added comment: MODERATE by ClinGen.

Four variants reported in at least 6 individuals. Age of onset in affected individuals varied from early in life to the 20s. Clinical features included hypertrophic cardiomyopathy, myopathy, peripheral neuropathy, exercise intolerance, headache, seizures, ataxia, dystonic posturing, optic atrophy, retinal dystrophy, cataracts, and hearing loss. Progressive atrophy and bilateral basal ganglia calcifications were seen on brain imaging.

Tissue biopsies identified ragged red fibers and decreased COX histochemical activity in muscle. Lab values showed increased blood lactate and increased creatine kinase. Decreased activities of complexes I, III, and IV were observed in biopsied muscle.

Heteroplasmy levels of the variants in affected individuals ranged from 88-92% in muscle, 40-56% in urine, undetectable to 32% in blood, 27% in buccal samples, and was undetectable when assessed in fibroblasts. Single fiber testing and cybrid analysis further supported variant pathogenicity. This gene-disease relationship is also supported by known biochemical function and functional alterations in patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in MT-TG; PMID: 10090480).; Changed publications: 8079988, 9199564, 11971101, 16120360, 32337339, 35432167, 10090480; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TG-related
Mendeliome v1.3195 MT-TG Zornitza Stark Marked gene: MT-TG as ready
Mendeliome v1.3195 MT-TG Zornitza Stark Gene: mt-tg has been classified as Green List (High Evidence).
Mendeliome v1.3195 MT-TG Zornitza Stark Classified gene: MT-TG as Green List (high evidence)
Mendeliome v1.3195 MT-TG Zornitza Stark Gene: mt-tg has been classified as Green List (High Evidence).
Mendeliome v1.3194 MT-TG Zornitza Stark Tag mtDNA tag was added to gene: MT-TG.
Mendeliome v1.3194 MT-TG Zornitza Stark gene: MT-TG was added
gene: MT-TG was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TG was set to MITOCHONDRIAL
Publications for gene: MT-TG were set to 8079988; 9199564; 11971101; 16120360; 32337339; 35432167; 10090480
Phenotypes for gene: MT-TG were set to Mitochondrial disease (MONDO:0044970), MT-TG-related
Review for gene: MT-TG was set to GREEN
Added comment: MODERATE by ClinGen.

Four variants reported in at least 6 individuals. Age of onset in affected individuals varied from early in life to the 20s. Clinical features included hypertrophic cardiomyopathy, myopathy, peripheral neuropathy, exercise intolerance, headache, seizures, ataxia, dystonic posturing, optic atrophy, retinal dystrophy, cataracts, and hearing loss. Progressive atrophy and bilateral basal ganglia calcifications were seen on brain imaging.

Tissue biopsies identified ragged red fibers and decreased COX histochemical activity in muscle. Lab values showed increased blood lactate and increased creatine kinase. Decreased activities of complexes I, III, and IV were observed in biopsied muscle.

Heteroplasmy levels of the variants in affected individuals ranged from 88-92% in muscle, 40-56% in urine, undetectable to 32% in blood, 27% in buccal samples, and was undetectable when assessed in fibroblasts. Single fiber testing and cybrid analysis further supported variant pathogenicity. This gene-disease relationship is also supported by known biochemical function and functional alterations in patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in MT-TG; PMID: 10090480).
Sources: Expert list
Mitochondrial disease v0.1046 MT-TF Zornitza Stark Phenotypes for gene: MT-TF were changed from MELAS; MERFF; Encephalopathy; Myopathy to Mitochondrial disease (MONDO:0044970), MT-TF-related
Mitochondrial disease v0.1045 MT-TF Zornitza Stark Publications for gene: MT-TF were set to
Mitochondrial disease v0.1044 MT-TF Zornitza Stark edited their review of gene: MT-TF: Added comment: DEFINITIVE by ClinGen.

Over 30 individuals reported. Age of onset in affected individuals varied from childhood to >60 years. Clinical features in affected individuals included mitochondrial myopathy, MELAS, myoclonic epilepsy and ragged red fibers (MERRF), chronic external progressive ophthalmoplegia (CPEO), Gitelman syndrome, epilepsy, epilepsia partialis continua (EPC), chronic kidney disease, retinal dystrophy, sensorineural hearing loss, neuropathy, and neurologic/cognitive/psychiatric decline. Some affected individuals had normal brain imaging while others had cerebral, cerebellar, and/or brainstem atrophy.

Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals. Laboratory investigations showed variable lactate levels (normal to elevated in blood, cerebrospinal fluid, and/or urine) and elevated creatine kinase (CK).

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed, and ranged from 58%-homoplasmic in muscle; 0-70% in hair, 0-homoplasmic in blood, fibroblast, and urine; and in one individual was 63% in a buccal sample.; Changed publications: 14659412, 9771776, 16806928, 21060018, 31463198, 32419253, 34607911, 21424749, 15184630, 20142618, 28267784, 31722346, 35472031, 9636664, 21882289, 16769874, 21914246, 31009750, 18977334; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TF-related
Mendeliome v1.3193 MT-TF Zornitza Stark edited their review of gene: MT-TF: Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TF-related
Mendeliome v1.3193 MT-TF Zornitza Stark Marked gene: MT-TF as ready
Mendeliome v1.3193 MT-TF Zornitza Stark Gene: mt-tf has been classified as Green List (High Evidence).
Mendeliome v1.3193 MT-TF Zornitza Stark Phenotypes for gene: MT-TF were changed from Mitochondrial disease (MONDO:0044970), MT-TF-relatedn to Mitochondrial disease (MONDO:0044970), MT-TF-related
Mendeliome v1.3192 MT-TF Zornitza Stark Classified gene: MT-TF as Green List (high evidence)
Mendeliome v1.3192 MT-TF Zornitza Stark Gene: mt-tf has been classified as Green List (High Evidence).
Mendeliome v1.3191 MT-TF Zornitza Stark Tag mtDNA tag was added to gene: MT-TF.
Mendeliome v1.3191 MT-TF Zornitza Stark gene: MT-TF was added
gene: MT-TF was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TF was set to MITOCHONDRIAL
Publications for gene: MT-TF were set to 14659412; 9771776; 16806928; 21060018; 31463198; 32419253; 34607911; 21424749; 15184630; 20142618; 28267784; 31722346; 35472031; 9636664; 21882289; 16769874; 21914246; 31009750; 18977334
Phenotypes for gene: MT-TF were set to Mitochondrial disease (MONDO:0044970), MT-TF-relatedn
Review for gene: MT-TF was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Over 30 individuals reported. Age of onset in affected individuals varied from childhood to >60 years. Clinical features in affected individuals included mitochondrial myopathy, MELAS, myoclonic epilepsy and ragged red fibers (MERRF), chronic external progressive ophthalmoplegia (CPEO), Gitelman syndrome, epilepsy, epilepsia partialis continua (EPC), chronic kidney disease, retinal dystrophy, sensorineural hearing loss, neuropathy, and neurologic/cognitive/psychiatric decline. Some affected individuals had normal brain imaging while others had cerebral, cerebellar, and/or brainstem atrophy.

Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals. Laboratory investigations showed variable lactate levels (normal to elevated in blood, cerebrospinal fluid, and/or urine) and elevated creatine kinase (CK).

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed, and ranged from 58%-homoplasmic in muscle; 0-70% in hair, 0-homoplasmic in blood, fibroblast, and urine; and in one individual was 63% in a buccal sample.
Sources: Expert list
Mendeliome v1.3190 MT-TE Zornitza Stark Tag mtDNA tag was added to gene: MT-TE.
Mitochondrial disease v0.1044 MT-TE Zornitza Stark Phenotypes for gene: MT-TE were changed from Mitochondrial myopathy; Deafness; Diabetes to Mitochondrial disease (MONDO:0044970), MT-TE-related
Mitochondrial disease v0.1043 MT-TE Zornitza Stark Publications for gene: MT-TE were set to
Mitochondrial disease v0.1042 MT-TE Zornitza Stark edited their review of gene: MT-TE: Added comment: DEFINITIVE by ClinGen.

More than 15 individuals reported. Age of onset in affected individuals varied from birth to 30s. Clinical features in affected individuals included (benign) infantile reversible COX deficiency myopathy (also referred to RIRCD); chronic external progressive ophthalmoplegia (CPEO), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap, myoclonic epilepsy and ragged red fibers (MERRF); pigmentary retinopathy, migraines, myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, and hearing loss. Brain imaging was variable. Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals.

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed, and were variable in other tissues when tested.; Changed publications: 8155739, 21194154, 17715279, 23334599, 7726155, 7726154, 9353617, 15048886, 15670724, 23847141, 23334599, 17266923, 17056256; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TE-related
Mendeliome v1.3190 MT-TE Zornitza Stark Marked gene: MT-TE as ready
Mendeliome v1.3190 MT-TE Zornitza Stark Gene: mt-te has been classified as Green List (High Evidence).
Mendeliome v1.3190 MT-TE Zornitza Stark Classified gene: MT-TE as Green List (high evidence)
Mendeliome v1.3190 MT-TE Zornitza Stark Gene: mt-te has been classified as Green List (High Evidence).
Mendeliome v1.3189 MT-TE Zornitza Stark gene: MT-TE was added
gene: MT-TE was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TE was set to MITOCHONDRIAL
Publications for gene: MT-TE were set to 8155739; 21194154; 17715279; 23334599; 7726155; 7726154; 9353617; 15048886; 15670724; 23847141; 23334599; 17266923; 17056256
Phenotypes for gene: MT-TE were set to Mitochondrial disease (MONDO:0044970), MT-TE-related
Review for gene: MT-TE was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 15 individuals reported. Age of onset in affected individuals varied from birth to 30s. Clinical features in affected individuals included (benign) infantile reversible COX deficiency myopathy (also referred to RIRCD); chronic external progressive ophthalmoplegia (CPEO), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap, myoclonic epilepsy and ragged red fibers (MERRF); pigmentary retinopathy, migraines, myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, and hearing loss. Brain imaging was variable. Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals.

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed, and were variable in other tissues when tested.
Sources: Expert list
Mendeliome v1.3188 MT-TD Zornitza Stark Tag mtDNA tag was added to gene: MT-TD.
Mitochondrial disease v0.1042 MT-TD Zornitza Stark Phenotypes for gene: MT-TD were changed from Mitochondrial myopathy to Mitochondrial disease (MONDO:0044970), MT-TD-related
Mitochondrial disease v0.1041 MT-TD Zornitza Stark Publications for gene: MT-TD were set to
Mitochondrial disease v0.1040 MT-TD Zornitza Stark edited their review of gene: MT-TD: Added comment: MODERATE by ClinGen.

At least 3 variants reported in unrelated individuals. These variants were generally present at high levels of heteroplasmy in muscle tissue and at lower to undetectable levels in other tissues such as blood, saliva, buccal tissue, urine, and fibroblasts, highlighting the diagnostic importance of muscle biopsy in MT-TD-related primary mitochondrial disease. Single fiber studies were performed in several individuals with results supporting variant pathogenicity.

This gene-disease association is also supported by functional implication given protein interaction with the multitude of other mitochondrial translation proteins linked to primary mitochondrial disease (PMID: 30030363 ). Respiratory deficient yeast strains due to a single variant in MT-TD have been created and compelling rescue studies have been performed (PMIDs: 7024270, 3054486). E. coli carrying the m.7526A>G variant were also shown to have significantly decreased aminoacylation rates (PMID: 19535463).; Changed publications: 9811342, 10488907, 16059939, 18676632, 23696415, 25447692, 27536005, 30030363, 3054486, 19535463; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TD-related
Mendeliome v1.3188 MT-TD Zornitza Stark Marked gene: MT-TD as ready
Mendeliome v1.3188 MT-TD Zornitza Stark Gene: mt-td has been classified as Green List (High Evidence).
Mendeliome v1.3188 MT-TD Zornitza Stark Classified gene: MT-TD as Green List (high evidence)
Mendeliome v1.3188 MT-TD Zornitza Stark Gene: mt-td has been classified as Green List (High Evidence).
Mendeliome v1.3187 MT-TD Zornitza Stark gene: MT-TD was added
gene: MT-TD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TD was set to MITOCHONDRIAL
Publications for gene: MT-TD were set to 9811342; 10488907; 16059939; 18676632; 23696415; 25447692; 27536005; 30030363; 3054486; 19535463
Phenotypes for gene: MT-TD were set to Mitochondrial disease (MONDO:0044970), MT-TD-related
Review for gene: MT-TD was set to GREEN
Added comment: MODERATE by ClinGen.

At least 3 variants reported in unrelated individuals. These variants were generally present at high levels of heteroplasmy in muscle tissue and at lower to undetectable levels in other tissues such as blood, saliva, buccal tissue, urine, and fibroblasts, highlighting the diagnostic importance of muscle biopsy in MT-TD-related primary mitochondrial disease. Single fiber studies were performed in several individuals with results supporting variant pathogenicity.

This gene-disease association is also supported by functional implication given protein interaction with the multitude of other mitochondrial translation proteins linked to primary mitochondrial disease (PMID: 30030363 ). Respiratory deficient yeast strains due to a single variant in MT-TD have been created and compelling rescue studies have been performed (PMIDs: 7024270, 3054486). E. coli carrying the m.7526A>G variant were also shown to have significantly decreased aminoacylation rates (PMID: 19535463).
Sources: Expert list
Mitochondrial disease v0.1040 MT-TC Zornitza Stark Publications for gene: MT-TC were set to
Mitochondrial disease v0.1039 MT-TC Zornitza Stark Phenotypes for gene: MT-TC were changed from MELAS; Dystonia to Mitochondrial disease (MONDO:0044970), MT-TC-related
Mitochondrial disease v0.1038 MT-TC Zornitza Stark Classified gene: MT-TC as Amber List (moderate evidence)
Mitochondrial disease v0.1038 MT-TC Zornitza Stark Gene: mt-tc has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1037 MT-TC Zornitza Stark edited their review of gene: MT-TC: Added comment: LIMITED by ClinGen.

There were 3 scoreable probands across >10 publications from 1996-2022. Notably, while cybrid analyses were performed (PMID:36039763), one of the variants, m.5783G>A, was excluded from scoring for three reasons: 1.) the reported phenotype of isolated hearing loss was non-specific and incompletely penetrant, but also 2.) the biochemical impact in cybrids was mild - moderate, and 3.) there was reduction in expression of mitochondrial replication genes (TWNK ~30% of control in cybrids) suggesting an alternative aetiology might be responsible for the biochemical impact reported.

The gene-disease association for MT-TC is also supported by the known interaction with a multitude of other mitochondrial translation proteins (PMID:30030363) and respiratory chain studies and Northern blot analysis supporting MT-TC dysfunction leading to Complex I deficiency (PMID:35252560).; Changed rating: AMBER; Changed publications: 8829635, 9185178, 17241783, 11453453, 16955414, 32169613, 36039763, 17724295, 35252560, 34433719, 30030363; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TC-related
Mendeliome v1.3186 MT-TC Zornitza Stark Marked gene: MT-TC as ready
Mendeliome v1.3186 MT-TC Zornitza Stark Gene: mt-tc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3186 MT-TC Zornitza Stark Classified gene: MT-TC as Amber List (moderate evidence)
Mendeliome v1.3186 MT-TC Zornitza Stark Gene: mt-tc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3185 MT-TC Zornitza Stark gene: MT-TC was added
gene: MT-TC was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TC was set to MITOCHONDRIAL
Publications for gene: MT-TC were set to 8829635; 9185178; 17241783; 11453453; 16955414; 32169613; 36039763; 17724295; 35252560; 34433719; 30030363
Phenotypes for gene: MT-TC were set to Mitochondrial disease (MONDO:0044970), MT-TC-related
Review for gene: MT-TC was set to AMBER
Added comment: LIMITED by ClinGen.

There were 3 scoreable probands across >10 publications from 1996-2022. Notably, while cybrid analyses were performed (PMID:36039763), one of the variants, m.5783G>A, was excluded from scoring for three reasons: 1.) the reported phenotype of isolated hearing loss was non-specific and incompletely penetrant, but also 2.) the biochemical impact in cybrids was mild - moderate, and 3.) there was reduction in expression of mitochondrial replication genes (TWNK ~30% of control in cybrids) suggesting an alternative aetiology might be responsible for the biochemical impact reported.

The gene-disease association for MT-TC is also supported by the known interaction with a multitude of other mitochondrial translation proteins (PMID:30030363) and respiratory chain studies and Northern blot analysis supporting MT-TC dysfunction leading to Complex I deficiency (PMID:35252560).
Sources: Expert list
Mendeliome v1.3184 NDP Sangavi Sivagnanasundram reviewed gene: NDP: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Norrie disease MONDO:0010691; Mode of inheritance: None
Mitochondrial disease v0.1037 MT-TA Zornitza Stark Phenotypes for gene: MT-TA were changed from Mitochondrial myopathy to Mitochondrial disease (MONDO:0044970), MT-TA-related
Mitochondrial disease v0.1036 MT-TA Zornitza Stark Publications for gene: MT-TA were set to
Mitochondrial disease v0.1035 MT-TA Zornitza Stark edited their review of gene: MT-TA: Added comment: DEFINITIVE by ClinGen.

More than 5 individuals reported. Variable age of onset. Features in affected individuals included myopathy (weakness, exercise intolerance), ptosis, ophthalmoplegia, lipomas, and hearing loss. Muscle biopsies showed ragged red fibers and COX-negative fibers, as well as respiratory chain enzyme deficiencies. Heteroplasmy levels in affected individuals tended to be highest in muscle when multiple tissues were assessed and were variable in other tissues when tested.; Changed publications: 11715067, 17825557, 14569122, 27014581, 20813205, 25873012, 16476954; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TA-related
Mendeliome v1.3184 MT-TA Zornitza Stark Marked gene: MT-TA as ready
Mendeliome v1.3184 MT-TA Zornitza Stark Gene: mt-ta has been classified as Green List (High Evidence).
Mendeliome v1.3184 MT-TA Zornitza Stark Classified gene: MT-TA as Green List (high evidence)
Mendeliome v1.3184 MT-TA Zornitza Stark Gene: mt-ta has been classified as Green List (High Evidence).
Mendeliome v1.3183 MT-TA Zornitza Stark gene: MT-TA was added
gene: MT-TA was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TA was set to MITOCHONDRIAL
Publications for gene: MT-TA were set to 11715067; 17825557; 14569122; 27014581; 20813205; 25873012; 16476954
Phenotypes for gene: MT-TA were set to Mitochondrial disease (MONDO:0044970), MT-TA-related
Review for gene: MT-TA was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 5 individuals reported. Variable age of onset. Features in affected individuals included myopathy (weakness, exercise intolerance), ptosis, ophthalmoplegia, lipomas, and hearing loss. Muscle biopsies showed ragged red fibers and COX-negative fibers, as well as respiratory chain enzyme deficiencies. Heteroplasmy levels in affected individuals tended to be highest in muscle when multiple tissues were assessed and were variable in other tissues when tested.
Sources: Expert list
Mitochondrial disease v0.1035 MT-RNR1 Zornitza Stark Phenotypes for gene: MT-RNR1 were changed from Deafness; Cardiomyopathy to Mitochondrial disease (MONDO:0044970), MT-RNR1-related
Mitochondrial disease v0.1034 MT-RNR1 Zornitza Stark Publications for gene: MT-RNR1 were set to 20301595
Mitochondrial disease v0.1033 MT-RNR1 Zornitza Stark edited their review of gene: MT-RNR1: Added comment: DEFINITIVE by ClinGen.

Over 70 affected individuals reported. Two variants, m.1555A>G and m.1494C>T, are recurrent.

These variants are predominantly associated with hearing loss. Some individuals with this variants have normal hearing, others have hearing loss following aminoglycoside exposure, and others have hearing loss and no known aminoglycoside exposure. Age of onset of hearing loss ranged from infancy (after aminoglycoside exposure) to adulthood. Hearing loss has been reported to be variable, stable in some individuals and progressive in others.

Additional variants in this gene have been reported to be associated with primary mitochondrial disease, however insufficient clinical detail was provided and/or there was a lack of comprehensive analyses excluding other causes, therefore these additional variants were not included in the ClinGen curation (m.827A>G – PMIDs: 16650816, 16782057, 18261986; m.961delTinsC - PMIDs: 7550368, 10326749; m.1027A>G – PMIDs: 23328039, 21205314, 20100600; m.1095T>C – PMIDs: 11313749, 11079536, 15637703).; Changed publications: 7698299, 16380089, 12920080, 24252789, 9490575, 8285309, 9040738, 7689389; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-RNR1-related
Mendeliome v1.3182 NDE1 Sangavi Sivagnanasundram reviewed gene: NDE1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116; Mode of inheritance: None
Mitochondrial disease v0.1033 NARS2 Sangavi Sivagnanasundram edited their review of gene: NARS2: Changed phenotypes: Leigh syndrome MONDO:0009723, combined oxidative phosphorylation defect type 24 MONDO:0014547
Mitochondrial disease v0.1033 NARS2 Sangavi Sivagnanasundram changed review comment from: Classified as LIMITED by ClinGen on 19/12/2019 however that was based lack of reported cases at the time of curation.; to: Classified as LIMITED by ClinGen on 19/12/2019 however, that is based on the lack of reported cases at the time of curation.
Mitochondrial disease v0.1033 NARS2 Sangavi Sivagnanasundram reviewed gene: NARS2: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005563; Phenotypes: Leigh syndrome MONDO:0009723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3182 NARS Sangavi Sivagnanasundram reviewed gene: NARS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3182 NALCN Sangavi Sivagnanasundram reviewed gene: NALCN: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3182 NAGLU Sangavi Sivagnanasundram reviewed gene: NAGLU: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3182 NAA10 Sangavi Sivagnanasundram reviewed gene: NAA10: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: NAA10-related syndrome, MONDO:0100124; Mode of inheritance: None
Mendeliome v1.3182 MYRF Sangavi Sivagnanasundram reviewed gene: MYRF: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: MYRF-related cardiac-urogenital syndrome MONDO:0032653; Mode of inheritance: None
Mendeliome v1.3182 MYOT Sangavi Sivagnanasundram reviewed gene: MYOT: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: myofibrillar myopathy 3, MONDO:0012215; Mode of inheritance: None
Mendeliome v1.3182 PIP5K1C Sangavi Sivagnanasundram commented on gene: PIP5K1C
Mendeliome v1.3182 PITRM1 Sangavi Sivagnanasundram reviewed gene: PITRM1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: spinocerebellar ataxia, autosomal recessive 30, MONDO:0030318; Mode of inheritance: None
Mendeliome v1.3182 PJA1 Sangavi Sivagnanasundram reviewed gene: PJA1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148; Mode of inheritance: None
Mendeliome v1.3182 MT-RNR1 Zornitza Stark Marked gene: MT-RNR1 as ready
Mendeliome v1.3182 MT-RNR1 Zornitza Stark Gene: mt-rnr1 has been classified as Green List (High Evidence).
Mendeliome v1.3182 MT-RNR1 Zornitza Stark Classified gene: MT-RNR1 as Green List (high evidence)
Mendeliome v1.3182 MT-RNR1 Zornitza Stark Gene: mt-rnr1 has been classified as Green List (High Evidence).
Mendeliome v1.3181 MT-RNR1 Zornitza Stark Tag mtDNA tag was added to gene: MT-RNR1.
Mendeliome v1.3181 MT-RNR1 Zornitza Stark gene: MT-RNR1 was added
gene: MT-RNR1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-RNR1 was set to MITOCHONDRIAL
Publications for gene: MT-RNR1 were set to 7698299; 16380089; 12920080; 24252789; 9490575; 8285309; 9040738; 7689389
Phenotypes for gene: MT-RNR1 were set to Mitochondrial disease (MONDO:0044970), MT-RNR1-related
Review for gene: MT-RNR1 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Over 70 affected individuals reported. Two variants, m.1555A>G and m.1494C>T, are recurrent.

These variants are predominantly associated with hearing loss. Some individuals with this variants have normal hearing, others have hearing loss following aminoglycoside exposure, and others have hearing loss and no known aminoglycoside exposure. Age of onset of hearing loss ranged from infancy (after aminoglycoside exposure) to adulthood. Hearing loss has been reported to be variable, stable in some individuals and progressive in others.

Additional variants in this gene have been reported to be associated with primary mitochondrial disease, however insufficient clinical detail was provided and/or there was a lack of comprehensive analyses excluding other causes, therefore these additional variants were not included in the ClinGen curation (m.827A>G – PMIDs: 16650816, 16782057, 18261986; m.961delTinsC - PMIDs: 7550368, 10326749; m.1027A>G – PMIDs: 23328039, 21205314, 20100600; m.1095T>C – PMIDs: 11313749, 11079536, 15637703).
Sources: Expert list
Mitochondrial disease v0.1033 MT-ND6 Zornitza Stark Phenotypes for gene: MT-ND6 were changed from Mitochondrial cardiomyopathy complex I deficiency; Leber's optic neuropathy; MELAS; Dystonia; Striatal necrosis, bilateral to Mitochondrial disease (MONDO:0044970), MT-ND6-related
Mitochondrial disease v0.1032 MT-ND6 Zornitza Stark Publications for gene: MT-ND6 were set to
Mitochondrial disease v0.1031 MT-ND6 Zornitza Stark edited their review of gene: MT-ND6: Added comment: DEFINITIVE by ClinGen.

More than 20 affected individuals reported, the m.14484T>C and m.14487T>C variants are recurrent.

Affected individuals present with a broad phenotypic spectrum of disease including Leber Hereditary Optic Neuropathy (LHON), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and LSS phenotypes, as well as migraines, tremor, multiple sclerosis, and cardiac involvement. The age of onset is also highly variable, ranging from infantile to adult.

Muscle biopsies revealed isolated complex I deficiency, and complex I and III deficiencies; and complex I deficiency was also seen in fibroblasts and liver. Metabolic screening investigations showed elevated lactate and pyruvate in cerebrospinal fluid (CSF) and blood.

Heteroplasmy levels in affected individuals ranged from 50% to >95% in skeletal muscle; 25% to >95% in blood, 76% to >95% in fibroblasts, and 65% to >95% in liver; and ranged in healthy family members from undetectable to 92% in blood, undetectable to 95% in urine, 14% to 95% in hair follicles, 16% to 68% in buccal, and was undetectable in muscle in healthy family members.; Changed publications: 5576045, 20019223, 21196529, 10894222, 14684687, 17535832, 19103152, 21749722, 23813926, 25356405, 14595656, 19062322, 11133798, 30741831, 21364701, 2018041; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-ND6-related
Mendeliome v1.3180 MT-ND6 Zornitza Stark Marked gene: MT-ND6 as ready
Mendeliome v1.3180 MT-ND6 Zornitza Stark Gene: mt-nd6 has been classified as Green List (High Evidence).
Mendeliome v1.3180 MT-ND6 Zornitza Stark Classified gene: MT-ND6 as Green List (high evidence)
Mendeliome v1.3180 MT-ND6 Zornitza Stark Gene: mt-nd6 has been classified as Green List (High Evidence).
Mendeliome v1.3179 MT-ND6 Zornitza Stark gene: MT-ND6 was added
gene: MT-ND6 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND6.
Mode of inheritance for gene gene: MT-ND6 was set to MITOCHONDRIAL
Publications for gene: MT-ND6 were set to 5576045; 20019223; 21196529; 10894222; 14684687; 17535832; 19103152; 21749722; 23813926; 25356405; 14595656; 19062322; 11133798; 30741831; 21364701; 2018041
Phenotypes for gene: MT-ND6 were set to Mitochondrial disease (MONDO:0044970), MT-ND6-related
Review for gene: MT-ND6 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 20 affected individuals reported, the m.14484T>C and m.14487T>C variants are recurrent.

Affected individuals present with a broad phenotypic spectrum of disease including Leber Hereditary Optic Neuropathy (LHON), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and LSS phenotypes, as well as migraines, tremor, multiple sclerosis, and cardiac involvement. The age of onset is also highly variable, ranging from infantile to adult.

Muscle biopsies revealed isolated complex I deficiency, and complex I and III deficiencies; and complex I deficiency was also seen in fibroblasts and liver. Metabolic screening investigations showed elevated lactate and pyruvate in cerebrospinal fluid (CSF) and blood.

Heteroplasmy levels in affected individuals ranged from 50% to >95% in skeletal muscle; 25% to >95% in blood, 76% to >95% in fibroblasts, and 65% to >95% in liver; and ranged in healthy family members from undetectable to 92% in blood, undetectable to 95% in urine, 14% to 95% in hair follicles, 16% to 68% in buccal, and was undetectable in muscle in healthy family members.
Sources: Expert list
Mitochondrial disease v0.1031 MT-ND5 Zornitza Stark Phenotypes for gene: MT-ND5 were changed from Mitochondrial complex I deficiency; Leber's optic neuropathy; MERFF to Mitochondrial disease (MONDO:0044970), MT-ND5-related
Mitochondrial disease v0.1030 MT-ND5 Zornitza Stark Publications for gene: MT-ND5 were set to
Mitochondrial disease v0.1029 MT-ND5 Zornitza Stark edited their review of gene: MT-ND5: Added comment: DEFINITIVE by ClinGen.

More than 20 individuals reported. Two variants are recurrent (m.13513G>A and m.13094T>C).

Affected individuals present with a broad phenotypic spectrum of disease including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; myoclonus epilepsy, ragged red fibers (MERRF); and cardiomyopathy. The age of onset is also highly variable, ranging from infantile to adult.

Muscle biopsies variably revealed ragged red fibers, isolated complex I deficiency, and variable combined deficiencies of complexes I, III, and/or IV. Metabolic screening investigations showed elevated lactate in cerebrospinal fluid (CSF) and blood and urinary excretion of Krebs cycle intermediates.

Heteroplasmy levels in affected individuals ranged from 28% - 90% in skeletal muscle, 23% to 77% in blood, undetectable to 90% in fibroblasts, 51% - 81% in urine; and ranged in healthy family members from undetectable to 20% in blood, undetectable to 25% to 95% in hair follicles, undetectable to 4-6% muscle, and ranged from 27%-45% in other tissues such as urine and buccal samples in healthy family members.; Changed publications: 17400793, 11938446, 12624137, 18495510, 23918514, 17535832, 29506874, 23034978, 16816025, 9299505, 18977334; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-ND5-related
Mendeliome v1.3178 MT-ND5 Zornitza Stark Marked gene: MT-ND5 as ready
Mendeliome v1.3178 MT-ND5 Zornitza Stark Gene: mt-nd5 has been classified as Green List (High Evidence).
Mendeliome v1.3178 MT-ND5 Zornitza Stark Classified gene: MT-ND5 as Green List (high evidence)
Mendeliome v1.3178 MT-ND5 Zornitza Stark Gene: mt-nd5 has been classified as Green List (High Evidence).
Mendeliome v1.3177 MT-ND5 Zornitza Stark gene: MT-ND5 was added
gene: MT-ND5 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND5.
Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL
Publications for gene: MT-ND5 were set to 17400793; 11938446; 12624137; 18495510; 23918514; 17535832; 29506874; 23034978; 16816025; 9299505; 18977334
Phenotypes for gene: MT-ND5 were set to Mitochondrial disease (MONDO:0044970), MT-ND5-related
Review for gene: MT-ND5 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 20 individuals reported. Two variants are recurrent (m.13513G>A and m.13094T>C).

Affected individuals present with a broad phenotypic spectrum of disease including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; myoclonus epilepsy, ragged red fibers (MERRF); and cardiomyopathy. The age of onset is also highly variable, ranging from infantile to adult.

Muscle biopsies variably revealed ragged red fibers, isolated complex I deficiency, and variable combined deficiencies of complexes I, III, and/or IV. Metabolic screening investigations showed elevated lactate in cerebrospinal fluid (CSF) and blood and urinary excretion of Krebs cycle intermediates.

Heteroplasmy levels in affected individuals ranged from 28% - 90% in skeletal muscle, 23% to 77% in blood, undetectable to 90% in fibroblasts, 51% - 81% in urine; and ranged in healthy family members from undetectable to 20% in blood, undetectable to 25% to 95% in hair follicles, undetectable to 4-6% muscle, and ranged from 27%-45% in other tissues such as urine and buccal samples in healthy family members.
Sources: Expert list
Mitochondrial disease v0.1029 MT-ND4L Zornitza Stark Phenotypes for gene: MT-ND4L were changed from Leber's optic atrophy to Mitochondrial disease (MONDO:0044970), MT-ND4L-related
Mitochondrial disease v0.1028 MT-ND4L Zornitza Stark Publications for gene: MT-ND4L were set to
Mitochondrial disease v0.1027 MT-ND4L Zornitza Stark Classified gene: MT-ND4L as Amber List (moderate evidence)
Mitochondrial disease v0.1027 MT-ND4L Zornitza Stark Gene: mt-nd4l has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1026 MT-ND4L Zornitza Stark edited their review of gene: MT-ND4L: Added comment: LIMITED by ClinGen.

Seven probands with m.10063T>C have been reported across five publications, all of whom had LHON. These cases were scored with reduced points by ClinGen given the mild impact this variant has been shown to have on complex I function. While three other missense variants (m.10543A>G, m.10591T>G, m.10680G>A) have been reported, the ClinGen Expert Panel agreed there was only sufficient evidence of pathogenicity for the m.10663T>C variant. Cases with m.10680G>A and m.10543A>G and m.10591T>G were reviewed but excluded from scoring due to a lack of compelling functional evidence to support pathogenicity. The m.10543A>G variant has been modeled in E. coli and showed a very mild reduction in NADH dehydrogenase activity (74% of control), which was not sufficient to be included in scoring.; Changed rating: AMBER; Changed publications: 8680405, 11935318, 17003408, 22879922, 24568867; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-ND4L-related
Mendeliome v1.3176 MT-ND4L Zornitza Stark Marked gene: MT-ND4L as ready
Mendeliome v1.3176 MT-ND4L Zornitza Stark Gene: mt-nd4l has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3176 MT-ND4L Zornitza Stark Classified gene: MT-ND4L as Amber List (moderate evidence)
Mendeliome v1.3176 MT-ND4L Zornitza Stark Gene: mt-nd4l has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3175 MT-ND4L Zornitza Stark gene: MT-ND4L was added
gene: MT-ND4L was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND4L.
Mode of inheritance for gene gene: MT-ND4L was set to MITOCHONDRIAL
Publications for gene: MT-ND4L were set to 8680405; 11935318; 17003408; 22879922; 24568867
Phenotypes for gene: MT-ND4L were set to Mitochondrial disease (MONDO:0044970), MT-ND4L-related
Review for gene: MT-ND4L was set to AMBER
Added comment: LIMITED by ClinGen.

Seven probands with m.10063T>C have been reported across five publications, all of whom had LHON. These cases were scored with reduced points by ClinGen given the mild impact this variant has been shown to have on complex I function. While three other missense variants (m.10543A>G, m.10591T>G, m.10680G>A) have been reported, the ClinGen Expert Panel agreed there was only sufficient evidence of pathogenicity for the m.10663T>C variant. Cases with m.10680G>A and m.10543A>G and m.10591T>G were reviewed but excluded from scoring due to a lack of compelling functional evidence to support pathogenicity. The m.10543A>G variant has been modeled in E. coli and showed a very mild reduction in NADH dehydrogenase activity (74% of control), which was not sufficient to be included in scoring.
Sources: Expert list
Mitochondrial disease v0.1026 MT-ND4 Zornitza Stark Phenotypes for gene: MT-ND4 were changed from Mitochondrial complex I deficiency; Leber's optic neuropathy; Dystonia to Mitochondrial disease (MONDO:0044970), MT-ND4-related
Mitochondrial disease v0.1025 MT-ND4 Zornitza Stark Publications for gene: MT-ND4 were set to
Mitochondrial disease v0.1024 MT-ND4 Zornitza Stark commented on gene: MT-ND4: DEFINITIVE by ClinGen.

Multiple individuals reported presenting with a broad phenotypic spectrum of clinical features including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; cerebellar ataxia, migraines, regression, developmental delay, leukoencephalopathy, myoclonus, seizures, stroke-like episodes, cognitive decline, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, ophthalmoplegia, short stature, and hypertrophic cardiomyopathy. Age of onset varied from infancy to adulthood. Muscle biopsy showed COX-negative fibers and complex I deficiency.

Heteroplasmy levels in affected individuals ranged from 60% - 83% in muscle, 40% - 80% in blood, and 76% - 78% in myoblasts, as well as from 57% - 73% in various other tissues (fibroblasts, liver, urine, buccal). Of note, the m.11778G>A common LHON variant was reported in affected individuals in the homoplasmic and heteroplasmic states.
Mendeliome v1.3174 MT-ND4 Zornitza Stark Marked gene: MT-ND4 as ready
Mendeliome v1.3174 MT-ND4 Zornitza Stark Gene: mt-nd4 has been classified as Green List (High Evidence).
Mitochondrial disease v0.1024 MT-ND4 Zornitza Stark edited their review of gene: MT-ND4: Changed publications: 12707444, 16120329, 15576045, 20502985, 27761019, 32445240, 32659360, 3201231; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-ND4-related
Mendeliome v1.3174 MT-ND4 Zornitza Stark Classified gene: MT-ND4 as Green List (high evidence)
Mendeliome v1.3174 MT-ND4 Zornitza Stark Gene: mt-nd4 has been classified as Green List (High Evidence).
Mendeliome v1.3173 MT-ND4 Zornitza Stark gene: MT-ND4 was added
gene: MT-ND4 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND4.
Mode of inheritance for gene gene: MT-ND4 was set to MITOCHONDRIAL
Publications for gene: MT-ND4 were set to 12707444; 16120329; 15576045; 20502985; 27761019; 32445240; 32659360; 3201231
Phenotypes for gene: MT-ND4 were set to Mitochondrial disease (MONDO:0044970), MT-ND4-related
Review for gene: MT-ND4 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported presenting with a broad phenotypic spectrum of clinical features including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; cerebellar ataxia, migraines, regression, developmental delay, leukoencephalopathy, myoclonus, seizures, stroke-like episodes, cognitive decline, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, ophthalmoplegia, short stature, and hypertrophic cardiomyopathy. Age of onset varied from infancy to adulthood. Muscle biopsy showed COX-negative fibers and complex I deficiency.

Heteroplasmy levels in affected individuals ranged from 60% - 83% in muscle, 40% - 80% in blood, and 76% - 78% in myoblasts, as well as from 57% - 73% in various other tissues (fibroblasts, liver, urine, buccal). Of note, the m.11778G>A common LHON variant was reported in affected individuals in the homoplasmic and heteroplasmic states.
Sources: Expert list
Mitochondrial disease v0.1024 MT-ND3 Zornitza Stark Phenotypes for gene: MT-ND3 were changed from Complex I deficiency to Mitochondrial disease (MONDO:0044970), MT-ND3-related
Mitochondrial disease v0.1023 MT-ND3 Zornitza Stark Publications for gene: MT-ND3 were set to
Mitochondrial disease v0.1022 MT-ND3 Zornitza Stark edited their review of gene: MT-ND3: Added comment: DEFINITIVE by ClinGen.

More than 15 affected individuals reported. Three variants are recurrent (m.10158T>C, m.10191T>C, m.10197G>A). Affected individuals present with a broad phenotypic spectrum of clinical features including LSS; Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); lactic acidosis, epilepsia partialis continua (EPC), epileptic encephalopathy, dystonia, and optic atrophy. The age of onset is also highly variable, ranging from infantile to adult. Muscle biopsy showed and complex I deficiency.; Changed publications: 1928099, 14705112, 14764913, 17152068, 20202874, 25118196, 25384404, 11456298, 19458970, 30199507, 29237403; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-ND3-related
Mendeliome v1.3172 MT-ND3 Zornitza Stark Marked gene: MT-ND3 as ready
Mendeliome v1.3172 MT-ND3 Zornitza Stark Gene: mt-nd3 has been classified as Green List (High Evidence).
Mendeliome v1.3172 MT-ND3 Zornitza Stark Classified gene: MT-ND3 as Green List (high evidence)
Mendeliome v1.3172 MT-ND3 Zornitza Stark Gene: mt-nd3 has been classified as Green List (High Evidence).
Mendeliome v1.3171 MT-ND3 Zornitza Stark gene: MT-ND3 was added
gene: MT-ND3 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND3.
Mode of inheritance for gene gene: MT-ND3 was set to MITOCHONDRIAL
Publications for gene: MT-ND3 were set to 1928099; 14705112; 14764913; 17152068; 20202874; 25118196; 25384404; 11456298; 19458970; 30199507; 29237403
Phenotypes for gene: MT-ND3 were set to Mitochondrial disease (MONDO:0044970), MT-ND3-related
Review for gene: MT-ND3 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 15 affected individuals reported. Three variants are recurrent (m.10158T>C, m.10191T>C, m.10197G>A). Affected individuals present with a broad phenotypic spectrum of clinical features including LSS; Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); lactic acidosis, epilepsia partialis continua (EPC), epileptic encephalopathy, dystonia, and optic atrophy. The age of onset is also highly variable, ranging from infantile to adult. Muscle biopsy showed and complex I deficiency.
Sources: Expert list
Mitochondrial disease v0.1022 MT-ND2 Zornitza Stark Phenotypes for gene: MT-ND2 were changed from Mitochondrial complex I deficiency; Leber's optic neuropathy to Mitochondrial disease (MONDO:0044970), MT-ND2-related
Mitochondrial disease v0.1021 MT-ND2 Zornitza Stark Publications for gene: MT-ND2 were set to
Mitochondrial disease v0.1020 MT-ND2 Zornitza Stark edited their review of gene: MT-ND2: Added comment: MODERATE by ClinGen. Multiple individuals reported. Age of onset in affected individuals ranged from 9 months old to childhood. Clinical features in affected individuals included Leigh syndrome spectrum, myopathy, ophthalmoplegia, and ptosis. Muscle biopsies revealed ragged red fibers and complex I deficiency. Metabolic screening labs showed elevated lactate and creatine kinase (CK). Heteroplasmy levels were >95% in blood, fibroblasts, and muscle in the individual with Leigh syndrome spectrum. However in the other two individuals with predominantly myopathic features, the variant was present at >94% in muscle and undetectable in other tissues tested.; Changed publications: 26258512, 16738010, 15781840, 12192017; Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-ND2-related
Mendeliome v1.3170 MT-ND2 Zornitza Stark Marked gene: MT-ND2 as ready
Mendeliome v1.3170 MT-ND2 Zornitza Stark Gene: mt-nd2 has been classified as Green List (High Evidence).
Mendeliome v1.3170 MT-ND2 Zornitza Stark Classified gene: MT-ND2 as Green List (high evidence)
Mendeliome v1.3170 MT-ND2 Zornitza Stark Gene: mt-nd2 has been classified as Green List (High Evidence).
Mendeliome v1.3169 MT-ND2 Zornitza Stark gene: MT-ND2 was added
gene: MT-ND2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-ND2 was set to MITOCHONDRIAL
Publications for gene: MT-ND2 were set to 26258512; 16738010; 15781840; 12192017
Phenotypes for gene: MT-ND2 were set to Mitochondrial disease (MONDO:0044970), MT-ND2-related
Review for gene: MT-ND2 was set to GREEN
Added comment: MODERATE by ClinGen.

Multiple individuals reported. Age of onset in affected individuals ranged from 9 months old to childhood. Clinical features in affected individuals included Leigh syndrome spectrum, myopathy, ophthalmoplegia, and ptosis. Muscle biopsies revealed ragged red fibers and complex I deficiency. Metabolic screening labs showed elevated lactate and creatine kinase (CK). Heteroplasmy levels were >95% in blood, fibroblasts, and muscle in the individual with Leigh syndrome spectrum. However in the other two individuals with predominantly myopathic features, the variant was present at >94% in muscle and undetectable in other tissues tested.
Sources: Expert list
Mitochondrial disease v0.1020 MT-ND1 Zornitza Stark Phenotypes for gene: MT-ND1 were changed from Mitochondrial complex I deficiency; Leber's optic neuropathy; Deafness; Dystonia to Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-ND1-related
Mitochondrial disease v0.1019 MT-ND1 Zornitza Stark Publications for gene: MT-ND1 were set to
Mitochondrial disease v0.1018 MT-ND1 Zornitza Stark edited their review of gene: MT-ND1: Added comment: Multiple individuals reported with variants in this gene and a range of phenotypes consistent with mitochondrial disease, including LHON and Leigh syndrome.; Changed publications: 39147111, 36717040, 34656796; Changed phenotypes: Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-ND1-related
Mendeliome v1.3168 MT-ND1 Zornitza Stark Marked gene: MT-ND1 as ready
Mendeliome v1.3168 MT-ND1 Zornitza Stark Gene: mt-nd1 has been classified as Green List (High Evidence).
Mendeliome v1.3168 MT-ND1 Zornitza Stark Classified gene: MT-ND1 as Green List (high evidence)
Mendeliome v1.3168 MT-ND1 Zornitza Stark Gene: mt-nd1 has been classified as Green List (High Evidence).
Mendeliome v1.3167 MT-ND1 Zornitza Stark gene: MT-ND1 was added
gene: MT-ND1 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND1.
Mode of inheritance for gene gene: MT-ND1 was set to MITOCHONDRIAL
Publications for gene: MT-ND1 were set to 39147111; 36717040; 34656796
Phenotypes for gene: MT-ND1 were set to Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-ND1-related
Review for gene: MT-ND1 was set to GREEN
Added comment: Multiple individuals reported with variants in this gene and a range of phenotypes consistent with mitochondrial disease, including LHON and Leigh syndrome.
Sources: Expert list
Mitochondrial disease v0.1018 MT-CYB Zornitza Stark Phenotypes for gene: MT-CYB were changed from Leber's optic atrophy; Encephalomyopathy; Cardiomyopathy to mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CYB-related
Mitochondrial disease v0.1017 MT-CYB Zornitza Stark changed review comment from: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease.; to: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease, including Leber's optic atrophy, encephalomyopathy, and cardiomyopathy.
Mendeliome v1.3166 MT-CYB Zornitza Stark changed review comment from: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease.
Sources: Expert list; to: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease, including Leber's optic atrophy, encephalomyopathy, and cardiomyopathy.
Sources: Expert list
Mitochondrial disease v0.1017 MT-CYB Zornitza Stark Publications for gene: MT-CYB were set to
Mitochondrial disease v0.1016 MT-CYB Zornitza Stark edited their review of gene: MT-CYB: Added comment: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease.; Changed publications: 39858655, 34804306, 26937408; Changed phenotypes: mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CYB-related
Mendeliome v1.3166 MT-CYB Zornitza Stark Marked gene: MT-CYB as ready
Mendeliome v1.3166 MT-CYB Zornitza Stark Gene: mt-cyb has been classified as Green List (High Evidence).
Mendeliome v1.3166 MT-CYB Zornitza Stark Classified gene: MT-CYB as Green List (high evidence)
Mendeliome v1.3166 MT-CYB Zornitza Stark Gene: mt-cyb has been classified as Green List (High Evidence).
Mendeliome v1.3165 MT-CYB Zornitza Stark gene: MT-CYB was added
gene: MT-CYB was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-CYB.
Mode of inheritance for gene gene: MT-CYB was set to MITOCHONDRIAL
Publications for gene: MT-CYB were set to 39858655; 34804306; 26937408
Phenotypes for gene: MT-CYB were set to mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CYB-related
Review for gene: MT-CYB was set to GREEN
Added comment: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease.
Sources: Expert list
Mitochondrial disease v0.1016 MT-CO2 Zornitza Stark Phenotypes for gene: MT-CO2 were changed from Cytochrome c oxidase deficiency to Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CO2-related
Mitochondrial disease v0.1015 MT-CO2 Zornitza Stark Publications for gene: MT-CO2 were set to
Mitochondrial disease v0.1014 MT-CO2 Zornitza Stark edited their review of gene: MT-CO2: Changed phenotypes: Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CO2-related
Mitochondrial disease v0.1014 MT-CO2 Zornitza Stark edited their review of gene: MT-CO2: Added comment: Multiple individuals reported with variants in this gene and a range of neurological and neuromuscular presentations consistent with mitochondrial disease.; Changed publications: 34325999, 30315213, 28521807
Mendeliome v1.3163 MT-CO2 Zornitza Stark Marked gene: MT-CO2 as ready
Mendeliome v1.3163 MT-CO2 Zornitza Stark Gene: mt-co2 has been classified as Green List (High Evidence).
Mendeliome v1.3163 MT-CO2 Zornitza Stark Classified gene: MT-CO2 as Green List (high evidence)
Mendeliome v1.3163 MT-CO2 Zornitza Stark Gene: mt-co2 has been classified as Green List (High Evidence).
Mendeliome v1.3162 MT-CO2 Zornitza Stark gene: MT-CO2 was added
gene: MT-CO2 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-CO2.
Mode of inheritance for gene gene: MT-CO2 was set to MITOCHONDRIAL
Publications for gene: MT-CO2 were set to 37640115; 34325999; 30315213; 28521807
Phenotypes for gene: MT-CO2 were set to Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CO2-related
Review for gene: MT-CO2 was set to GREEN
Added comment: Multiple individuals reported with variants in this gene and a range of neurological and neuromuscular presentations consistent with mitochondrial disease.
Sources: Expert list
Mendeliome v1.3161 MT-CO1 Zornitza Stark Marked gene: MT-CO1 as ready
Mendeliome v1.3161 MT-CO1 Zornitza Stark Gene: mt-co1 has been classified as Green List (High Evidence).
Mendeliome v1.3161 MT-CO1 Zornitza Stark Classified gene: MT-CO1 as Green List (high evidence)
Mendeliome v1.3161 MT-CO1 Zornitza Stark Gene: mt-co1 has been classified as Green List (High Evidence).
Mendeliome v1.3160 MT-CO1 Zornitza Stark Tag mtDNA tag was added to gene: MT-CO1.
Mendeliome v1.3160 MT-CO1 Zornitza Stark gene: MT-CO1 was added
gene: MT-CO1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-CO1 was set to MITOCHONDRIAL
Publications for gene: MT-CO1 were set to 30743023; 39460813; 24956508
Phenotypes for gene: MT-CO1 were set to Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CO1-related
Review for gene: MT-CO1 was set to GREEN
Added comment: Multiple individuals reported with a range of clinical presentations consistent with mitochondrial disease.
Sources: Expert list
Mitochondrial disease v0.1014 MT-CO1 Zornitza Stark Publications for gene: MT-CO1 were set to
Mitochondrial disease v0.1013 MT-CO1 Zornitza Stark edited their review of gene: MT-CO1: Changed publications: 30743023, 39460813, 24956508; Changed phenotypes: Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CO1-related
Mendeliome v1.3159 MT-ATP8 Zornitza Stark Marked gene: MT-ATP8 as ready
Mendeliome v1.3159 MT-ATP8 Zornitza Stark Gene: mt-atp8 has been classified as Green List (High Evidence).
Mendeliome v1.3159 MT-ATP8 Zornitza Stark Classified gene: MT-ATP8 as Green List (high evidence)
Mendeliome v1.3159 MT-ATP8 Zornitza Stark Gene: mt-atp8 has been classified as Green List (High Evidence).
Mendeliome v1.3158 MT-ATP8 Zornitza Stark gene: MT-ATP8 was added
gene: MT-ATP8 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ATP8.
Mode of inheritance for gene gene: MT-ATP8 was set to MITOCHONDRIAL
Publications for gene: MT-ATP8 were set to 40112238
Phenotypes for gene: MT-ATP8 were set to Mitochondrial complex V (ATP synthase) deficiency, MONDO:0014471, MT-ATP8-related
Review for gene: MT-ATP8 was set to GREEN
Added comment: Multiple individuals reported with wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI.
Sources: Expert list
Mendeliome v1.3157 MT-ATP6 Zornitza Stark Marked gene: MT-ATP6 as ready
Mendeliome v1.3157 MT-ATP6 Zornitza Stark Gene: mt-atp6 has been classified as Green List (High Evidence).
Mendeliome v1.3157 MT-ATP6 Zornitza Stark Classified gene: MT-ATP6 as Green List (high evidence)
Mendeliome v1.3157 MT-ATP6 Zornitza Stark Gene: mt-atp6 has been classified as Green List (High Evidence).
Mitochondrial disease v0.1013 MT-ATP6 Zornitza Stark Phenotypes for gene: MT-ATP6 were changed from Mitochondrial complex V (ATP synthase) deficiency to Mitochondrial complex V (ATP synthase) deficiency, MONDO:0014471, MT-ATP6-related
Mitochondrial disease v0.1012 MT-ATP6 Zornitza Stark Publications for gene: MT-ATP6 were set to
Mendeliome v1.3156 MT-ATP6 Zornitza Stark gene: MT-ATP6 was added
gene: MT-ATP6 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ATP6.
Mode of inheritance for gene gene: MT-ATP6 was set to MITOCHONDRIAL
Publications for gene: MT-ATP6 were set to 40112238
Phenotypes for gene: MT-ATP6 were set to Mitochondrial complex V (ATP synthase) deficiency, MONDO:0014471, MT-ATP6-related
Review for gene: MT-ATP6 was set to GREEN
Added comment: Multiple individuals reported with wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI.
Sources: Expert list
Mitochondrial disease v0.1011 MT-ATP6 Zornitza Stark edited their review of gene: MT-ATP6: Added comment: Multiple individuals reported with wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI.; Changed publications: 40112238
Mitochondrial disease v0.1011 MT-ATP6 Zornitza Stark edited their review of gene: MT-ATP6: Changed phenotypes: Mitochondrial complex V (ATP synthase) deficiency, MONDO:0014471, MT-ATP6-related
Mitochondrial disease v0.1011 PDHA1 Zornitza Stark Marked gene: PDHA1 as ready
Mitochondrial disease v0.1011 PDHA1 Zornitza Stark Gene: pdha1 has been classified as Green List (High Evidence).
Mitochondrial disease v0.1011 PDHA1 Zornitza Stark Phenotypes for gene: PDHA1 were changed from to Pyruvate dehydrogenase E1-alpha deficiency - MIM#312170
Mitochondrial disease v0.1010 PDHA1 Zornitza Stark Publications for gene: PDHA1 were set to
Mitochondrial disease v0.1009 PDHA1 Zornitza Stark Mode of inheritance for gene: PDHA1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.3155 BRSK2 Zornitza Stark Phenotypes for gene: BRSK2 were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BRSK2-related
Mendeliome v1.3154 BRSK2 Zornitza Stark edited their review of gene: BRSK2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BRSK2-related
Intellectual disability syndromic and non-syndromic v1.310 BRSK2 Zornitza Stark Phenotypes for gene: BRSK2 were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BRSK2-related
Cardiac conduction disease v1.1 NNT Bryony Thompson Marked gene: NNT as ready
Cardiac conduction disease v1.1 NNT Bryony Thompson Gene: nnt has been classified as Red List (Low Evidence).
Cardiac conduction disease v1.1 NNT Bryony Thompson gene: NNT was added
gene: NNT was added to Cardiac conduction disease. Sources: Literature
Mode of inheritance for gene: NNT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NNT were set to 26025024
Phenotypes for gene: NNT were set to left ventricular noncompaction MONDO:0018901
Review for gene: NNT was set to RED
Added comment: Only a single publication reporting an association with LVNC from 2015. Biallelic variants cause a mitochondrial disease that was first reported in 2012; therefore, more evidence of an association with LVNC would be expected.
Sources: Literature
Mitochondrial disease v0.1008 NNT Bryony Thompson Classified gene: NNT as Green List (high evidence)
Mitochondrial disease v0.1008 NNT Bryony Thompson Added comment: Comment on list classification: Classified as a primary mitochondrial disease by the ClinGen Mitochondrial Diseases GCEP
Mitochondrial disease v0.1008 NNT Bryony Thompson Gene: nnt has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.309 BRSK2 Sarah Milton reviewed gene: BRSK2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, BRSK2-related; Mode of inheritance: None
Mendeliome v1.3154 BMP7 Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract; Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) to Congenital anomaly of kidney and urinary tract, MONDO:0019719, BMP7-related; Isolated craniosynostosis, MONDO:0015337, BMP7-related; Mayer-Rokitansky-Kuster-Hauser syndrome, MONDO:0017771, BMP7-related
Mendeliome v1.3153 BMP7 Sarah Milton reviewed gene: BMP7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital anomaly of kidney and urinary tract, MONDO:0019719, BMP7-related, Isolated craniosynostosis, MONDO:0015337, BMP7-related, Mayer-Rokitansky-Kuster-Hauser syndrome, MONDO:0017771, BMP7-related; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v1.309 UPF1 Zornitza Stark Phenotypes for gene: UPF1 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092, UPF1-related
Syndromic Retinopathy v0.232 CYP2U1 Zornitza Stark Marked gene: CYP2U1 as ready
Syndromic Retinopathy v0.232 CYP2U1 Zornitza Stark Gene: cyp2u1 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.232 CYP2U1 Zornitza Stark Classified gene: CYP2U1 as Green List (high evidence)
Syndromic Retinopathy v0.232 CYP2U1 Zornitza Stark Gene: cyp2u1 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.231 CYP2U1 Zornitza Stark gene: CYP2U1 was added
gene: CYP2U1 was added to Syndromic Retinopathy. Sources: Expert Review
Mode of inheritance for gene: CYP2U1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP2U1 were set to 23176821; 26914923; 33107650; 34828401; 38058766; 39605873
Phenotypes for gene: CYP2U1 were set to Spastic paraplegia 56, autosomal recessive, OMIM:615030
Review for gene: CYP2U1 was set to GREEN
Added comment: CYP2U1 is known to cause hereditary spastic paraplegia, with a variable spectrum of other symptoms being reported: intellectual disability, dystonia, pseudoxanthoma elasticum, and visual impairments (pigmentary degenerative maculopathy, loss of visual acuity, photophobia). There are at least 8 unrelated individuals with retinal abnormalities with biallelic variants in CYP2U1, harbouring missense, stop-gained, splice-altering, and frameshift variants (PMID: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873). The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases) – sometimes appearing as the first symptom, before spasticity (e.g. PMID:26914923, 39605873).

FUNCTIONAL EVIDENCE: A Cyp2u1−/− mouse model recapitulated the retinal impairments observed in patients – mice exhibited a late-onset (18 mo) ophthalmologic phenotype characterized by a cone dystrophy (PMID: 34546337 Pujol et al., 2021). Skin fibroblasts of an individual with c.61_73del, p.(Leu21Trpfs∗19) in CYP2U1 showed reduced oxygen consumption compared to controls, as well as structural abnormalities of the mitochondrial membrane (PMID: 23176821 Tesson et al., 2012). Expressing CYP2U1 with missense variants in HEK293T cells demonstrated that most missense variants were functionally inactive, due to loss of proper heme binding or destabilization of the protein structure (PMID: 29034544 Durand et al., 2018). Thus, the proposed disease mechanism is LoF leading to mitochondrial dysfunction - a common driver for degenerative retinal disease.
Sources: Expert Review
Hereditary Neuropathy - complex v1.33 TTC19 Zornitza Stark Marked gene: TTC19 as ready
Hereditary Neuropathy - complex v1.33 TTC19 Zornitza Stark Gene: ttc19 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v1.33 TTC19 Zornitza Stark Classified gene: TTC19 as Green List (high evidence)
Hereditary Neuropathy - complex v1.33 TTC19 Zornitza Stark Gene: ttc19 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v1.32 TTC19 Zornitza Stark gene: TTC19 was added
gene: TTC19 was added to Hereditary Neuropathy - complex. Sources: Expert list
Mode of inheritance for gene: TTC19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC19 were set to 40946707; 37927170; 25652355
Phenotypes for gene: TTC19 were set to Mitochondrial complex III deficiency, nuclear type 2, MIM#615157
Review for gene: TTC19 was set to GREEN
Added comment: Neuropathy reported in at least 3 individuals with this condition.
Sources: Expert list
Clefting disorders v0.274 CTGF Zornitza Stark Marked gene: CTGF as ready
Clefting disorders v0.274 CTGF Zornitza Stark Gene: ctgf has been classified as Amber List (Moderate Evidence).
Clefting disorders v0.274 CTGF Zornitza Stark Classified gene: CTGF as Amber List (moderate evidence)
Clefting disorders v0.274 CTGF Zornitza Stark Gene: ctgf has been classified as Amber List (Moderate Evidence).
Clefting disorders v0.273 CTGF Zornitza Stark gene: CTGF was added
gene: CTGF was added to Clefting disorders. Sources: Expert Review
Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTGF were set to 39506047; 39414788; 12736220
Phenotypes for gene: CTGF were set to Kyphomelic dysplasia, OMIM:211350; kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
Review for gene: CTGF was set to AMBER
Added comment: PMID: 39506047 (2025) reported three individuals from two unrelated families with different homozygous CCN2 variants and kyphomelic dysplasia - all had cleft palate or bifid uvula as part of their phenotype. Ccn2-deficient mice also show skeletal dysmorphisms as well as secondary cleft palate, supporting this association.
Sources: Expert Review
Mendeliome v1.3153 TBX2 Zornitza Stark reviewed gene: TBX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 20206336, 22052739, 21271665, https://doi.org/10.1101/2024.07.18.24310488; Phenotypes: Hearing loss disorder, MONDO:0005365, TBX2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Deafness_IsolatedAndComplex v1.226 TBX2 Zornitza Stark Marked gene: TBX2 as ready
Deafness_IsolatedAndComplex v1.226 TBX2 Zornitza Stark Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Deafness_IsolatedAndComplex v1.226 TBX2 Zornitza Stark Classified gene: TBX2 as Amber List (moderate evidence)
Deafness_IsolatedAndComplex v1.226 TBX2 Zornitza Stark Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Deafness_IsolatedAndComplex v1.225 TBX2 Zornitza Stark gene: TBX2 was added
gene: TBX2 was added to Deafness_IsolatedAndComplex. Sources: Expert Review
Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX2 were set to 20206336; 22052739; 21271665; https://doi.org/10.1101/2024.07.18.24310488
Phenotypes for gene: TBX2 were set to Hearing loss disorder, MONDO:0005365, TBX2-related
Review for gene: TBX2 was set to AMBER
Added comment: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple.

A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS.

Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern.

Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood.

Functional data:
Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss.
Sources: Expert Review
Mendeliome v1.3153 NTN1 Zornitza Stark Phenotypes for gene: NTN1 were changed from Mirror movements 4 MIM#618264 to Mirror movements 4 MIM#618264; Hearing loss disorder, MONDO:0005365, NTN1-related
Mendeliome v1.3152 NTN1 Zornitza Stark Publications for gene: NTN1 were set to 25763452; 28945198; 33472083
Mendeliome v1.3151 NTN1 Zornitza Stark reviewed gene: NTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39648562; Phenotypes: Hearing loss disorder, MONDO:0005365, NTN1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Deafness_IsolatedAndComplex v1.224 NTN1 Zornitza Stark Marked gene: NTN1 as ready
Deafness_IsolatedAndComplex v1.224 NTN1 Zornitza Stark Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Deafness_IsolatedAndComplex v1.224 NTN1 Zornitza Stark Classified gene: NTN1 as Amber List (moderate evidence)
Deafness_IsolatedAndComplex v1.224 NTN1 Zornitza Stark Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Deafness_IsolatedAndComplex v1.223 NTN1 Zornitza Stark edited their review of gene: NTN1: Changed rating: AMBER
Deafness_IsolatedAndComplex v1.223 NTN1 Zornitza Stark gene: NTN1 was added
gene: NTN1 was added to Deafness_IsolatedAndComplex. Sources: Expert Review
Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NTN1 were set to 39648562
Phenotypes for gene: NTN1 were set to Hearing loss disorder, MONDO:0005365, NTN1-related
Added comment: PMID: 39648562 (Toms et al., 2024) reports a patient with bilateral sensorineural hearing loss, heterozygous for a de novo variant in NTN1: NM_004822.3:c.1483T>A p.(Tyr495Asn). Sequencing method: WGS.The patient (Female, 30 years old, White British) also had chorioretinal coloboma and microphthalmia, and right hand polydactyly. The C-terminus variant is not found in gnomAD v4.1.0; in silico prediction tools: Revel score = 0.5 (Uncertain), AlphaMissense score = 0.806 (Deleterious Supporting).

In PMID: 39648562, morpholino knockdown of ntn1a in zebrafish (86% gene similarity to human ortholog) had ocular coloboma and sensory hair cell defects. At 5 dpf, hair cells of the lateral line neuromasts were found have abnormal morphology. There was also a significant reduction in the overall number of sensory hair cells present.
Sources: Expert Review
Combined Immunodeficiency v1.129 GNAI2 Zornitza Stark Marked gene: GNAI2 as ready
Combined Immunodeficiency v1.129 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v1.129 GNAI2 Zornitza Stark Classified gene: GNAI2 as Green List (high evidence)
Combined Immunodeficiency v1.129 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v1.128 GNAI2 Zornitza Stark gene: GNAI2 was added
gene: GNAI2 was added to Combined Immunodeficiency. Sources: Literature
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNAI2 were set to 31036916; 40926810; 39298586
Phenotypes for gene: GNAI2 were set to Syndromic disease MONDO:0002254, GNAI2-related
Review for gene: GNAI2 was set to GREEN
Added comment: PMID: 40926810 | 20 individuals from 18 families with a multisystem syndrome termed MAGIS (“Midline malformations of the brain, Anterior pituitary gland dysfunction, Growth retardation, Immunodysregulation/immunodeficiency, and Skeletal defects”) caused by heterozygous germline activating mutations. Considerable phenotypic heterogeneity with inter- and intra-familial variability. Majority of variants occur at recurrent residues Thr182 (Thr182Ala/Ile/Pro in six families) and Arg179 (Arg179His/Cys in seven patients from five families). The patients’ mutations were clustered in the P-loop and switch regions of the Ras-like domain of Gα, which is critical for guanine-nucleotide binding and GTPase activity. See PMID: 39298586 supplementary data for patient details of the above cohort. Other common features in the cohort also include intellectual disability (9/17), neurodevelopmental delay (13/19), motor delay (13/19), deafness (11/15), cryptochordism (7/14).

Immune-mediated disease (95%) is widely present in MAGIS as both immunodeficiency (90%) and immune dysregulation (50%; systemic autoinflammation, 15%, autoimmunity, 35%, and splenomegaly, 35%).
Sources: Literature
Disorders of immune dysregulation v1.28 GNAI2 Zornitza Stark Marked gene: GNAI2 as ready
Disorders of immune dysregulation v1.28 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.28 GNAI2 Zornitza Stark Classified gene: GNAI2 as Green List (high evidence)
Disorders of immune dysregulation v1.28 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.27 GNAI2 Zornitza Stark gene: GNAI2 was added
gene: GNAI2 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNAI2 were set to 31036916; 40926810; 39298586
Phenotypes for gene: GNAI2 were set to Syndromic disease MONDO:0002254, GNAI2-related
Review for gene: GNAI2 was set to GREEN
Added comment: PMID: 40926810 | 20 individuals from 18 families with a multisystem syndrome termed MAGIS (“Midline malformations of the brain, Anterior pituitary gland dysfunction, Growth retardation, Immunodysregulation/immunodeficiency, and Skeletal defects”) caused by heterozygous germline activating mutations. Considerable phenotypic heterogeneity with inter- and intra-familial variability. Majority of variants occur at recurrent residues Thr182 (Thr182Ala/Ile/Pro in six families) and Arg179 (Arg179His/Cys in seven patients from five families). The patients’ mutations were clustered in the P-loop and switch regions of the Ras-like domain of Gα, which is critical for guanine-nucleotide binding and GTPase activity. See PMID: 39298586 supplementary data for patient details of the above cohort. Other common features in the cohort also include intellectual disability (9/17), neurodevelopmental delay (13/19), motor delay (13/19), deafness (11/15), cryptochordism (7/14).

Immune-mediated disease (95%) is widely present in MAGIS as both immunodeficiency (90%) and immune dysregulation (50%; systemic autoinflammation, 15%, autoimmunity, 35%, and splenomegaly, 35%).
Sources: Literature
Pituitary hormone deficiency v0.39 GNAI2 Zornitza Stark Marked gene: GNAI2 as ready
Pituitary hormone deficiency v0.39 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Pituitary hormone deficiency v0.39 GNAI2 Zornitza Stark Classified gene: GNAI2 as Green List (high evidence)
Pituitary hormone deficiency v0.39 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Pituitary hormone deficiency v0.38 GNAI2 Zornitza Stark gene: GNAI2 was added
gene: GNAI2 was added to Pituitary hormone deficiency. Sources: Literature
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNAI2 were set to 31036916; 40926810; 39298586
Phenotypes for gene: GNAI2 were set to Syndromic disease MONDO:0002254, GNAI2-related
Review for gene: GNAI2 was set to GREEN
Added comment: PMID: 40926810 | 20 individuals from 18 families with a multisystem syndrome termed MAGIS (“Midline malformations of the brain, Anterior pituitary gland dysfunction, Growth retardation, Immunodysregulation/immunodeficiency, and Skeletal defects”) caused by heterozygous germline activating mutations. Considerable phenotypic heterogeneity with inter- and intra-familial variability. Majority of variants occur at recurrent residues Thr182 (Thr182Ala/Ile/Pro in six families) and Arg179 (Arg179His/Cys in seven patients from five families). The patients’ mutations were clustered in the P-loop and switch regions of the Ras-like domain of Gα, which is critical for guanine-nucleotide binding and GTPase activity. See PMID: 39298586 supplementary data for patient details of the above cohort. Other common features in the cohort also include intellectual disability (9/17), neurodevelopmental delay (13/19), motor delay (13/19), deafness (11/15), cryptochordism (7/14).
Sources: Literature
Growth failure v1.82 GNAI2 Zornitza Stark Marked gene: GNAI2 as ready
Growth failure v1.82 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Growth failure v1.82 GNAI2 Zornitza Stark Classified gene: GNAI2 as Green List (high evidence)
Growth failure v1.82 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.308 GNAI2 Zornitza Stark Phenotypes for gene: GNAI2 were changed from Syndromic intellectual disability to Syndromic disease MONDO:0002254, GNAI2-related
Intellectual disability syndromic and non-syndromic v1.307 GNAI2 Zornitza Stark Publications for gene: GNAI2 were set to 31036916
Intellectual disability syndromic and non-syndromic v1.306 GNAI2 Zornitza Stark Classified gene: GNAI2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.306 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Mendeliome v1.3151 GNAI2 Zornitza Stark Phenotypes for gene: GNAI2 were changed from Pituitary adenoma, ACTH-secreting, somatic; Ventricular tachycardia, idiopathic 192605; Syndromic developmental disorder to Syndromic disease MONDO:0002254, GNAI2-related
Mendeliome v1.3150 GNAI2 Zornitza Stark Publications for gene: GNAI2 were set to PMID: 31036916
Mendeliome v1.3149 GNAI2 Zornitza Stark Classified gene: GNAI2 as Green List (high evidence)
Mendeliome v1.3149 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.305 TRPC5 Zornitza Stark Publications for gene: TRPC5 were set to 36323681; 24817631; 23033978; 33504798; 28191890
Mendeliome v1.3148 TRPC5 Zornitza Stark Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Mendeliome v1.3147 BMPR1A Zornitza Stark Phenotypes for gene: BMPR1A were changed from Polyposis, juvenile intestinal, MIM# 174900 to BMPR1A-related juvenile polyposis syndrome MONDO:0700348
Callosome v0.561 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765
Callosome v0.560 CDK5 Zornitza Stark Classified gene: CDK5 as Green List (high evidence)
Callosome v0.560 CDK5 Zornitza Stark Gene: cdk5 has been classified as Green List (High Evidence).
Callosome v0.559 CDK5 Zornitza Stark edited their review of gene: CDK5: Added comment: PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.

Also note multiple animal models.; Changed rating: GREEN; Changed publications: 25560765, 40186457, 32273484, 32097629, 28854363, 7490100
Fetal anomalies v1.420 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765; 32273484; 32097629; 28854363; 7490100
Fetal anomalies v1.419 CDK5 Zornitza Stark Classified gene: CDK5 as Green List (high evidence)
Fetal anomalies v1.419 CDK5 Zornitza Stark Gene: cdk5 has been classified as Green List (High Evidence).
Fetal anomalies v1.418 CDK5 Zornitza Stark edited their review of gene: CDK5: Added comment: PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.; Changed rating: GREEN; Changed publications: 25560765, 32273484, 32097629, 28854363, 7490100, 40186457
Genetic Epilepsy v1.213 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765
Genetic Epilepsy v1.212 CDK5 Zornitza Stark Classified gene: CDK5 as Green List (high evidence)
Genetic Epilepsy v1.212 CDK5 Zornitza Stark Gene: cdk5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.211 CDK5 Zornitza Stark reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40186457; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, MIM# 616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebellar and Pontocerebellar Hypoplasia v1.89 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765; 32273484; 32097629; 28854363; 7490100
Cerebellar and Pontocerebellar Hypoplasia v1.88 CDK5 Zornitza Stark Classified gene: CDK5 as Green List (high evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.88 CDK5 Zornitza Stark Gene: cdk5 has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.87 CDK5 Zornitza Stark edited their review of gene: CDK5: Added comment: PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.; Changed rating: GREEN; Changed publications: 25560765, 32273484, 32097629, 28854363, 7490100, 40186457
Lissencephaly and Band Heterotopia v1.23 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765; 32273484; 32097629; 28854363; 7490100
Lissencephaly and Band Heterotopia v1.22 CDK5 Zornitza Stark Classified gene: CDK5 as Green List (high evidence)
Lissencephaly and Band Heterotopia v1.22 CDK5 Zornitza Stark Gene: cdk5 has been classified as Green List (High Evidence).
Lissencephaly and Band Heterotopia v1.21 CDK5 Zornitza Stark edited their review of gene: CDK5: Added comment: PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.; Changed rating: GREEN; Changed publications: 25560765, 32273484, 32097629, 28854363, 7490100, 40186457
Mendeliome v1.3146 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765; 32273484; 32097629; 28854363; 7490100
Mendeliome v1.3145 CDK5 Zornitza Stark Classified gene: CDK5 as Green List (high evidence)
Mendeliome v1.3145 CDK5 Zornitza Stark Gene: cdk5 has been classified as Green List (High Evidence).
Vitreoretinopathy v1.9 RS1 Zornitza Stark Publications for gene: RS1 were set to 20301401, 25999676
Vitreoretinopathy v1.8 RS1 Zornitza Stark Classified gene: RS1 as Green List (high evidence)
Vitreoretinopathy v1.8 RS1 Zornitza Stark Gene: rs1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v1.26 PACSIN3 Zornitza Stark Phenotypes for gene: PACSIN3 were changed from Myopathy, MONDO:0005336, PACSIN3-related to Congenital myopathy 27, MIM# 621343
Rhabdomyolysis and Metabolic Myopathy v1.25 PACSIN3 Zornitza Stark edited their review of gene: PACSIN3: Changed phenotypes: Congenital myopathy 27, MIM# 621343
Muscular dystrophy and myopathy_Paediatric v1.97 PACSIN3 Zornitza Stark Phenotypes for gene: PACSIN3 were changed from Myopathy, MONDO:0005336, PACSIN3-related to Congenital myopathy 27, MIM# 621343
Muscular dystrophy and myopathy_Paediatric v1.96 PACSIN3 Zornitza Stark edited their review of gene: PACSIN3: Changed phenotypes: Congenital myopathy 27, MIM# 621343
Mendeliome v1.3144 PACSIN3 Zornitza Stark Phenotypes for gene: PACSIN3 were changed from Myopathy, MONDO:0005336, PACSIN3-related to Congenital myopathy 27, MIM# 621343
Mendeliome v1.3143 PACSIN3 Zornitza Stark edited their review of gene: PACSIN3: Changed phenotypes: Congenital myopathy 27, MIM# 621343
Growth failure v1.81 GNAI2 Rylee Peters gene: GNAI2 was added
gene: GNAI2 was added to Growth failure. Sources: Literature
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNAI2 were set to 40926810; 39298586
Phenotypes for gene: GNAI2 were set to Syndromic disease MONDO:0002254, GNAI2-related
Review for gene: GNAI2 was set to GREEN
Added comment: PMID: 40926810 | 20 individuals from 18 families with a multisystem syndrome termed MAGIS (“Midline malformations of the brain, Anterior pituitary gland dysfunction, Growth retardation, Immunodysregulation/immunodeficiency, and Skeletal defects”) caused by heterozygous germline activating mutations. Considerable phenotypic heterogeneity with inter- and intra-familial variability.

Majority of variants occur at recurrent residues Thr182 (Thr182Ala/Ile/Pro in six families) and Arg179 (Arg179His/Cys in seven patients from five families). The patients’ mutations were clustered in the P-loop and switch regions of the Ras-like domain of Gα, which is critical for guanine-nucleotide binding and GTPase activity.

See PMID: 39298586 supplementary data for patient details of the above cohort. Other common features in the cohort also include intellectual disability (9/17), neurodevelopmental delay (13/19), motor delay (13/19), deafness (11/15), cryptochordism (7/14).
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.304 GNAI2 Rylee Peters reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40926810, 39298586; Phenotypes: Syndromic disease MONDO:0002254, GNAI2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3143 GNAI2 Rylee Peters reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40926810, 39298586; Phenotypes: Syndromic disease MONDO:0002254, GNAI2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.304 TRPC5 Rylee Peters reviewed gene: TRPC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 40907672; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TRPC5-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3143 TRPC5 Rylee Peters reviewed gene: TRPC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 40907672; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TRPC5-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3143 BMPR1A Leah Frajman reviewed gene: BMPR1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: BMPR1A-related juvenile polyposis syndrome MONDO:0700348; Mode of inheritance: None
Mendeliome v1.3143 PRKCI Sangavi Sivagnanasundram edited their review of gene: PRKCI: Changed rating: GREEN
Mendeliome v1.3143 PRKCI Sangavi Sivagnanasundram changed review comment from: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

The gene is not constrained for LoF in gnomAD and there are no pathogenic SNVs reported in ClinVar at this present time. Amber until further evidence is published in support of this gene-disease association.
Sources: Literature; to: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

Sources: Literature
Clefting disorders v0.272 PRKCI Sangavi Sivagnanasundram edited their review of gene: PRKCI: Changed rating: GREEN
Clefting disorders v0.272 PRKCI Sangavi Sivagnanasundram changed review comment from: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

The gene is not constrained for LoF in gnomAD and there are no pathogenic SNVs reported in ClinVar at this present time. Amber until further evidence is published in support of this gene-disease association.
Sources: Literature; to: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

Sources: Literature
Mendeliome v1.3143 CDK5 Arina Puzriakova reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40186457; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3143 ANLN Zornitza Stark Publications for gene: ANLN were set to 24676636; 30002222
Mendeliome v1.3142 ANLN Zornitza Stark edited their review of gene: ANLN: Added comment: Further reports but evidence is conflicting, including variants with implausibly high pop frequency.

Gbadegesin et al (2014); Hall et al (2018) 2 x families reported with FSGS (USA) and missense variants G618C (v4: absent) and R431C (v4: 63 hets, 0 hom). R431C was identified in 6 affected family members and absent in 6 unaffected family members. G618C was present in the proband and absent in 4 unaffected family members, the other 2 affected individuals from this family were not genotyped (deceased). Missense demostrated as LoF with both in vitro and in vivo (zebrafish). R431C was shown to disrupt interaction with CD2AP (primarily LoF effect), causing downstream hyperactivation of the PI3K/AKT/mTOR/Rac1 signaling pathway, which drives podocytes hypermotility.

Geminiganesan et al (2021) 1 x 2 year old child (India) with early-onset steroid resistant nephrotic syndrome, whole-exome sequencing and genome-wide linkage studies, a missense variant in ANLN was identified p.Thr821Met (v4: 508 hets, 0 hom).

Zhang et al (2023) 3 x children with steroid resistant nephrotic syndrome (China). 2 x missense (p.M1099I - LP (v4:1 het, 0 hom), p.S140T - VUS (v4: 6 hets, 0 hom) and 1 x stop gain reported p.R39X - LP ( v4: 1 het, 0 hom).

Lin et al (2023) 3 x unrelated individuals with missense E841K (China, v4: 618 hets, 2 hom). In famly A the variant was de novo, in family 2 only the proband as tested, in family 3 the variant was inherited from an affected father. 4 x unaffected individuals did not have the variant. Knockout mouse model inconclusive, did not show any effect until 36 weeks. Zebrafish model was also inconclusive.; Changed publications: 24676636, 30002222, 34819827, 38322629, 37957688
Proteinuria v0.230 ANLN Zornitza Stark Publications for gene: ANLN were set to 24676636; 30002222
Mendeliome v1.3142 COL4A3BP Zornitza Stark Phenotypes for gene: COL4A3BP were changed from Intellectual developmental disorder 34 (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Mendeliome v1.3141 COL4A3BP Zornitza Stark edited their review of gene: COL4A3BP: Changed phenotypes: Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Mendeliome v1.3141 COL4A3BP Zornitza Stark Phenotypes for gene: COL4A3BP were changed from Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351) to Intellectual developmental disorder 34 (MIM#616351)
Clefting disorders v0.272 PRKCI Zornitza Stark Marked gene: PRKCI as ready
Clefting disorders v0.272 PRKCI Zornitza Stark Gene: prkci has been classified as Green List (High Evidence).
Clefting disorders v0.272 PRKCI Zornitza Stark Phenotypes for gene: PRKCI were changed from Van der Woude syndrome MONDO:0019508 to Van der Woude syndrome MONDO:0019508, PRKCI-related
Clefting disorders v0.271 PRKCI Zornitza Stark Classified gene: PRKCI as Green List (high evidence)
Clefting disorders v0.271 PRKCI Zornitza Stark Gene: prkci has been classified as Green List (High Evidence).
Clefting disorders v0.270 PRKCI Zornitza Stark reviewed gene: PRKCI: Rating: GREEN; Mode of pathogenicity: None; Publications: 40902599; Phenotypes: Van der Woude syndrome MONDO:0019508, PRKCI-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3140 PRKCI Zornitza Stark Marked gene: PRKCI as ready
Mendeliome v1.3140 PRKCI Zornitza Stark Gene: prkci has been classified as Green List (High Evidence).
Mendeliome v1.3140 PRKCI Zornitza Stark Phenotypes for gene: PRKCI were changed from Van der Woude syndrome MONDO:0019508 to Van der Woude syndrome MONDO:0019508, PRKCI-related
Mendeliome v1.3139 PRKCI Zornitza Stark Classified gene: PRKCI as Green List (high evidence)
Mendeliome v1.3139 PRKCI Zornitza Stark Gene: prkci has been classified as Green List (High Evidence).
Mendeliome v1.3138 PRKCI Zornitza Stark reviewed gene: PRKCI: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Van der Woude syndrome MONDO:0019508, PRKCI-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.304 TMEM167A Zornitza Stark Marked gene: TMEM167A as ready
Intellectual disability syndromic and non-syndromic v1.304 TMEM167A Zornitza Stark Gene: tmem167a has been classified as Green List (High Evidence).
Genetic Epilepsy v1.211 TMEM167A Zornitza Stark Marked gene: TMEM167A as ready
Genetic Epilepsy v1.211 TMEM167A Zornitza Stark Gene: tmem167a has been classified as Green List (High Evidence).
Microcephaly v1.339 TMEM167A Zornitza Stark Marked gene: TMEM167A as ready
Microcephaly v1.339 TMEM167A Zornitza Stark Gene: tmem167a has been classified as Green List (High Evidence).
Mendeliome v1.3138 TMEM167A Zornitza Stark Marked gene: TMEM167A as ready
Mendeliome v1.3138 TMEM167A Zornitza Stark Gene: tmem167a has been classified as Green List (High Evidence).
Monogenic Diabetes v0.147 TMEM167A Zornitza Stark Marked gene: TMEM167A as ready
Monogenic Diabetes v0.147 TMEM167A Zornitza Stark Gene: tmem167a has been classified as Green List (High Evidence).
Mendeliome v1.3138 BAIAP3 Zornitza Stark Marked gene: BAIAP3 as ready
Mendeliome v1.3138 BAIAP3 Zornitza Stark Gene: baiap3 has been classified as Red List (Low Evidence).
Mendeliome v1.3138 BAIAP3 Zornitza Stark gene: BAIAP3 was added
gene: BAIAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BAIAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BAIAP3 were set to 40943168
Phenotypes for gene: BAIAP3 were set to Retinitis pigmentosa MONDO:0019200, BAIAP3-related
Review for gene: BAIAP3 was set to RED
Added comment: 1 individual with retinitis pigmentosa with onset at 18yrs. Trio WGS identified biallelic missense variants in BAIAP3 gene (c.556C>G [p.Arg186Gly] and c.3099C>G [p.His1033Gln]). Both variants were very rare in gnomAD, and the healthy brother was heterozygous for one variant. BAIAP3 interacts with SNARE proteins, whose function is essential for endosome-mediated retrograde trafficking. Single-cell RNA sequencing profiling showed enhanced expression of the BAIAP3 gene in ciliated cells, astrocytes, excitatory and inhibitory neurons, and enteroendocrine cells. Confocal microscopy analysis showed elongated cilia in patient-derived and BAIAP3-depleted fibroblasts compared to control cells.
Sources: Literature
Retinitis pigmentosa v0.177 BAIAP3 Zornitza Stark Marked gene: BAIAP3 as ready
Retinitis pigmentosa v0.177 BAIAP3 Zornitza Stark Gene: baiap3 has been classified as Red List (Low Evidence).
Additional findings_Adult v1.129 Bryony Thompson Panel status changed from internal to public
Vitreoretinopathy v1.7 RS1 Sangavi Sivagnanasundram gene: RS1 was added
gene: RS1 was added to Vitreoretinopathy. Sources: Other
Mode of inheritance for gene: RS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RS1 were set to 20301401, 25999676
Phenotypes for gene: RS1 were set to Retinoschisis MONDO:0004579
Review for gene: RS1 was set to GREEN
Added comment: 4-40% of individuals with XLRS develop vitreous haemorrhage. Retinoschisis is also referred to vitreous veils of the retina.

PMID: 25999676
10 individuals presented with macular schisis. Vitreous haemorhaging was a presenting feature in 4 individuals from different families.
Sources: Other
Intellectual disability syndromic and non-syndromic v1.304 KDM5A Rylee Peters reviewed gene: KDM5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 33350388; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), KDM5A-related, AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3137 KDM5A Rylee Peters reviewed gene: KDM5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 33350388; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), KDM5A-related, AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Proteinuria v0.229 ANLN Melanie Marty reviewed gene: ANLN: Rating: AMBER; Mode of pathogenicity: None; Publications: 24676636, 30002222, 34819827, 38322629, 37957688; Phenotypes: Focal segmental glomerulosclerosis 8, MIM#616032; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hydrocephalus_Ventriculomegaly v0.130 TRIM71 Elena Savva Phenotypes for gene: TRIM71 were changed from Congenital hydrocephalus 4 (MIM#618667) to Congenital hydrocephalus 4 (MIM#618667)
Hydrocephalus_Ventriculomegaly v0.129 TRIM71 Elena Savva Phenotypes for gene: TRIM71 were changed from Congenital hydrocephalus 4 (MIM#618667) to Congenital hydrocephalus 4 (MIM#618667)
Hydrocephalus_Ventriculomegaly v0.129 TRIM71 Elena Savva Phenotypes for gene: TRIM71 were changed from Hydrocephalus, congenital communicating, 1 618667 to Congenital hydrocephalus 4 (MIM#618667)
Fetal anomalies v1.418 TRIM71 Elena Savva Phenotypes for gene: TRIM71 were changed from Hydrocephalus, congenital communicating, 1 - #618667 to Congenital hydrocephalus 4 (MIM#618667)
Mendeliome v1.3137 TRIM71 Elena Savva Phenotypes for gene: TRIM71 were changed from Congenital hydrocephalus 4 (MIM#618667) to Congenital hydrocephalus 4 (MIM#618667)
Mendeliome v1.3137 TRIM71 Elena Savva Phenotypes for gene: TRIM71 were changed from Hydrocephalus, congenital communicating, 1 618667 to Congenital hydrocephalus 4 (MIM#618667)
Genetic Epilepsy v1.211 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Intellectual disability syndromic and non-syndromic v1.304 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Intellectual developmental disorder 34 (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Disorders of immune dysregulation v1.26 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Intellectual developmental disorder 34 (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Genetic Epilepsy v1.210 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Intellectual developmental disorder 34 (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Fetal anomalies v1.417 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Mental retardation, autosomal dominant 34, MIM# 616351 to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Mendeliome v1.3136 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Mendeliome v1.3135 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Intellectual developmental disorder 34 (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Clefting disorders v0.270 PRKCI Sangavi Sivagnanasundram gene: PRKCI was added
gene: PRKCI was added to Clefting disorders. Sources: Literature
Mode of inheritance for gene: PRKCI was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRKCI were set to 40902599
Phenotypes for gene: PRKCI were set to Van der Woude syndrome MONDO:0019508
Review for gene: PRKCI was set to AMBER
Added comment: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

The gene is not constrained for LoF in gnomAD and there are no pathogenic SNVs reported in ClinVar at this present time. Amber until further evidence is published in support of this gene-disease association.
Sources: Literature
Mendeliome v1.3134 PRKCI Sangavi Sivagnanasundram gene: PRKCI was added
gene: PRKCI was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKCI was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRKCI were set to 40902599
Phenotypes for gene: PRKCI were set to Van der Woude syndrome MONDO:0019508
Review for gene: PRKCI was set to AMBER
Added comment: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

The gene is not constrained for LoF in gnomAD and there are no pathogenic SNVs reported in ClinVar at this present time. Amber until further evidence is published in support of this gene-disease association.
Sources: Literature
Genetic Epilepsy v1.209 TMEM167A Chirag Patel Classified gene: TMEM167A as Green List (high evidence)
Genetic Epilepsy v1.209 TMEM167A Chirag Patel Gene: tmem167a has been classified as Green List (High Evidence).
Microcephaly v1.339 TMEM167A Chirag Patel Classified gene: TMEM167A as Green List (high evidence)
Microcephaly v1.339 TMEM167A Chirag Patel Gene: tmem167a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.303 TMEM167A Chirag Patel Classified gene: TMEM167A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.303 TMEM167A Chirag Patel Gene: tmem167a has been classified as Green List (High Evidence).
Mendeliome v1.3134 TMEM167A Chirag Patel Classified gene: TMEM167A as Green List (high evidence)
Mendeliome v1.3134 TMEM167A Chirag Patel Gene: tmem167a has been classified as Green List (High Evidence).
Microcephaly v1.338 TMEM167A Chirag Patel gene: TMEM167A was added
gene: TMEM167A was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to PMID: 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome MONDO:0100328, TMEM167A-related
Review for gene: TMEM167A was set to GREEN
Added comment: 6 individuals from 6 unrelated families (4/6 consanguineous) presenting with neonatal diabetes onset <4mths (6/6), severe microcephaly (6/6), epilepsy (5/6), and developmental delay (4/6).

Whole genome sequencing identified biallelic variants in TMEM167A gene. Variants were homozygous in 5/6 families, and variant types were missense (4), frameshift (1), and splice (1), and all variants were rare/unreported in gnomAD. Segregation studies not reported in paper.

Microcephaly, epilepsy and diabetes syndrome has 2 known associated genes (IER3IP1 and YIPF5) which encode proteins involved in endoplasmic reticulum to Golgi trafficking. TMEM167A is highly expressed in developing and adult human pancreas and brain. Both TMEM167A depletion in EndoC-βH1 cells and knock‑in of p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction.
Sources: Literature
Monogenic Diabetes v0.147 TMEM167A Chirag Patel Classified gene: TMEM167A as Green List (high evidence)
Monogenic Diabetes v0.147 TMEM167A Chirag Patel Gene: tmem167a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.302 TMEM167A Chirag Patel gene: TMEM167A was added
gene: TMEM167A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to PMID: 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome MONDO:0100328, TMEM167A-related
Review for gene: TMEM167A was set to GREEN
Added comment: 6 individuals from 6 unrelated families (4/6 consanguineous) presenting with neonatal diabetes onset <4mths (6/6), severe microcephaly (6/6), epilepsy (5/6), and developmental delay (4/6).

Whole genome sequencing identified biallelic variants in TMEM167A gene. Variants were homozygous in 5/6 families, and variant types were missense (4), frameshift (1), and splice (1), and all variants were rare/unreported in gnomAD. Segregation studies not reported in paper.

Microcephaly, epilepsy and diabetes syndrome has 2 known associated genes (IER3IP1 and YIPF5) which encode proteins involved in endoplasmic reticulum to Golgi trafficking. TMEM167A is highly expressed in developing and adult human pancreas and brain. Both TMEM167A depletion in EndoC-βH1 cells and knock‑in of p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction.
Sources: Literature
Mendeliome v1.3133 TMEM167A Chirag Patel gene: TMEM167A was added
gene: TMEM167A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to PMID: 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome MONDO:0100328, TMEM167A-related
Review for gene: TMEM167A was set to GREEN
Added comment: 6 individuals from 6 unrelated families (4/6 consanguineous) presenting with neonatal diabetes onset <4mths (6/6), severe microcephaly (6/6), epilepsy (5/6), and developmental delay (4/6).

Whole genome sequencing identified biallelic variants in TMEM167A gene. Variants were homozygous in 5/6 families, and variant types were missense (4), frameshift (1), and splice (1), and all variants were rare/unreported in gnomAD. Segregation studies not reported in paper.

Microcephaly, epilepsy and diabetes syndrome has 2 known associated genes (IER3IP1 and YIPF5) which encode proteins involved in endoplasmic reticulum to Golgi trafficking. TMEM167A is highly expressed in developing and adult human pancreas and brain. Both TMEM167A depletion in EndoC-βH1 cells and knock‑in of p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction.
Sources: Literature
Genetic Epilepsy v1.208 TMEM167A Chirag Patel gene: TMEM167A was added
gene: TMEM167A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to PMID: 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome MONDO:0100328, TMEM167A-related
Review for gene: TMEM167A was set to GREEN
Added comment: 6 individuals from 6 unrelated families (4/6 consanguineous) presenting with neonatal diabetes onset <4mths (6/6), severe microcephaly (6/6), epilepsy (5/6), and developmental delay (4/6).

Whole genome sequencing identified biallelic variants in TMEM167A gene. Variants were homozygous in 5/6 families, and variant types were missense (4), frameshift (1), and splice (1), and all variants were rare/unreported in gnomAD. Segregation studies not reported in paper.

Microcephaly, epilepsy and diabetes syndrome has 2 known associated genes (IER3IP1 and YIPF5) which encode proteins involved in endoplasmic reticulum to Golgi trafficking. TMEM167A is highly expressed in developing and adult human pancreas and brain. Both TMEM167A depletion in EndoC-βH1 cells and knock‑in of p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction.
Sources: Literature
Monogenic Diabetes v0.146 TMEM167A Chirag Patel gene: TMEM167A was added
gene: TMEM167A was added to Monogenic Diabetes. Sources: Literature
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to PMID: 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome MONDO:0100328, TMEM167A-related
Review for gene: TMEM167A was set to GREEN
Added comment: 6 individuals from 6 unrelated families (4/6 consanguineous) presenting with neonatal diabetes onset <4mths (6/6), severe microcephaly (6/6), epilepsy (5/6), and developmental delay (4/6).

Whole genome sequencing identified biallelic variants in TMEM167A gene. Variants were homozygous in 5/6 families, and variant types were missense (4), frameshift (1), and splice (1), and all variants were rare/unreported in gnomAD. Segregation studies not reported in paper.

Microcephaly, epilepsy and diabetes syndrome has 2 known associated genes (IER3IP1 and YIPF5) which encode proteins involved in endoplasmic reticulum to Golgi trafficking. TMEM167A is highly expressed in developing and adult human pancreas and brain. Both TMEM167A depletion in EndoC-βH1 cells and knock‑in of p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction.
Sources: Literature
Retinitis pigmentosa v0.177 BAIAP3 Chirag Patel gene: BAIAP3 was added
gene: BAIAP3 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
Mode of inheritance for gene: BAIAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BAIAP3 were set to PMID: 40943168
Phenotypes for gene: BAIAP3 were set to Retinitis pigmentosa MONDO:0019200, BAIAP3-related
Review for gene: BAIAP3 was set to RED
Added comment: 1 individual with retinitis pigmentosa with onset at 18yrs. Trio WGS identified biallelic missense variants in BAIAP3 gene (c.556C>G [p.Arg186Gly] and c.3099C>G [p.His1033Gln]). Both variants were very rare in gnomAD, and the healthy brother was heterozygous for one variant.

BAIAP3 interacts with SNARE proteins, whose function is essential for endosome-mediated retrograde trafficking. Single-cell RNA sequencing
profiling showed enhanced expression of the BAIAP3 gene in ciliated cells, astrocytes, excitatory and inhibitory neurons, and enteroendocrine cells.

Confocal microscopy analysis showed elongated cilia in patient-derived and BAIAP3-depleted fibroblasts compared to control cells.
Sources: Literature
Mitochondrial disease v0.1007 QRSL1 Zornitza Stark Phenotypes for gene: QRSL1 were changed from Combined oxidative phosphorylation deficiency 40 to Combined oxidative phosphorylation deficiency 40 MIM#618835
Mitochondrial disease v0.1006 QRSL1 Zornitza Stark edited their review of gene: QRSL1: Changed phenotypes: Combined oxidative phosphorylation deficiency 40 MIM#618835
Mendeliome v1.3132 QRSL1 Zornitza Stark Phenotypes for gene: QRSL1 were changed from Combined oxidative phosphorylation deficiency 40 to Combined oxidative phosphorylation deficiency 40 MIM#618835
Intellectual disability syndromic and non-syndromic v1.301 RAB11A Zornitza Stark Publications for gene: RAB11A were set to 29100083
Intellectual disability syndromic and non-syndromic v1.300 RAB11A Zornitza Stark Phenotypes for gene: RAB11A were changed from Intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, RAB11A-related
Intellectual disability syndromic and non-syndromic v1.299 RAB11A Zornitza Stark edited their review of gene: RAB11A: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, RAB11A-related
Mendeliome v1.3131 RAB11A Zornitza Stark Phenotypes for gene: RAB11A were changed from Intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, RAB11A-related
Mendeliome v1.3130 CETN3 Zornitza Stark Marked gene: CETN3 as ready
Mendeliome v1.3130 CETN3 Zornitza Stark Gene: cetn3 has been classified as Red List (Low Evidence).
Mendeliome v1.3130 CETN3 Zornitza Stark Classified gene: CETN3 as Red List (low evidence)
Mendeliome v1.3130 CETN3 Zornitza Stark Gene: cetn3 has been classified as Red List (Low Evidence).
Microcephaly v1.337 CETN3 Zornitza Stark Marked gene: CETN3 as ready
Microcephaly v1.337 CETN3 Zornitza Stark Gene: cetn3 has been classified as Red List (Low Evidence).
Microcephaly v1.337 CETN3 Zornitza Stark Classified gene: CETN3 as Red List (low evidence)
Microcephaly v1.337 CETN3 Zornitza Stark Gene: cetn3 has been classified as Red List (Low Evidence).
Glycogen Storage Diseases v1.3 PYGM Zornitza Stark Phenotypes for gene: PYGM were changed from McArdle disease, MIM# 232600; Glycogen storage disease, autosomal dominant to McArdle disease, MIM# 232600; Disorder of glycogen metabolism MONDO:0002412, PYGM-related, AD
Glycogen Storage Diseases v1.2 PYGM Zornitza Stark edited their review of gene: PYGM: Changed phenotypes: McArdle disease, MIM# 232600, Disorder of glycogen metabolism MONDO:0002412, PYGM-related, AD
Mendeliome v1.3129 PYGM Zornitza Stark Phenotypes for gene: PYGM were changed from McArdle disease, MIM# 232600; Glycogen storage disease, autosomal dominant to McArdle disease, MIM# 232600; Disorder of glycogen metabolism MONDO:0002412, PYGM-related, AD
Intellectual disability syndromic and non-syndromic v1.299 ZNF865 Zornitza Stark Marked gene: ZNF865 as ready
Intellectual disability syndromic and non-syndromic v1.299 ZNF865 Zornitza Stark Gene: znf865 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.299 ZNF865 Zornitza Stark Classified gene: ZNF865 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.299 ZNF865 Zornitza Stark Gene: znf865 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.298 ZNF865 Zornitza Stark reviewed gene: ZNF865: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ZNF865‑associated neurodevelopmental disorder MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3128 ZNF865 Zornitza Stark Marked gene: ZNF865 as ready
Mendeliome v1.3128 ZNF865 Zornitza Stark Gene: znf865 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3128 ZNF865 Zornitza Stark Classified gene: ZNF865 as Amber List (moderate evidence)
Mendeliome v1.3128 ZNF865 Zornitza Stark Gene: znf865 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3127 ZNF865 Zornitza Stark reviewed gene: ZNF865: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ZNF865‑associated neurodevelopmental disorder MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3127 PTPRC Zornitza Stark Phenotypes for gene: PTPRC were changed from Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive MIM# 608971; Hepatitis C virus, susceptibility to MIM# 609532 to Immunodeficiency 105, severe combined MIM#619924; Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive MIM# 608971; Hepatitis C virus, susceptibility to MIM# 609532
Mendeliome v1.3126 PTPN22 Zornitza Stark Phenotypes for gene: PTPN22 were changed from to Autoimmune disease MONDO:0007179, PTPN22-related
Early-onset Parkinson disease v2.39 PTPA Zornitza Stark Phenotypes for gene: PTPA were changed from Intellectual disability, MONDO: 36073231, PTPA-related; Parkisonism to Intellectual disability, MONDO: 36073231, PTPA-related; Parkinson disease MONDO:0005180, PTPA-related
Early-onset Parkinson disease v2.38 PTPA Zornitza Stark edited their review of gene: PTPA: Changed phenotypes: Intellectual disability, MONDO: 36073231, PTPA-related, Parkinson disease MONDO:0005180, PTPA-related
Mendeliome v1.3125 PTPA Zornitza Stark Phenotypes for gene: PTPA were changed from Intellectual disability, MONDO: 36073231, PTPA-related to Intellectual disability, MONDO: 36073231, PTPA-related; Parkinson disease MONDO:0005180, PTPA-related
Bleeding and Platelet Disorders v1.59 PTGS1 Zornitza Stark Phenotypes for gene: PTGS1 were changed from Platelet dysfunction; bleeding to Platelet-type bleeding disorder 12 MONDO:0011588
Bleeding and Platelet Disorders v1.58 PTGS1 Zornitza Stark edited their review of gene: PTGS1: Changed phenotypes: Platelet-type bleeding disorder 12 MONDO:0011588
Mendeliome v1.3124 PTGS1 Zornitza Stark Phenotypes for gene: PTGS1 were changed from Platelet dysfunction; bleeding to Platelet-type bleeding disorder 12 MONDO:0011588
Fetal anomalies v1.416 PTCH1 Zornitza Stark Phenotypes for gene: PTCH1 were changed from Holoprosencephaly 7, MIM# 610828 to Holoprosencephaly 7, MIM# 610828; Exstrophy-epispadias complex MONDO:0017919, PTCH1-related
Differences of Sex Development v1.17 PTCH1 Zornitza Stark Phenotypes for gene: PTCH1 were changed from Bladder exstrophy and epispadias complex (BEEC) to Exstrophy-epispadias complex MONDO:0017919, PTCH1-related
Differences of Sex Development v1.16 PTCH1 Zornitza Stark reviewed gene: PTCH1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Exstrophy-epispadias complex MONDO:0017919, PTCH1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.127 PTCH1 Zornitza Stark Marked gene: PTCH1 as ready
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.127 PTCH1 Zornitza Stark Gene: ptch1 has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.127 PTCH1 Zornitza Stark Phenotypes for gene: PTCH1 were changed from Bladder exstrophy and epispadias complex (BEEC) to Exstrophy-epispadias complex MONDO:0017919, PTCH1-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 PTCH1 Zornitza Stark reviewed gene: PTCH1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Exstrophy-epispadias complex MONDO:0017919, PTCH1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3123 PTCH1 Zornitza Stark Phenotypes for gene: PTCH1 were changed from Holoprosencephaly 7, MIM# 610828; Bladder exstrophy and epispadias complex (BEEC) to Holoprosencephaly 7, MIM# 610828; Exstrophy-epispadias complex MONDO:0017919, PTCH1-related
Mitochondrial disease v0.1006 PTCD1 Zornitza Stark Phenotypes for gene: PTCD1 were changed from Cardiomyopathy to Cardiomyopathy MONDO:0004994, PTCD1-related
Mitochondrial disease v0.1005 PTCD1 Zornitza Stark edited their review of gene: PTCD1: Changed phenotypes: Cardiomyopathy MONDO:0004994, PTCD1-related
Mendeliome v1.3122 PTCD1 Zornitza Stark Phenotypes for gene: PTCD1 were changed from Cardiomyopathy to Cardiomyopathy MONDO:0004994, PTCD1-related
Intellectual disability syndromic and non-syndromic v1.298 PSMC1 Zornitza Stark Phenotypes for gene: PSMC1 were changed from Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071 to Birk-Aharoni syndrome MIM# 620071
Intellectual disability syndromic and non-syndromic v1.297 PSMC1 Zornitza Stark edited their review of gene: PSMC1: Changed phenotypes: Birk-Aharoni syndrome MIM# 620071
Mendeliome v1.3121 PSMC1 Zornitza Stark Phenotypes for gene: PSMC1 were changed from Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071 to Birk-Aharoni syndrome MIM# 620071
Bone Marrow Failure v1.126 SRP72 Zornitza Stark Publications for gene: SRP72 were set to 22541560; 31254415
Bone Marrow Failure v1.125 SRP72 Zornitza Stark edited their review of gene: SRP72: Added comment: PMID: 40922878 14yo with pruritus, pancytopenia, decreased bone marrow proliferation, low granulocyte proportion, increased erythrocyte proportion, and rare megakaryocytes. Heterozygous for c.1442_1448del, p.Ile481Thrfs*12 which was inherited from his unaffected 46yo father. This variant is absent from gnomad but there are more than 10 other NMD-predicted variants with >/=5 hets in gnomad.; Changed publications: 22541560, 31254415, 40922878
Mendeliome v1.3120 SRP72 Zornitza Stark Publications for gene: SRP72 were set to 22541560; 31254415
Autoinflammatory Disorders v2.21 TOM1 Zornitza Stark Marked gene: TOM1 as ready
Autoinflammatory Disorders v2.21 TOM1 Zornitza Stark Gene: tom1 has been classified as Amber List (Moderate Evidence).
Autoinflammatory Disorders v2.21 TOM1 Zornitza Stark Classified gene: TOM1 as Amber List (moderate evidence)
Autoinflammatory Disorders v2.21 TOM1 Zornitza Stark Gene: tom1 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.336 CETN3 Rylee Peters gene: CETN3 was added
gene: CETN3 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: CETN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CETN3 were set to 40926052
Phenotypes for gene: CETN3 were set to microcephaly, MONDO:0001149, CETN3-related
Review for gene: CETN3 was set to RED
Added comment: PMID: 40926052: 1x cHet individual with primary microcephaly (-2 SD at birth and -3 SD at 5yo), motor delay, enlarged bilateral ventricles on MRI, horizontal nystagmus. Two frameshift variants identified, p.Lys15Glufs*9 (5’ NMD-escape; 432 hets, 2 homs in gnomAD v4) and p.Asp40Lysfs*5 (NMD-predicted; filtered out in v4).

CETN3-KO hCOs (human cerebral organoids) were significantly smaller than control hCOs.
The identified patient variants were introduced into WT iPSCs. Western blot analysis demonstrated a complete loss of CETN3 protein in both CETN3-KO cells and CETN3-mutant iPSCs. These were then used to generate hCOs, both of which exhibited reduced size compared to their respective controls.

Forebrain-specific Cetn3-ablated mice were also generated. At embryonic day 13.5 a significant but subtle reduction in forebrain size was detected in Cetn3-KO mice compared to control, while no difference was observed at P0.
Sources: Literature
Mendeliome v1.3119 CETN3 Rylee Peters gene: CETN3 was added
gene: CETN3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CETN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CETN3 were set to 40926052
Phenotypes for gene: CETN3 were set to microcephaly, MONDO:0001149, CETN3-related
Review for gene: CETN3 was set to RED
Added comment: PMID: 40926052: 1x cHet individual with primary microcephaly (-2 SD at birth and -3 SD at 5yo), motor delay, enlarged bilateral ventricles on MRI, horizontal nystagmus. Two frameshift variants identified, p.Lys15Glufs*9 (5’ NMD-escape; 432 hets, 2 homs in gnomAD v4) and p.Asp40Lysfs*5 (NMD-predicted; filtered out in v4).

CETN3-KO hCOs (human cerebral organoids) were significantly smaller than control hCOs.
The identified patient variants were introduced into WT iPSCs. Western blot analysis demonstrated a complete loss of CETN3 protein in both CETN3-KO cells and CETN3-mutant iPSCs. These were then used to generate hCOs, both of which exhibited reduced size compared to their respective controls.

Forebrain-specific Cetn3-ablated mice were also generated. At embryonic day 13.5 a significant but subtle reduction in forebrain size was detected in Cetn3-KO mice compared to control, while no difference was observed at P0.
Sources: Literature
Autoinflammatory Disorders v2.20 TOM1 Zornitza Stark gene: TOM1 was added
gene: TOM1 was added to Autoinflammatory Disorders. Sources: Literature
Mode of inheritance for gene: TOM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TOM1 were set to 31263572; 40936361; 33864888
Phenotypes for gene: TOM1 were set to Immunodeficiency 85 and autoimmunity MIM#619510
Review for gene: TOM1 was set to AMBER
Added comment: PMID 31263572: Parent and child reported with onset of atopic eczema and recurrent respiratory infections in the first decade of life; autoimmune enteropathy with vomiting, diarrhoea, and poor overall growth. More variable features included autoimmune oligoarthritis, interstitial pneumonitis, and EBV viremia. Laboratory studies showed hypogammaglobulinaemia and abnormal T-cell function, consistent with a combined immunodeficiency. Missense variant in TOM1, with limited functional data.

PMID: 33864888 reports a new unrelated patient to the previous family, a 2yo with congenital autoimmune enteropathy, exocrine pancreatic insufficiency, failure to thrive, hepatitis, atopic dermatitis, pityriasis alba, hypogammaglobulinemia, lymphopenia. Has a canonical splice variant c.267+2T>C which they have shown has 2 splicing outcomes; intron 4 retention leading to a stopgain, or cryptic donor splicing causing an in frame deletion of ~130 amino acids of the vesicular trafficking domain.

PMID: 40936361 no new patients just more functional data on the originally reported missense Gly307Asp. Typically TOM1 binding to TOLLIP decreases the affinity of TOLLIP to phosphatidylinositol 3-phosphate (PtdIns3P), increasing the commitment of both proteins to cargo trafficking. This variant was shown to reduce this inhibitory effect, and impair TOM1's ability to inhibit TOLLIP binding to PtdIns3P. Patient cells also displayed delayed autophagosome clearance and more robust phosphorylation of ERK1/2 and AKT.
Sources: Literature
Mendeliome v1.3119 TOM1 Zornitza Stark Publications for gene: TOM1 were set to 31263572; 40936361
Combined Immunodeficiency v1.127 TOM1 Zornitza Stark Classified gene: TOM1 as Amber List (moderate evidence)
Combined Immunodeficiency v1.127 TOM1 Zornitza Stark Gene: tom1 has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v1.126 TOM1 Zornitza Stark edited their review of gene: TOM1: Added comment: PMID: 33864888 reports a new unrelated patient to the previous family, a 2yo with congenital autoimmune enteropathy, exocrine pancreatic insufficiency, failure to thrive, hepatitis, atopic dermatitis, pityriasis alba, hypogammaglobulinemia, lymphopenia. Has a canonical splice variant c.267+2T>C which they have shown has 2 splicing outcomes; intron 4 retention leading to a stopgain, or cryptic donor splicing causing an in frame deletion of ~130 amino acids of the vesicular trafficking domain.

PMID: 40936361 no new patients just more functional data on the originally reported missense Gly307Asp. Typically TOM1 binding to TOLLIP decreases the affinity of TOLLIP to phosphatidylinositol 3-phosphate (PtdIns3P), increasing the commitment of both proteins to cargo trafficking. This variant was shown to reduce this inhibitory effect, and impair TOM1's ability to inhibit TOLLIP binding to PtdIns3P. Patient cells also displayed delayed autophagosome clearance and more robust phosphorylation of ERK1/2 and AKT.; Changed rating: AMBER; Changed publications: 31263572, 40936361, 33864888; Changed phenotypes: Immunodeficiency 85 and autoimmunity, MIM# 619510
Mendeliome v1.3118 RAB11A Lucy Spencer reviewed gene: RAB11A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, RAB11A-related; Mode of inheritance: None
Mendeliome v1.3118 TOM1 Zornitza Stark Publications for gene: TOM1 were set to 31263572
Mendeliome v1.3117 TOM1 Zornitza Stark Classified gene: TOM1 as Amber List (moderate evidence)
Mendeliome v1.3117 TOM1 Zornitza Stark Gene: tom1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3116 QRSL1 Lucy Spencer reviewed gene: QRSL1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 40 MIM#618835; Mode of inheritance: None
Fetal anomalies v1.415 SNAPIN Zornitza Stark Marked gene: SNAPIN as ready
Fetal anomalies v1.415 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Fetal anomalies v1.415 SNAPIN Zornitza Stark Classified gene: SNAPIN as Green List (high evidence)
Fetal anomalies v1.415 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.297 SNAPIN Zornitza Stark Marked gene: SNAPIN as ready
Intellectual disability syndromic and non-syndromic v1.297 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.297 SNAPIN Zornitza Stark Classified gene: SNAPIN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.297 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Callosome v0.559 SNAPIN Zornitza Stark Marked gene: SNAPIN as ready
Callosome v0.559 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Callosome v0.559 SNAPIN Zornitza Stark Classified gene: SNAPIN as Green List (high evidence)
Callosome v0.559 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Mendeliome v1.3116 PYGM Lucy Spencer reviewed gene: PYGM: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Disorder of glycogen metabolism MONDO:0002412, PYGM-related, AD; Mode of inheritance: None
Microcephaly v1.336 SNAPIN Zornitza Stark Marked gene: SNAPIN as ready
Microcephaly v1.336 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Microcephaly v1.336 SNAPIN Zornitza Stark Classified gene: SNAPIN as Green List (high evidence)
Microcephaly v1.336 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Mendeliome v1.3116 SNAPIN Zornitza Stark Marked gene: SNAPIN as ready
Mendeliome v1.3116 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Mendeliome v1.3116 SNAPIN Zornitza Stark Classified gene: SNAPIN as Green List (high evidence)
Mendeliome v1.3116 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.296 ZNF865 Sangavi Sivagnanasundram gene: ZNF865 was added
gene: ZNF865 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF865 were set to 40936200
Phenotypes for gene: ZNF865 were set to ZNF865‑associated neurodevelopmental disorder MONDO:0700092
Review for gene: ZNF865 was set to AMBER
Added comment: PMID: 40936200
18 patients reported with DD, hypotonia and six individuals were reported with some dysmorphic features (frontal bossing, a broad nasal bridge, hypertelorism, and low-set ears)
All 18 individuals were reported with de novo truncating variants in ZNF865. All variants were rare/absent in gnomAD v4.1.

The mechanism of disease for this gene is unknown. No pathogenic SNVs have been reported in ClinVar at this stage however there are reports of VUS’s and pathogenic CNVs.
Sources: Literature
Autoinflammatory Disorders v2.19 PSMB8 Zornitza Stark Publications for gene: PSMB8 were set to 21129723; 21881205; 21852578; 21953331
Autoinflammatory Disorders v2.18 PSMB8 Zornitza Stark Mode of inheritance for gene: PSMB8 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3115 PSMB8 Zornitza Stark Publications for gene: PSMB8 were set to 21129723; 21881205; 21852578; 21953331
Mendeliome v1.3114 PSMB8 Zornitza Stark Mode of inheritance for gene: PSMB8 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3113 ZNF865 Sangavi Sivagnanasundram gene: ZNF865 was added
gene: ZNF865 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF865 were set to 40936200
Phenotypes for gene: ZNF865 were set to ZNF865‑associated neurodevelopmental disorder MONDO:0700092
Review for gene: ZNF865 was set to AMBER
Added comment: PMID: 40936200
18 patients reported with DD, hypotonia and six individuals were reported with some dysmorphic features (frontal bossing, a broad nasal bridge, hypertelorism, and low-set ears)
All 18 individuals were reported with de novo truncating variants in ZNF865. All variants were rare/absent in gnomAD v4.1.

The mechanism of disease for this gene is unknown. No pathogenic SNVs have been reported in ClinVar at this stage however there are reports of VUS’s and pathogenic CNVs.
Sources: Literature
Mendeliome v1.3113 PTPRC Lucy Spencer reviewed gene: PTPRC: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 105, severe combined MIM#619924; Mode of inheritance: None
Mendeliome v1.3113 PTPN22 Lucy Spencer reviewed gene: PTPN22: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoimmune disease MONDO:0007179, PTPN22-related; Mode of inheritance: None
Mendeliome v1.3113 PTPA Lucy Spencer reviewed gene: PTPA: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Parkinson disease MONDO:0005180, PTPA-related; Mode of inheritance: None
Mendeliome v1.3113 PTGS1 Lucy Spencer reviewed gene: PTGS1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Platelet-type bleeding disorder 12 MONDO:0011588; Mode of inheritance: None
Mendeliome v1.3113 PTCH1 Lucy Spencer reviewed gene: PTCH1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Exstrophy-epispadias complex MONDO:0017919, PTCH1-related; Mode of inheritance: None
Mendeliome v1.3113 PTCD1 Lucy Spencer reviewed gene: PTCD1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy MONDO:0004994, PTCD1-related; Mode of inheritance: None
Mendeliome v1.3113 PSMC1 Lucy Spencer reviewed gene: PSMC1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Birk-Aharoni syndrome MIM# 620071; Mode of inheritance: None
Mendeliome v1.3113 PSMB8 Lucy Spencer reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3113 SRP72 Lucy Spencer reviewed gene: SRP72: Rating: AMBER; Mode of pathogenicity: None; Publications: 40922878; Phenotypes: Bone marrow failure syndrome 1, MIM#614675; Mode of inheritance: None
Mendeliome v1.3113 TOM1 Lucy Spencer reviewed gene: TOM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 40936361, 33864888; Phenotypes: Immunodeficiency 85 and autoimmunity MIM#619510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Microcephaly v1.335 SNAPIN Lucy Spencer gene: SNAPIN was added
gene: SNAPIN was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 40930097; 26539891
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder (MONDO:0700092), SNAPIN-related
Review for gene: SNAPIN was set to GREEN
Added comment: PMID: 40930097 6 patients from 5 families with neuroanatomical, craniofacial, and skeletal anomalies on prenatal ultrasound/MRI, all homozygous for variants in SNAPIN. 2 stopgain, 1 canonical splice, 5 missense. common phenotypes: ventriculomegaly 5/6, cerebellar hypoplasia/atrophy 5/6, clubfeet 4/6, corpus callosum agenesis 4/6, flexion contractures 4/6, microcephaly 3/6, micrognathia/retrognathia 4/6. The patients with the nonsense or splice variants did not survive the perinatal period, while those with missense survived into early childhood.

This paper also mentions a 7th patient reported in PMID: 26539891, who has ID, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy, and hypotonia. They are homozygous for a missense variant Asn55Tyr. Of note, the other paper report this as Arg55Trp and one of their patients also has this variant, based off the transcript information provided in both papers Arg55Trp is correct.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.296 SNAPIN Lucy Spencer gene: SNAPIN was added
gene: SNAPIN was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 40930097; 26539891
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder (MONDO:0700092), SNAPIN-related
Review for gene: SNAPIN was set to GREEN
Added comment: PMID: 40930097 6 patients from 5 families with neuroanatomical, craniofacial, and skeletal anomalies on prenatal ultrasound/MRI, all homozygous for variants in SNAPIN. 2 stopgain, 1 canonical splice, 5 missense. common phenotypes: ventriculomegaly 5/6, cerebellar hypoplasia/atrophy 5/6, clubfeet 4/6, corpus callosum agenesis 4/6, flexion contractures 4/6, microcephaly 3/6, micrognathia/retrognathia 4/6. The patients with the nonsense or splice variants did not survive the perinatal period, while those with missense survived into early childhood.

This paper also mentions a 7th patient reported in PMID: 26539891, who has ID, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy, and hypotonia. They are homozygous for a missense variant Asn55Tyr. Of note, the other paper report this as Arg55Trp and one of their patients also has this variant, based off the transcript information provided in both papers Arg55Trp is correct.
Sources: Literature
Callosome v0.558 SNAPIN Lucy Spencer gene: SNAPIN was added
gene: SNAPIN was added to Callosome. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 40930097; 26539891
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder (MONDO:0700092), SNAPIN-related
Review for gene: SNAPIN was set to GREEN
Added comment: PMID: 40930097 6 patients from 5 families with neuroanatomical, craniofacial, and skeletal anomalies on prenatal ultrasound/MRI, all homozygous for variants in SNAPIN. 2 stopgain, 1 canonical splice, 5 missense. common phenotypes: ventriculomegaly 5/6, cerebellar hypoplasia/atrophy 5/6, clubfeet 4/6, corpus callosum agenesis 4/6, flexion contractures 4/6, microcephaly 3/6, micrognathia/retrognathia 4/6. The patients with the nonsense or splice variants did not survive the perinatal period, while those with missense survived into early childhood.

This paper also mentions a 7th patient reported in PMID: 26539891, who has ID, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy, and hypotonia. They are homozygous for a missense variant Asn55Tyr. Of note, the other paper report this as Arg55Trp and one of their patients also has this variant, based off the transcript information provided in both papers Arg55Trp is correct.
Sources: Literature
Fetal anomalies v1.414 SNAPIN Lucy Spencer gene: SNAPIN was added
gene: SNAPIN was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 40930097; 26539891
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder (MONDO:0700092), SNAPIN-related
Review for gene: SNAPIN was set to GREEN
Added comment: PMID: 40930097 6 patients from 5 families with neuroanatomical, craniofacial, and skeletal anomalies on prenatal ultrasound/MRI, all homozygous for variants in SNAPIN. 2 stopgain, 1 canonical splice, 5 missense. common phenotypes: ventriculomegaly 5/6, cerebellar hypoplasia/atrophy 5/6, clubfeet 4/6, corpus callosum agenesis 4/6, flexion contractures 4/6, microcephaly 3/6, micrognathia/retrognathia 4/6. The patients with the nonsense or splice variants did not survive the perinatal period, while those with missense survived into early childhood.

This paper also mentions a 7th patient reported in PMID: 26539891, who has ID, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy, and hypotonia. They are homozygous for a missense variant Asn55Tyr. Of note, the other paper report this as Arg55Trp and one of their patients also has this variant, based off the transcript information provided in both papers Arg55Trp is correct.
Sources: Literature
Mendeliome v1.3113 SNAPIN Lucy Spencer gene: SNAPIN was added
gene: SNAPIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 40930097; 26539891
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder (MONDO:0700092), SNAPIN-related
Review for gene: SNAPIN was set to GREEN
Added comment: PMID: 40930097 6 patients from 5 families with neuroanatomical, craniofacial, and skeletal anomalies on prenatal ultrasound/MRI, all homozygous for variants in SNAPIN. 2 stopgain, 1 canonical splice, 5 missense. common phenotypes: ventriculomegaly 5/6, cerebellar hypoplasia/atrophy 5/6, clubfeet 4/6, corpus callosum agenesis 4/6, flexion contractures 4/6, microcephaly 3/6, micrognathia/retrognathia 4/6. The patients with the nonsense or splice variants did not survive the perinatal period, while those with missense survived into early childhood.

This paper also mentions a 7th patient reported in PMID: 26539891, who has ID, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy, and hypotonia. They are homozygous for a missense variant Asn55Tyr. Of note, the other paper report this as Arg55Trp and one of their patients also has this variant, based off the transcript information provided in both papers Arg55Trp is correct.

PMID: 40930097 Knockout zebrafish models recapitulated the human phenotype. This phenotype was rescued by injecting WT human SNAPIN RNA. Injection with the 2 missense variants observed in patients in this study was able to partially rescue the phenotype but it was significantly worse than the rescue with WT injection. One of these missense variants is absent from gnomad (Arg55Trp) while the other (Glu49Asp) has 167 hets and 1 hom.
Sources: Literature
Autoinflammatory Disorders v2.17 PSMB8 Rylee Peters reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40666351, https://dx.doi.org/10.2139/ssrn.5370606; Phenotypes: Proteosome-associated autoinflammatory syndrome MONDO:0009726, PSMB8-related, AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3113 PSMB8 Rylee Peters reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40666351, https://dx.doi.org/10.2139/ssrn.5370606; Phenotypes: Proteosome-associated autoinflammatory syndrome MONDO:0009726, PSMB8-related, AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hyperinsulinism v1.48 HK1 Chirag Patel changed review comment from: NB: Common variant type is within intron 2

Whole genome sequencing/Sanger sequencing in screening 3 large international cohorts with unresolved with hyperinsulinism. They identified 89 individuals with 32 different non-coding variants within the HK1 cis-regulatory region. Variant types included SNVs, indels, and CNVs. There was sufficient evidence to classify 20/32 different variants as pathogenic or likely pathogenic. There was variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood.; to: NB: Common disease-causing variants are within intron 2

Whole genome sequencing/Sanger sequencing in screening 3 large international cohorts with unresolved with hyperinsulinism. They identified 89 individuals with 32 different non-coding variants within the HK1 cis-regulatory region. Variant types included SNVs, indels, and CNVs. There was sufficient evidence to classify 20/32 different variants as pathogenic or likely pathogenic. There was variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood.
Mendeliome v1.3113 HK1 Chirag Patel reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40033430; Phenotypes: Hyperinsulinism MONDO:0002177, HK1-related; Mode of inheritance: None
Hyperinsulinism v1.48 HK1 Chirag Patel reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40033430; Phenotypes: Hyperinsulinism MONDO:0002177, HK1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3113 MCMDC2 Zornitza Stark Marked gene: MCMDC2 as ready
Mendeliome v1.3113 MCMDC2 Zornitza Stark Gene: mcmdc2 has been classified as Green List (High Evidence).
Mendeliome v1.3113 MCMDC2 Zornitza Stark Publications for gene: MCMDC2 were set to PMID: 40897906, 35172124, 39789727, 36732629
Mendeliome v1.3112 MCMDC2 Zornitza Stark Classified gene: MCMDC2 as Green List (high evidence)
Mendeliome v1.3112 MCMDC2 Zornitza Stark Gene: mcmdc2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.32 MCMDC2 Zornitza Stark Marked gene: MCMDC2 as ready
Infertility and Recurrent Pregnancy Loss v1.32 MCMDC2 Zornitza Stark Gene: mcmdc2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.32 MCMDC2 Zornitza Stark Classified gene: MCMDC2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.32 MCMDC2 Zornitza Stark Gene: mcmdc2 has been classified as Green List (High Evidence).
Eye Anterior Segment Abnormalities v1.15 KERA Zornitza Stark Marked gene: KERA as ready
Eye Anterior Segment Abnormalities v1.15 KERA Zornitza Stark Gene: kera has been classified as Green List (High Evidence).
Mendeliome v1.3111 TGFB2 Zornitza Stark Phenotypes for gene: TGFB2 were changed from Loeys-Dietz syndrome 4, MIM# 614816 to Loeys-Dietz syndrome 4, MIM# 614816; Camurati-Engelmann disease 2, MIM# 606631
Mendeliome v1.3110 TGFB2 Zornitza Stark Publications for gene: TGFB2 were set to
Mendeliome v1.3109 TGFB2 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen.; to: DEFINITIVE by ClinGen for LDS.
Mendeliome v1.3109 TGFB2 Zornitza Stark edited their review of gene: TGFB2: Added comment: Second skeletal phenotype associated with variants in this gene: Camurati-Engelmann disease-2 (CAEND2). This is an autosomal dominant disorder characterized by progressive diaphyseal dysplasia, associated with a waddling gait, muscle weakness, and severe leg pain. Bone striations are present in the spine, pelvis, and long tubular bones, with epiphyseal sclerosis. Coarse sclerotic trabeculae are observed in the short tubular bones. Skull involvement may be minimal. Four unrelated families reported in PMIDs 39014191 and 40204055. Variants were de novo in 3 of the families, and segregated with disease in the fourth.; Changed publications: 39014191, 40204055; Changed phenotypes: Loeys-Dietz syndrome 4, MIM# 614816, Camurati-Engelmann disease 2, MIM# 606631
Skeletal dysplasia v0.321 TGFB2 Zornitza Stark Marked gene: TGFB2 as ready
Skeletal dysplasia v0.321 TGFB2 Zornitza Stark Gene: tgfb2 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.321 TGFB2 Zornitza Stark Phenotypes for gene: TGFB2 were changed from Loeys-Dietz syndrome 4 614816 to Loeys-Dietz syndrome 4, MIM# 614816; Camurati-Engelmann disease 2, MIM# 606631
Skeletal dysplasia v0.320 TGFB2 Zornitza Stark Publications for gene: TGFB2 were set to
Skeletal dysplasia v0.319 TGFB2 Zornitza Stark edited their review of gene: TGFB2: Added comment: Second skeletal phenotype associated with variants in this gene: Camurati-Engelmann disease-2 (CAEND2).

This is an autosomal dominant disorder characterized by progressive diaphyseal dysplasia, associated with a waddling gait, muscle weakness, and severe leg pain. Bone striations are present in the spine, pelvis, and long tubular bones, with epiphyseal sclerosis. Coarse sclerotic trabeculae are observed in the short tubular bones. Skull involvement may be minimal.

Four unrelated families reported in PMIDs 39014191 and 40204055. Variants were de novo in 3 of the families, and segregated with disease in the fourth.; Changed publications: 39014191, 40204055; Changed phenotypes: Loeys-Dietz syndrome 4, MIM# 614816, Camurati-Engelmann disease 2, MIM# 606631
Genetic Epilepsy v1.207 ALDH4A1 Zornitza Stark Marked gene: ALDH4A1 as ready
Genetic Epilepsy v1.207 ALDH4A1 Zornitza Stark Gene: aldh4a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.207 ALDH4A1 Zornitza Stark Classified gene: ALDH4A1 as Green List (high evidence)
Genetic Epilepsy v1.207 ALDH4A1 Zornitza Stark Gene: aldh4a1 has been classified as Green List (High Evidence).
Mendeliome v1.3109 PLD4 Zornitza Stark Marked gene: PLD4 as ready
Mendeliome v1.3109 PLD4 Zornitza Stark Gene: pld4 has been classified as Green List (High Evidence).
Vasculitis v0.91 PLD4 Krithika Murali Classified gene: PLD4 as Green List (high evidence)
Vasculitis v0.91 PLD4 Krithika Murali Gene: pld4 has been classified as Green List (High Evidence).
Vasculitis v0.91 PLD4 Krithika Murali Classified gene: PLD4 as Green List (high evidence)
Vasculitis v0.91 PLD4 Krithika Murali Gene: pld4 has been classified as Green List (High Evidence).
Vasculitis v0.90 PLD4 Krithika Murali Marked gene: PLD4 as ready
Vasculitis v0.90 PLD4 Krithika Murali Gene: pld4 has been classified as Red List (Low Evidence).
Autoinflammatory Disorders v2.17 PLD4 Krithika Murali Classified gene: PLD4 as Green List (high evidence)
Autoinflammatory Disorders v2.17 PLD4 Krithika Murali Gene: pld4 has been classified as Green List (High Evidence).
Autoinflammatory Disorders v2.16 PLD4 Krithika Murali Marked gene: PLD4 as ready
Autoinflammatory Disorders v2.16 PLD4 Krithika Murali Gene: pld4 has been classified as Red List (Low Evidence).
Vasculitis v0.90 PLD4 Krithika Murali gene: PLD4 was added
gene: PLD4 was added to Vasculitis. Sources: Literature
Mode of inheritance for gene: PLD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD4 were set to PMID:40931063
Phenotypes for gene: PLD4 were set to Systemic lupus erythematosus - MONDO:0007915, PLD4-related
Review for gene: PLD4 was set to GREEN
Added comment: PMID:40931063 Wang et al 2025 (Nature) - report 5 unrelated individuals with SLE and biallelic variants in PLD4. Variants were either PTC or missense variants that localised to the catalytic domain. Functional evidence supported LoF mechanism with the variants impairing PLD4 exonuclease activity resulting in aberrant type I IFN signalling activation. pld4-deficient mice had an autoimmune phenotype.
Sources: Literature
Autoinflammatory Disorders v2.16 PLD4 Krithika Murali gene: PLD4 was added
gene: PLD4 was added to Autoinflammatory Disorders. Sources: Literature
Mode of inheritance for gene: PLD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD4 were set to PMID:40931063
Phenotypes for gene: PLD4 were set to Systemic lupus erythematosus - MONDO:0007915, PLD4-related
Review for gene: PLD4 was set to GREEN
Added comment: PMID:40931063 Wang et al 2025 (Nature) - report 5 unrelated individuals with SLE and biallelic variants in PLD4. Variants were either PTC or missense variants that localised to the catalytic domain. Functional evidence supported LoF mechanism with the variants impairing PLD4 exonuclease activity resulting in aberrant type I IFN signalling activation. pld4-deficient mice had an autoimmune phenotype.
Sources: Literature
Genetic Epilepsy v1.206 ALDH4A1 Sinead OSullivan gene: ALDH4A1 was added
gene: ALDH4A1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: ALDH4A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH4A1 were set to 9700195, 31884946
Phenotypes for gene: ALDH4A1 were set to Hyperprolinaemia, type II, MIM#239510
Review for gene: ALDH4A1 was set to GREEN
Added comment: At least 5 unrelated families reported, clinical features are predominantly ID and seizures.
Sources: Expert list
Mendeliome v1.3109 PLD4 Krithika Murali Classified gene: PLD4 as Green List (high evidence)
Mendeliome v1.3109 PLD4 Krithika Murali Gene: pld4 has been classified as Green List (High Evidence).
Mendeliome v1.3108 PLD4 Krithika Murali gene: PLD4 was added
gene: PLD4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD4 were set to PMID:40931063
Phenotypes for gene: PLD4 were set to Systemic lupus erythematosus - MONDO:0007915, PLD4-related
Review for gene: PLD4 was set to GREEN
Added comment: PMID:40931063 Wang et al 2025 (Nature) - report 5 unrelated individuals with SLE and biallelic variants in PLD4. Variants were either PTC or missense variants that localised to the catalytic domain. Functional evidence supported LoF mechanism with the variants impairing PLD4 exonuclease activity resulting in aberrant type I IFN signalling activation. pld4-deficient mice had an autoimmune phenotype.
Sources: Literature
Ataxia v1.54 SKOR2 Bryony Thompson Marked gene: SKOR2 as ready
Ataxia v1.54 SKOR2 Bryony Thompson Gene: skor2 has been classified as Green List (High Evidence).
Eye Anterior Segment Abnormalities v1.15 KERA Krithika Murali Classified gene: KERA as Green List (high evidence)
Eye Anterior Segment Abnormalities v1.15 KERA Krithika Murali Gene: kera has been classified as Green List (High Evidence).
Eye Anterior Segment Abnormalities v1.14 KERA Krithika Murali gene: KERA was added
gene: KERA was added to Eye Anterior Segment Abnormalities. Sources: Literature
Mode of inheritance for gene: KERA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KERA were set to PMID: 32830442; 25967529; 31059048
Phenotypes for gene: KERA were set to Cornea plana 2, autosomal recessive, MIM# 217300
Review for gene: KERA was set to GREEN
Added comment: Anterior segmental dysgenesis is associated with this condition.
In addition to cornea plana, corneal opacity and microcornea also reported.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.31 MCMDC2 Sarah Milton gene: MCMDC2 was added
gene: MCMDC2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MCMDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCMDC2 were set to PMID: 40897906; 35172124; 39789727; 36732629
Phenotypes for gene: MCMDC2 were set to Azoospermia, MONDO:0100459, MCMDC2-related
Review for gene: MCMDC2 was set to GREEN
Added comment: MCMDC2 encodes minichromosome maintenance domain-containing 2. It is involved in meiotic recombination and double stranded break repair for maintenance of fertility.

6 male individuals have been described thus far with homozygous missense/nonsense/fs variants with non obstructive azoospermia. Loss of function is the proposed mechanism of disease.

MCMDC2 knockout mice have issues with double stranded break repair in meiosis and subsequent aberrant gametogenesis.

1 female individual has been described with a homozygous nonsense variant with premature ovarian insufficiency, in the same publication a heterozygous female was also described to have the same phenotype. Functional studies on variants in these two individuals demonstrated homologous repair efficiency to be reduced compared to wild type.

Homozygous LOF variants are absent in gnomAD v4.
Sources: Literature
Mendeliome v1.3107 MCMDC2 Sarah Milton gene: MCMDC2 was added
gene: MCMDC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCMDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCMDC2 were set to PMID: 40897906, 35172124, 39789727, 36732629
Phenotypes for gene: MCMDC2 were set to Azoospermia, MONDO:0100459, MCMDC2-related
Review for gene: MCMDC2 was set to GREEN
Added comment: MCMDC2 encodes minichromosome maintenance domain-containing 2. It is involved in meiotic recombination and double stranded break repair for maintenance of fertility.

6 male individuals have been described thus far with homozygous missense/nonsense/fs variants with non obstructive azoospermia. Loss of function is the proposed mechanism of disease.

MCMDC2 knockout mice have issues with double stranded break repair in meiosis and subsequent aberrant gametogenesis.

1 female individual has been described with a homozygous nonsense variant with premature ovarian insufficiency, in the same publication a heterozygous female was also described to have the same phenotype. Functional studies on variants in these two individuals demonstrated homologous repair efficiency to be reduced compared to wild type.

Homozygous LOF variants are absent in gnomAD v4.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.296 SKOR2 Zornitza Stark Marked gene: SKOR2 as ready
Intellectual disability syndromic and non-syndromic v1.296 SKOR2 Zornitza Stark Gene: skor2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.296 SKOR2 Zornitza Stark Classified gene: SKOR2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.296 SKOR2 Zornitza Stark Gene: skor2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.295 SKOR2 Zornitza Stark gene: SKOR2 was added
gene: SKOR2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SKOR2 were set to 40890458; 29997391; 21937600
Phenotypes for gene: SKOR2 were set to complex neurodevelopmental disorder with motor features MONDO:0100516
Review for gene: SKOR2 was set to GREEN
Added comment: 3 unrelated families with consistent phenotypes and a supportive mouse model:
PMID: 40890458 - 2 unrelated consanguineous Iranian families with a combination of learning disability, facial dysmorphisms, and motor and speech impairments with homozygous variants (c.374 G>C: p.Arg125Pro & c.1271_1274del: p.K424Rfs*71). The homozygous missense variant segregated with disease in 8 individuals (no unaffected individuals tested were homozygous).

PMID: 29997391 - proband with neurodevelopmental delay, hypotonia, ataxia, cerebellar dysplasia from a consanguineous Turkish family with a homozygous null variant (NM_001278063.1:c.2750C>G; p.Ser917*). None of the 4 healthy siblings were homozygous for the variant.

PMID: 21937600 - Skor2 -/- mouse model had defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Mouse had unstable gait.
Sources: Literature
Mendeliome v1.3107 SKOR2 Zornitza Stark Marked gene: SKOR2 as ready
Mendeliome v1.3107 SKOR2 Zornitza Stark Gene: skor2 has been classified as Green List (High Evidence).
Ataxia v1.54 SKOR2 Zornitza Stark Marked gene: SKOR2 as ready
Ataxia v1.54 SKOR2 Zornitza Stark Gene: skor2 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.319 BNIP1 Zornitza Stark Phenotypes for gene: BNIP1 were changed from spondyloepiphyseal dysplasia MONDO:0016761 to Spondylopeiphyseal dysplasia, Holling type, MIM# 621345
Skeletal dysplasia v0.318 BNIP1 Zornitza Stark reviewed gene: BNIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondylopeiphyseal dysplasia, Holling type, MIM# 621345; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3107 BNIP1 Zornitza Stark Phenotypes for gene: BNIP1 were changed from spondyloepiphyseal dysplasia MONDO:0016761 to Spondylopeiphyseal dysplasia, Holling type, MIM# 621345
Mendeliome v1.3106 BNIP1 Zornitza Stark reviewed gene: BNIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondylopeiphyseal dysplasia, Holling type, MIM# 621345; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia v1.54 SKOR2 Bryony Thompson Classified gene: SKOR2 as Green List (high evidence)
Ataxia v1.54 SKOR2 Bryony Thompson Gene: skor2 has been classified as Green List (High Evidence).
Mendeliome v1.3106 SKOR2 Bryony Thompson Classified gene: SKOR2 as Green List (high evidence)
Mendeliome v1.3106 SKOR2 Bryony Thompson Gene: skor2 has been classified as Green List (High Evidence).
Ataxia v1.53 SKOR2 Bryony Thompson gene: SKOR2 was added
gene: SKOR2 was added to Ataxia - paediatric. Sources: Literature
Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SKOR2 were set to 40890458; 29997391; 21937600
Phenotypes for gene: SKOR2 were set to complex neurodevelopmental disorder with motor features MONDO:0100516
Review for gene: SKOR2 was set to GREEN
Added comment: 3 unrelated families with consistent phenotypes and a supportive mouse model:
PMID: 40890458 - 2 unrelated consanguineous Iranian families with a combination of learning disability, facial dysmorphisms, and motor and speech impairments with homozygous variants (c.374 G>C: p.Arg125Pro & c.1271_1274del: p.K424Rfs*71). The homozygous missense variant segregated with disease in 8 individuals (no unaffected individuals tested were homozygous).

PMID: 29997391 - proband with neurodevelopmental delay, hypotonia, ataxia, cerebellar dysplasia from a consanguineous Turkish family with a homozygous null variant (NM_001278063.1:c.2750C>G; p.Ser917*). None of the 4 healthy siblings were homozygous for the variant.

PMID: 21937600 - Skor2 -/- mouse model had defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Mouse had unstable gait.
Sources: Literature
Mendeliome v1.3105 SKOR2 Bryony Thompson gene: SKOR2 was added
gene: SKOR2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SKOR2 were set to 40890458; 29997391; 21937600
Phenotypes for gene: SKOR2 were set to complex neurodevelopmental disorder with motor features MONDO:0100516
Review for gene: SKOR2 was set to GREEN
Added comment: 3 unrelated families with consistent phenotypes and a supportive mouse model:
PMID: 40890458 - 2 unrelated consanguineous Iranian families with a combination of learning disability, facial dysmorphisms, and motor and speech impairments with homozygous variants (c.374 G>C: p.Arg125Pro & c.1271_1274del: p.K424Rfs*71). The homozygous missense variant segregated with disease in 8 individuals (no unaffected individuals tested were homozygous).

PMID: 29997391 - proband with neurodevelopmental delay, hypotonia, ataxia, cerebellar dysplasia from a consanguineous Turkish family with a homozygous null variant (NM_001278063.1:c.2750C>G; p.Ser917*). None of the 4 healthy siblings were homozygous for the variant.

PMID: 21937600 - Skor2 -/- mouse model had defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Mouse had unstable gait.
Sources: Literature
Mendeliome v1.3104 SLC38A6 Bryony Thompson Marked gene: SLC38A6 as ready
Mendeliome v1.3104 SLC38A6 Bryony Thompson Gene: slc38a6 has been classified as Red List (Low Evidence).
Mendeliome v1.3104 SLC38A6 Bryony Thompson edited their review of gene: SLC38A6: Changed rating: RED
Mendeliome v1.3104 SLC38A6 Bryony Thompson gene: SLC38A6 was added
gene: SLC38A6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC38A6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC38A6 were set to 40931016
Phenotypes for gene: SLC38A6 were set to essential tremor MONDO:0003233
Review for gene: SLC38A6 was set to AMBER
Added comment: The study identified SLC38A6 variants in 71 unrelated Chinese ET families (≈9.2% of families) and 47 unrelated sporadic cases, with 15 distinct protein‑altering variants. However, many of the 15 variants are >2% in the East Asian population, which is inconsistent with the incidence of essential tremor in the population (~1%). The study does not contain any statistical enrichment analyses or case-control analyses. It also reports incomplete segregation and non-segregation of variants (called a phenocopy by the authors). A null mouse model (Slc38a6-/-) displays tremor and delineated cerebellar cellular abnormalities. In vitro assessment of 3 of the most common missense variants (p.Y108F [gnomAD total 0.0002; East Asian 0.006, p.M281T [gnomAD total 0.0015; East Asian 0.0227] and p.G318S [gnomAD total 0.0021; East Asian 0.0278]) significantly impaired L-arginine (L-Arg) uptake in HeLa cells. Given the prevalence of the reported variants in the East Asian population, the genetic evidence for this gene-disease association is limited.
Sources: Literature
Fetal anomalies v1.414 PATJ Zornitza Stark Marked gene: PATJ as ready
Fetal anomalies v1.414 PATJ Zornitza Stark Gene: patj has been classified as Red List (Low Evidence).
Fetal anomalies v1.414 PATJ Zornitza Stark gene: PATJ was added
gene: PATJ was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PATJ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PATJ were set to 40931526
Phenotypes for gene: PATJ were set to Ciliopathy, MONDO:0005308, PATJ-related
Review for gene: PATJ was set to RED
Added comment: PATJ encodes PALS1-associated tight junction protein.

PMID: 40931526 describes 1 affected fetus with hydrocephalus and polycystic kidney disease with a homozygous NMD predicted variant.

Some supportive zebrafish functional data.

Homozygous NMD predicted variants are rare in gnomAD v4.
Sources: Literature
Mendeliome v1.3103 PATJ Zornitza Stark Marked gene: PATJ as ready
Mendeliome v1.3103 PATJ Zornitza Stark Gene: patj has been classified as Red List (Low Evidence).
Mendeliome v1.3103 PATJ Zornitza Stark Classified gene: PATJ as Red List (low evidence)
Mendeliome v1.3103 PATJ Zornitza Stark Gene: patj has been classified as Red List (Low Evidence).
Mendeliome v1.3102 PATJ Sarah Milton changed review comment from: PATJ encodes PALS1-associated tight junction protein.

PMID: 40931526 describes 1 affected fetus with hydrocephalus and polycystic kidney disease with a homozygous NMD predicted variant.

Some supportive zebrafish functional data.

Homozygous NMD predicted variants rare in gnomAD v4.
Sources: Literature; to: PATJ encodes PALS1-associated tight junction protein.

PMID: 40931526 describes 1 affected fetus with hydrocephalus and polycystic kidney disease with a homozygous NMD predicted variant.

Some supportive zebrafish functional data.

Homozygous NMD predicted variants are rare in gnomAD v4.
Sources: Literature
Mendeliome v1.3102 PATJ Sarah Milton gene: PATJ was added
gene: PATJ was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PATJ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PATJ were set to PMID: 40931526
Phenotypes for gene: PATJ were set to Ciliopathy, MONDO:0005308, PATJ-related
Review for gene: PATJ was set to RED
Added comment: PATJ encodes PALS1-associated tight junction protein.

PMID: 40931526 describes 1 affected fetus with hydrocephalus and polycystic kidney disease with a homozygous NMD predicted variant.

Some supportive zebrafish functional data.

Homozygous NMD predicted variants rare in gnomAD v4.
Sources: Literature
Photosensitivity Syndromes v1.10 GTF2H4 Zornitza Stark Marked gene: GTF2H4 as ready
Photosensitivity Syndromes v1.10 GTF2H4 Zornitza Stark Gene: gtf2h4 has been classified as Red List (Low Evidence).
Photosensitivity Syndromes v1.10 GTF2H4 Zornitza Stark gene: GTF2H4 was added
gene: GTF2H4 was added to Photosensitivity Syndromes. Sources: Literature
Mode of inheritance for gene: GTF2H4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF2H4 were set to 40924495; 40924475
Phenotypes for gene: GTF2H4 were set to Xeroderma pigmentosa, MONDO:0019600, GTF2H4-related
Review for gene: GTF2H4 was set to RED
Added comment: Singe individual reported in two papers with biallelic LoF variants, one canonical splice site and the other frameshift. Supportive functional data.
Sources: Literature
Mendeliome v1.3102 DHRS9 Zornitza Stark Marked gene: DHRS9 as ready
Mendeliome v1.3102 DHRS9 Zornitza Stark Gene: dhrs9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3102 DHRS9 Zornitza Stark Classified gene: DHRS9 as Amber List (moderate evidence)
Mendeliome v1.3102 DHRS9 Zornitza Stark Gene: dhrs9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3101 DHRS9 Zornitza Stark gene: DHRS9 was added
gene: DHRS9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHRS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS9 were set to 40945732; 32752300; 38256219
Phenotypes for gene: DHRS9 were set to Genetic epilepsy, MONDO:0100575, DHRS9
Review for gene: DHRS9 was set to AMBER
Added comment: PMID 40945732: Single individual reported with compound heterozygous missense variants, c.605C>T (p.S202L); c.856G>C (p.D286H) and early onset epilepsy. Functional studies conducted on both variants separately, demonstrating loss of function.

PMID 32752300: compound het missense variants in an individual with epilepsy.

PMID 38256219: put forward as a candidate gene in an epilepsy cohort, compound het missense variants identified c.785C>T (p.Ser262Leu) and c.1036G>C (p.Asp346His).
Sources: Literature
Genetic Epilepsy v1.206 DHRS9 Zornitza Stark changed review comment from: PMID 32752300: compound het missekse variants in an individual with epilepsy.
PMID 38256219: put forward as a candidate gene in an epilepsy cohort, compound het missense variants identified c.785C>T (p.Ser262Leu) and c.1036G>C (p.Asp346His).; to: PMID 32752300: compound het missense variants in an individual with epilepsy.
PMID 38256219: put forward as a candidate gene in an epilepsy cohort, compound het missense variants identified c.785C>T (p.Ser262Leu) and c.1036G>C (p.Asp346His).
Genetic Epilepsy v1.206 DHRS9 Zornitza Stark changed review comment from: Single individual reported with compound heterozygous missense variants, c.605C>T (p.S202L); c.856G>C (p.D286H) and early onset epilepsy. Functional studies conducted on both variants separately, demonstrating loss of function.
Sources: Literature; to: PMID 40945732: Single individual reported with compound heterozygous missense variants, c.605C>T (p.S202L); c.856G>C (p.D286H) and early onset epilepsy. Functional studies conducted on both variants separately, demonstrating loss of function.
Sources: Literature
Genetic Epilepsy v1.206 DHRS9 Zornitza Stark Publications for gene: DHRS9 were set to 40945732
Genetic Epilepsy v1.205 DHRS9 Zornitza Stark Marked gene: DHRS9 as ready
Genetic Epilepsy v1.205 DHRS9 Zornitza Stark Gene: dhrs9 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.205 DHRS9 Zornitza Stark Classified gene: DHRS9 as Amber List (moderate evidence)
Genetic Epilepsy v1.205 DHRS9 Zornitza Stark Gene: dhrs9 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.204 DHRS9 Zornitza Stark edited their review of gene: DHRS9: Added comment: PMID 32752300: compound het missekse variants in an individual with epilepsy.
PMID 38256219: put forward as a candidate gene in an epilepsy cohort, compound het missense variants identified c.785C>T (p.Ser262Leu) and c.1036G>C (p.Asp346His).; Changed rating: AMBER; Changed publications: 40945732, 32752300, 38256219
Genetic Epilepsy v1.204 DHRS9 Zornitza Stark gene: DHRS9 was added
gene: DHRS9 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: DHRS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS9 were set to 40945732
Phenotypes for gene: DHRS9 were set to Genetic epilepsy, MONDO:0100575, DHRS9
Review for gene: DHRS9 was set to RED
Added comment: Single individual reported with compound heterozygous missense variants, c.605C>T (p.S202L); c.856G>C (p.D286H) and early onset epilepsy. Functional studies conducted on both variants separately, demonstrating loss of function.
Sources: Literature
Mendeliome v1.3100 MAP3K6 Zornitza Stark Marked gene: MAP3K6 as ready
Mendeliome v1.3100 MAP3K6 Zornitza Stark Gene: map3k6 has been classified as Red List (Low Evidence).
Mendeliome v1.3100 MAP3K6 Zornitza Stark gene: MAP3K6 was added
gene: MAP3K6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAP3K6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K6 were set to 33728376; 40947452
Phenotypes for gene: MAP3K6 were set to Neurovascular disorder, MONDO:0043218, MAP3K6-related
Review for gene: MAP3K6 was set to RED
Added comment: PMID 33728376: large multiplex family segregating a missense variant, p.Asp108Asn and stroke episodes, cognitive impairment and tremor. Same family reported in PMID 40947452, with additional feature of basal ganglia calcification.
Sources: Literature
Stroke v1.27 MAP3K6 Zornitza Stark Marked gene: MAP3K6 as ready
Stroke v1.27 MAP3K6 Zornitza Stark Gene: map3k6 has been classified as Red List (Low Evidence).
Stroke v1.27 MAP3K6 Zornitza Stark gene: MAP3K6 was added
gene: MAP3K6 was added to Stroke. Sources: Literature
Mode of inheritance for gene: MAP3K6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K6 were set to 33728376; 40947452
Phenotypes for gene: MAP3K6 were set to Neurovascular disorder, MONDO:0043218, MAP3K6-related
Review for gene: MAP3K6 was set to RED
Added comment: PMID 33728376: large multiplex family segregating a missense variant, p.Asp108Asn and stroke episodes, cognitive impairment and tremor. Same family reported in PMID 40947452, with additional feature of basal ganglia calcification.
Sources: Literature
Ataxia v1.52 ELFN1 Zornitza Stark Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092, ELFN1-related to Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344
Ataxia v1.51 ELFN1 Zornitza Stark reviewed gene: ELFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.203 ELFN1 Zornitza Stark Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092, ELFN1-related to Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344
Genetic Epilepsy v1.202 ELFN1 Zornitza Stark reviewed gene: ELFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3099 ELFN1 Zornitza Stark Marked gene: ELFN1 as ready
Mendeliome v1.3099 ELFN1 Zornitza Stark Gene: elfn1 has been classified as Green List (High Evidence).
Mendeliome v1.3099 ELFN1 Zornitza Stark Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092, ELFN1-related to Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344
Mendeliome v1.3098 ELFN1 Zornitza Stark reviewed gene: ELFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autism v0.216 ELFN1 Zornitza Stark Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092, ELFN1-related to Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344
Autism v0.215 ELFN1 Zornitza Stark reviewed gene: ELFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: ICoNS v0.15 ALDH7A1 Zornitza Stark Marked gene: ALDH7A1 as ready
Genomic newborn screening: ICoNS v0.15 ALDH7A1 Zornitza Stark Gene: aldh7a1 has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.15 ALDH7A1 Zornitza Stark Phenotypes for gene: ALDH7A1 were changed from Epilepsy, early-onset, 4, vitamin B6-dependent to Epilepsy, pyridoxine-dependent, MIM#266100
Genomic newborn screening: ICoNS v0.14 ALDH7A1 Zornitza Stark Classified gene: ALDH7A1 as Green List (high evidence)
Genomic newborn screening: ICoNS v0.14 ALDH7A1 Zornitza Stark Gene: aldh7a1 has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.13 ALDH7A1 Zornitza Stark reviewed gene: ALDH7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, pyridoxine-dependent, MIM#266100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: ICoNS v0.13 GAMT Zornitza Stark Marked gene: GAMT as ready
Genomic newborn screening: ICoNS v0.13 GAMT Zornitza Stark Gene: gamt has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.13 GAMT Zornitza Stark Publications for gene: GAMT were set to
Genomic newborn screening: ICoNS v0.12 GAMT Zornitza Stark Classified gene: GAMT as Green List (high evidence)
Genomic newborn screening: ICoNS v0.12 GAMT Zornitza Stark Gene: gamt has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.11 GAMT Zornitza Stark reviewed gene: GAMT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral creatine deficiency syndrome 2, MIM#612736; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: ICoNS v0.11 ABCC8 Zornitza Stark Marked gene: ABCC8 as ready
Genomic newborn screening: ICoNS v0.11 ABCC8 Zornitza Stark Gene: abcc8 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: ICoNS v0.11 ABCC8 Zornitza Stark Phenotypes for gene: ABCC8 were changed from Diabetes mellitus, noninsulin-dependent MIM#125853 Diabetes mellitus, permanent neonatal 3 MIM# 618857 AD, AR Diabetes mellitus, transient neonatal 2 MIM#610374 Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450 AD, AR Hypoglycemia of infancy, leucine-sensitive MIM#240800 AD Maturity-onset diabetes of the young, type 12 MIM#621196 AD to Diabetes mellitus, permanent neonatal 3 MIM# 618857
Genomic newborn screening: ICoNS v0.10 ABCC8 Zornitza Stark Classified gene: ABCC8 as Amber List (moderate evidence)
Genomic newborn screening: ICoNS v0.10 ABCC8 Zornitza Stark Gene: abcc8 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: ICoNS v0.9 ABCC8 Zornitza Stark reviewed gene: ABCC8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, permanent neonatal 3 MIM# 618857; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: ICoNS v0.9 ABCC8 Lilian Downie gene: ABCC8 was added
gene: ABCC8 was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: ABCC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ABCC8 were set to PMID: 20301620; 32027066; 20922570; 16885549
Phenotypes for gene: ABCC8 were set to Diabetes mellitus, noninsulin-dependent MIM#125853 Diabetes mellitus, permanent neonatal 3 MIM# 618857 AD, AR Diabetes mellitus, transient neonatal 2 MIM#610374 Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450 AD, AR Hypoglycemia of infancy, leucine-sensitive MIM#240800 AD Maturity-onset diabetes of the young, type 12 MIM#621196 AD
Review for gene: ABCC8 was set to GREEN
Added comment: Gene-disease association:
Curated by ClinGen: definitive for monogenic diabetes
Moderate for pulmonary hypertension.

LOF heterozygous variants cause hyperinsulinism and neonatal hypoglycemia. requires a paternal pathogenic variant and a somatic second hit on the maternal allele. There is no phenotype for an isolated maternal pathogenic variant.

GoF missense variants cause neonatal diabetes mellitus: Clinical manifestations at diagnosis include intrauterine growth restriction (IUGR; a reflection of insulin deficiency in utero), hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and poor weight gain.: KATP channel unable to close in response to ATP, impairing insulin secretion

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

NB Ashkenazi founder variants: NP_000343.2:p.Phe1387del or NM_000352.6:c.3989-9G>A.
Finnish founder variants NP_000343.2:p.Val187Asp or NP_000343.2:p.Glu1506Lys.

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide (Sulfonylurea), oral pancreatic enzymes,

Not included by GUARDIAN ?reason ?variable phenotypes, some are adult onset, would need to make variant level decisions on reporting

Variable expression - variants can be inherited and cause T2DM in a parent

Not included in newborn screening currently
Sources: Expert list
Genomic newborn screening: ICoNS v0.8 TCN2 Lilian Downie Marked gene: TCN2 as ready
Genomic newborn screening: ICoNS v0.8 TCN2 Lilian Downie Gene: tcn2 has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.8 TCN2 Lilian Downie Classified gene: TCN2 as Green List (high evidence)
Genomic newborn screening: ICoNS v0.8 TCN2 Lilian Downie Added comment: Comment on list classification: Not on BabySeq 1 list, on other pilots.
Detectable on TMS but ?not in standard NBS
Genomic newborn screening: ICoNS v0.8 TCN2 Lilian Downie Gene: tcn2 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.53 NTN1 Zornitza Stark Classified gene: NTN1 as Amber List (moderate evidence)
Congenital hypothyroidism v0.53 NTN1 Zornitza Stark Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Congenital hypothyroidism v0.52 JAG1 Zornitza Stark Marked gene: JAG1 as ready
Congenital hypothyroidism v0.52 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.52 JAG1 Zornitza Stark Phenotypes for gene: JAG1 were changed from Alagille syndrome 1 to Alagille syndrome, MIM#118450
Congenital hypothyroidism v0.51 JAG1 Zornitza Stark Classified gene: JAG1 as Green List (high evidence)
Congenital hypothyroidism v0.51 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Mendeliome v1.3098 TRPC4AP Zornitza Stark Marked gene: TRPC4AP as ready
Mendeliome v1.3098 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3098 TRPC4AP Zornitza Stark Classified gene: TRPC4AP as Amber List (moderate evidence)
Mendeliome v1.3098 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3097 TRPC4AP Zornitza Stark gene: TRPC4AP was added
gene: TRPC4AP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC4AP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPC4AP were set to 32428920; 26786105
Phenotypes for gene: TRPC4AP were set to Thyroid hypoplasia, MONDO:0019861, TRPC4AP-related
Review for gene: TRPC4AP was set to AMBER
Added comment: De novo LoF TRPC4AP variant identified on WES in a child with thyroid dyshormonogenesis.
179 patients with CHTD sequenced using a panel of target genes identifying four variants in TRPC4AP. During development, Choukair et al. showed that Trpc4ap is expressed in the brain, the thyroid bud, and the kidney of the African clawed frog (Xenopus laevis). This team showed that disabling Trpc4ap in the African clawed frog leads to thyroid hypoplasia during development. It was also shown that TRPC4AP interacted with IKBKG which activates the NF-κB signaling pathway and regulates the genes involved in the growth and survival of thyrocytes. Furthermore, the NF-kB would control the expression of NKX2-1, PAX8, TPO, NIS, and TG.18 The authors conclude that TRPC4AP would be a new candidate gene for TDs. Insufficient clinical cases for green. Candidate gene.
Sources: Literature
Congenital hypothyroidism v0.50 TRPC4AP Zornitza Stark Marked gene: TRPC4AP as ready
Congenital hypothyroidism v0.50 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Congenital hypothyroidism v0.50 TRPC4AP Zornitza Stark Phenotypes for gene: TRPC4AP were changed from Thyroid hypoplasia to Thyroid hypoplasia, MONDO:0019861, TRPC4AP-related
Congenital hypothyroidism v0.49 TRPC4AP Zornitza Stark Classified gene: TRPC4AP as Amber List (moderate evidence)
Congenital hypothyroidism v0.49 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Congenital hypothyroidism v0.48 TRPC4AP Zornitza Stark reviewed gene: TRPC4AP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.294 PSMB1 Zornitza Stark Phenotypes for gene: PSMB1 were changed from Intellectual disability; microcephaly to Neurodevelopmental disorder MONDO:0700092, PSMB1-related
Intellectual disability syndromic and non-syndromic v1.293 PSMB1 Zornitza Stark edited their review of gene: PSMB1: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, PSMB1-related
Mendeliome v1.3096 PSMB1 Zornitza Stark Phenotypes for gene: PSMB1 were changed from Intellectual disability; microcephaly to Neurodevelopmental disorder MONDO:0700092, PSMB1-related
Mendeliome v1.3095 PSAT1 Zornitza Stark Phenotypes for gene: PSAT1 were changed from Phosphoserine aminotransferase deficiency 610992; Neu-Laxova syndrome 2 616038 to Neurometabolic disorder due to serine deficiency MONDO:0018162, PSAT1-related
Hereditary Neuropathy_CMT - isolated v1.63 PRX Zornitza Stark Phenotypes for gene: PRX were changed from Dejerine Sottas disease, autosomal recessive, 145900; Charcot Marie Tooth disease, type 4F, 614895; HMSN to Charcot-Marie-Tooth disease type 4 MONDO:0018995
Hereditary Neuropathy_CMT - isolated v1.62 PRX Zornitza Stark edited their review of gene: PRX: Changed phenotypes: Charcot-Marie-Tooth disease type 4 MONDO:0018995
Mendeliome v1.3094 PRX Zornitza Stark Phenotypes for gene: PRX were changed from Charcot-Marie-Tooth disease, type 4F, MIM# 614895; Dejerine-Sottas disease, MIM# 145900 to Charcot-Marie-Tooth disease type 4 MONDO:0018995
Paroxysmal Dyskinesia v0.142 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Paroxysmal Dyskinesia v0.141 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Alternating Hemiplegia and Hemiplegic Migraine v0.59 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066; Episodic kinesigenic dyskinesia 1, 128200; Seizures, benign familial infantile, 2, 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Ataxia v1.51 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Episodic kinesigenic dyskinesia 1 MIM#128200; Convulsions, familial infantile, with paroxysmal choreoathetosis MIM#602066; Seizures, benign familial infantile, 2 MIM#605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Ataxia v1.50 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Genetic Epilepsy v1.202 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Genetic Epilepsy v1.201 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Brain Channelopathies v1.4 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Brain Channelopathies v1.3 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Mendeliome v1.3093 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Deafness_IsolatedAndComplex v1.222 PRPS1 Zornitza Stark Phenotypes for gene: PRPS1 were changed from Deafness, X-linked 1, MIM# 304500; Charcot-Marie-Tooth disease, X-linked recessive, 5, MIM# 311070; Arts syndrome, MIM# 301835 to PRPS1 deficiency disorder MONDO:0100061
Deafness_IsolatedAndComplex v1.221 PRPS1 Zornitza Stark edited their review of gene: PRPS1: Changed phenotypes: PRPS1 deficiency disorder MONDO:0100061
Mendeliome v1.3092 PRPS1 Zornitza Stark Phenotypes for gene: PRPS1 were changed from Arts syndrome MIM#301835; Charcot-Marie-Tooth disease, X-linked recessive, 5 MIM#311070; Deafness, X-linked 1 MIM#304500; Gout, PRPS-related MIM#300661; Phosphoribosylpyrophosphate synthetase superactivity MIM#300661 to PRPS1 deficiency disorder MONDO:0100061; Phosphoribosylpyrophosphate synthetase superactivity MIM#300661
Macular Dystrophy/Stargardt Disease v0.56 PRPH2 Zornitza Stark Marked gene: PRPH2 as ready
Macular Dystrophy/Stargardt Disease v0.56 PRPH2 Zornitza Stark Gene: prph2 has been classified as Green List (High Evidence).
Macular Dystrophy/Stargardt Disease v0.56 PRPH2 Zornitza Stark Phenotypes for gene: PRPH2 were changed from Leber congenital amaurosis 18, MIM#608133; Macular dystrophy, vitelliform, 3, MIM#608161; Retinitis pigmentosa 7 and digenic form, MIM#608133; Choroidal dystrophy, central areolar 2, MIM#613105; Macular dystrophy, patterned, 1, MIM#169150; Retinitis punctata albescens, MIM#136880 to PRPH2-related retinopathy MONDO:1040055
Macular Dystrophy/Stargardt Disease v0.55 PRPH2 Zornitza Stark Mode of inheritance for gene: PRPH2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Macular Dystrophy/Stargardt Disease v0.54 PRPH2 Zornitza Stark reviewed gene: PRPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: PRPH2-related retinopathy MONDO:1040055; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3091 PRPH2 Zornitza Stark Phenotypes for gene: PRPH2 were changed from Leber congenital amaurosis 18, MIM#608133; Macular dystrophy, vitelliform, 3, MIM#608161; Retinitis pigmentosa 7 and digenic form, MIM#608133; Choroidal dystrophy, central areolar 2, MIM#613105; Macular dystrophy, patterned, 1, MIM#169150; Retinitis punctata albescens, MIM#136880 to PRPH2-related retinopathy MONDO:1040055
Mendeliome v1.3090 PROM1 Zornitza Stark Phenotypes for gene: PROM1 were changed from Inherited retinal dystrophy, MONDO:0019118; Cone-rod dystrophy 12, MIM# 612657; Macular dystrophy, retinal, 2, MI# 608051; Retinitis pigmentosa 41, MIM# 612095; Stargardt disease 4, MIM# 603786 to PROM1-related dominant retinopathy MONDO:1040053; Cone-rod dystrophy 12, MIM# 612657; Retinitis pigmentosa 41, MIM# 612095
Mendeliome v1.3089 PRKAG3 Zornitza Stark Phenotypes for gene: PRKAG3 were changed from increased glycogen content in skeletal muscle to Skeletal muscle glycogen content and metabolism QTL MIM#619030
Mendeliome v1.3088 PSMB1 Lucy Spencer reviewed gene: PSMB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PSMB1-related; Mode of inheritance: None
Mendeliome v1.3088 PSAT1 Lucy Spencer reviewed gene: PSAT1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurometabolic disorder due to serine deficiency MONDO:0018162, PSAT1-related; Mode of inheritance: None
Mendeliome v1.3088 PRX Lucy Spencer reviewed gene: PRX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease type 4 MONDO:0018995; Mode of inheritance: None
Mendeliome v1.3088 PRRT2 Lucy Spencer reviewed gene: PRRT2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556; Mode of inheritance: None
Mendeliome v1.3088 PRPS1 Lucy Spencer reviewed gene: PRPS1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRPS1 deficiency disorder MONDO:0100061; Mode of inheritance: None
Mendeliome v1.3088 PRPH2 Lucy Spencer reviewed gene: PRPH2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRPH2-related retinopathy MONDO:1040055; Mode of inheritance: None
Mendeliome v1.3088 PROM1 Lucy Spencer reviewed gene: PROM1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PROM1-related dominant retinopathy MONDO:1040053; Mode of inheritance: None
Mendeliome v1.3088 PRKAG3 Lucy Spencer reviewed gene: PRKAG3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal muscle glycogen content and metabolism QTL MIM#619030; Mode of inheritance: None
Ataxia v1.50 PRDX3 Zornitza Stark Phenotypes for gene: PRDX3 were changed from Cerebellar ataxia (early onset, mild to moderate, progressive) to Cerebellar ataxia MONDO:0000437, PRDX3-related
Ataxia v1.49 PRDX3 Zornitza Stark Deleted their comment
Ataxia v1.49 PRDX3 Zornitza Stark edited their review of gene: PRDX3: Changed phenotypes: Cerebellar ataxia MONDO:0000437, PRDX3-related
Mitochondrial disease v0.1005 PRDX3 Zornitza Stark Deleted their comment
Mitochondrial disease v0.1005 PRDX3 Zornitza Stark Phenotypes for gene: PRDX3 were changed from Cerebellar ataxia (early onset, mild to moderate, progressive) to Cerebellar ataxia MONDO:0000437, PRDX3-related
Mitochondrial disease v0.1004 PRDX3 Zornitza Stark edited their review of gene: PRDX3: Changed phenotypes: Cerebellar ataxia MONDO:0000437, PRDX3-related
Mendeliome v1.3088 PRDX3 Zornitza Stark Phenotypes for gene: PRDX3 were changed from cerebellar ataxia (early onset, mild to moderate, progressive) to Cerebellar ataxia MONDO:0000437, PRDX3-related
Mendeliome v1.3087 PRDX3 Lucy Spencer reviewed gene: PRDX3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar ataxia MONDO:0000437, PRDX3-related; Mode of inheritance: None
Mendeliome v1.3087 HEY2 Zornitza Stark Phenotypes for gene: HEY2 were changed from congenital heart disease MONDO:0005453; thoracic aortic aneurysms to Congenital heart disease, MONDO:0005453, HEY2-related; thoracic aortic aneurysms
Mendeliome v1.3086 HEY2 Zornitza Stark Publications for gene: HEY2 were set to 32820247
Mendeliome v1.3085 HEY2 Zornitza Stark Deleted their comment
Mendeliome v1.3085 HEY2 Zornitza Stark commented on gene: HEY2: Further family reported segregating a missense variant and Tetralogy of Fallot.
Mendeliome v1.3085 HEY2 Zornitza Stark edited their review of gene: HEY2: Added comment: Further family reported segregating a missense variant and Tetralogy of Fallot.; Changed publications: 32820247, 40481234; Changed phenotypes: Congenital heart disease, MONDO:0005453, HEY2-related
Congenital Heart Defect v0.461 HEY2 Zornitza Stark Phenotypes for gene: HEY2 were changed from congenital heart defects and thoracic aortic aneurysms to Congenital heart disease, MONDO:0005453, HEY2-related
Congenital Heart Defect v0.460 HEY2 Zornitza Stark Publications for gene: HEY2 were set to PMID: 32820247
Congenital Heart Defect v0.459 HEY2 Zornitza Stark reviewed gene: HEY2: Rating: RED; Mode of pathogenicity: None; Publications: 40481234; Phenotypes: Congenital heart disease, MONDO:0005453, HEY2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3085 ENPP5 Zornitza Stark Marked gene: ENPP5 as ready
Mendeliome v1.3085 ENPP5 Zornitza Stark Gene: enpp5 has been classified as Red List (Low Evidence).
Mendeliome v1.3085 ENPP5 Zornitza Stark gene: ENPP5 was added
gene: ENPP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ENPP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENPP5 were set to 40457511
Phenotypes for gene: ENPP5 were set to Skeletal dysplasia, MONDO:0018230, ENPP5-related
Review for gene: ENPP5 was set to RED
Added comment: Single affected individual reported distinct oro-dental phenotype including premaxillary and gingival overgrowth and hypercementosis and a homozygous missense variant p.Gly58Val, affecting a conserved glycine residue predicted to be within a putative active binding site of the ENPP5 protein. In mice, RNA-seq and immunofluorescence confirmed Enpp5 expression in functional osteoblasts of the maxilla and mandible, periodontal ligament, odontoblasts, and ameloblasts.
Sources: Literature
Skeletal dysplasia v0.318 ENPP5 Zornitza Stark Marked gene: ENPP5 as ready
Skeletal dysplasia v0.318 ENPP5 Zornitza Stark Gene: enpp5 has been classified as Red List (Low Evidence).
Skeletal dysplasia v0.318 ENPP5 Zornitza Stark gene: ENPP5 was added
gene: ENPP5 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ENPP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENPP5 were set to 40457511
Phenotypes for gene: ENPP5 were set to Skeletal dysplasia, MONDO:0018230, ENPP5-related
Review for gene: ENPP5 was set to RED
Added comment: Single affected individual reported distinct oro-dental phenotype including premaxillary and gingival overgrowth and hypercementosis and a homozygous missense variant p.Gly58Val, affecting a conserved glycine residue predicted to be within a putative active binding site of the ENPP5 protein. In mice, RNA-seq and immunofluorescence confirmed Enpp5 expression in functional osteoblasts of the maxilla and mandible, periodontal ligament, odontoblasts, and ameloblasts.
Sources: Literature
Mendeliome v1.3084 AXDND1 Zornitza Stark Marked gene: AXDND1 as ready
Mendeliome v1.3084 AXDND1 Zornitza Stark Gene: axdnd1 has been classified as Red List (Low Evidence).
Mendeliome v1.3084 AXDND1 Zornitza Stark gene: AXDND1 was added
gene: AXDND1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AXDND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AXDND1 were set to 40457935
Phenotypes for gene: AXDND1 were set to Spermatogenic failure, MONDO:0004983, AXDND1-related
Review for gene: AXDND1 was set to RED
Added comment: Single family reported with bi-allelic LoF variant.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.31 AXDND1 Zornitza Stark Marked gene: AXDND1 as ready
Infertility and Recurrent Pregnancy Loss v1.31 AXDND1 Zornitza Stark Gene: axdnd1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.31 AXDND1 Zornitza Stark gene: AXDND1 was added
gene: AXDND1 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: AXDND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AXDND1 were set to 40457935
Phenotypes for gene: AXDND1 were set to Spermatogenic failure, MONDO:0004983, AXDND1-related
Review for gene: AXDND1 was set to RED
Added comment: Single family reported with bi-allelic LoF variant.
Sources: Literature
Mendeliome v1.3083 KDF1 Zornitza Stark Marked gene: KDF1 as ready
Mendeliome v1.3083 KDF1 Zornitza Stark Gene: kdf1 has been classified as Green List (High Evidence).
Mendeliome v1.3083 KDF1 Zornitza Stark Classified gene: KDF1 as Green List (high evidence)
Mendeliome v1.3083 KDF1 Zornitza Stark Gene: kdf1 has been classified as Green List (High Evidence).
Mendeliome v1.3082 KDF1 Zornitza Stark gene: KDF1 was added
gene: KDF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDF1 were set to 27838789; 40463401; 38501196
Phenotypes for gene: KDF1 were set to Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MIM# 617337
Review for gene: KDF1 was set to GREEN
Added comment: Three families reported.
Sources: Literature
Ectodermal Dysplasia v0.102 KDF1 Zornitza Stark Marked gene: KDF1 as ready
Ectodermal Dysplasia v0.102 KDF1 Zornitza Stark Gene: kdf1 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.102 KDF1 Zornitza Stark Phenotypes for gene: KDF1 were changed from ?Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type to Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MIM# 617337
Ectodermal Dysplasia v0.101 KDF1 Zornitza Stark reviewed gene: KDF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27838789, 40463401, 38501196; Phenotypes: Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MIM# 617337; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3081 KCNA4 Zornitza Stark Marked gene: KCNA4 as ready
Mendeliome v1.3081 KCNA4 Zornitza Stark Gene: kcna4 has been classified as Red List (Low Evidence).
Mendeliome v1.3081 KCNA4 Zornitza Stark gene: KCNA4 was added
gene: KCNA4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA4 were set to 40472070
Phenotypes for gene: KCNA4 were set to Epilepsy, MONDO:0005027, KCNA4-related
Review for gene: KCNA4 was set to RED
Added comment: Single individual with de novo missense variant reported.
Sources: Literature
Genetic Epilepsy v1.201 KCNA4 Zornitza Stark Marked gene: KCNA4 as ready
Genetic Epilepsy v1.201 KCNA4 Zornitza Stark Gene: kcna4 has been classified as Red List (Low Evidence).
Genetic Epilepsy v1.201 KCNA4 Zornitza Stark gene: KCNA4 was added
gene: KCNA4 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KCNA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA4 were set to 40472070
Phenotypes for gene: KCNA4 were set to Epilepsy, MONDO:0005027, KCNA4-related
Review for gene: KCNA4 was set to RED
Added comment: Single individual with de novo missense variant reported.
Sources: Literature
Mendeliome v1.3080 LIMK1 Zornitza Stark Marked gene: LIMK1 as ready
Mendeliome v1.3080 LIMK1 Zornitza Stark Gene: limk1 has been classified as Red List (Low Evidence).
Mendeliome v1.3080 LIMK1 Zornitza Stark gene: LIMK1 was added
gene: LIMK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LIMK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LIMK1 were set to 40491492
Phenotypes for gene: LIMK1 were set to Endocrine system disorder, MONDO:0005151, LIMK1-related
Review for gene: LIMK1 was set to RED
Added comment: Two individuals reported with divergent phenotypes and divergent underlying mechanisms postulated.

One individual exhibited epileptic encephalopathy and developmental delay, while the other showed common variable immune deficiency and glucose dysregulation. Actin polymerization was significantly decreased in individual 1, whereas it was increased in individual 2. Insulin-secreting cell lines expressing the LIMK1 variant of individual 1 exhibited significantly slower exocytosis, contrasting the rapid and uncontrolled exocytosis in individual 2. Intriguingly, both variants led to increased overall insulin secretion.

Hold off further panel distribution until phenotypic associations clarified through further case reports.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.293 GBX1 Zornitza Stark Marked gene: GBX1 as ready
Intellectual disability syndromic and non-syndromic v1.293 GBX1 Zornitza Stark Gene: gbx1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.293 GBX1 Zornitza Stark gene: GBX1 was added
gene: GBX1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBX1 were set to 40519143
Phenotypes for gene: GBX1 were set to Neurodevelopmental disorder, MONDO:0700092, GBX1-related
Review for gene: GBX1 was set to RED
Added comment: Single individual with de novo LoF variant with DD and focal epilepsy. Zebrafish model had abnormal morphology of the interocular area. Furthermore, the zebrafish larvae exhibited an increased susceptibility to neurophysiological abnormalities associated with epileptiform activity.
Sources: Literature
Mendeliome v1.3079 GBX1 Zornitza Stark Marked gene: GBX1 as ready
Mendeliome v1.3079 GBX1 Zornitza Stark Gene: gbx1 has been classified as Red List (Low Evidence).
Mendeliome v1.3079 GBX1 Zornitza Stark gene: GBX1 was added
gene: GBX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBX1 were set to 40519143
Phenotypes for gene: GBX1 were set to Neurodevelopmental disorder, MONDO:0700092, GBX1-related
Review for gene: GBX1 was set to RED
Added comment: Single individual with de novo LoF variant with DD and focal epilepsy. Zebrafish model had abnormal morphology of the interocular area. Furthermore, the zebrafish larvae exhibited an increased susceptibility to neurophysiological abnormalities associated with epileptiform activity.
Sources: Literature
Genetic Epilepsy v1.200 GBX1 Zornitza Stark Marked gene: GBX1 as ready
Genetic Epilepsy v1.200 GBX1 Zornitza Stark Gene: gbx1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v1.200 GBX1 Zornitza Stark gene: GBX1 was added
gene: GBX1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBX1 were set to 40519143
Phenotypes for gene: GBX1 were set to Neurodevelopmental disorder, MONDO:0700092, GBX1-related
Review for gene: GBX1 was set to RED
Added comment: Single individual with de novo LoF variant with DD and focal epilepsy. Zebrafish model had abnormal morphology of the interocular area. Furthermore, the zebrafish larvae exhibited an increased susceptibility to neurophysiological abnormalities associated with epileptiform activity.
Sources: Literature
Congenital Heart Defect v0.459 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Congenital Heart Defect v0.459 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.459 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Congenital Heart Defect v0.459 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.458 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to AMBER
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Fetal anomalies v1.413 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Fetal anomalies v1.413 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.413 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Fetal anomalies v1.413 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.412 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to AMBER
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Mendeliome v1.3078 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Mendeliome v1.3078 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3078 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Mendeliome v1.3078 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3077 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to AMBER
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Craniosynostosis v1.71 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Craniosynostosis v1.71 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.71 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Craniosynostosis v1.71 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.70 DHRS3 Zornitza Stark edited their review of gene: DHRS3: Changed rating: AMBER
Craniosynostosis v1.70 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to GREEN
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Mendeliome v1.3076 DMRTA2 Zornitza Stark Marked gene: DMRTA2 as ready
Mendeliome v1.3076 DMRTA2 Zornitza Stark Gene: dmrta2 has been classified as Red List (Low Evidence).
Mendeliome v1.3076 DMRTA2 Zornitza Stark gene: DMRTA2 was added
gene: DMRTA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DMRTA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRTA2 were set to 40541527; 26757254
Phenotypes for gene: DMRTA2 were set to Microcephaly, MONDO:0001149, DMRTA2-related
Review for gene: DMRTA2 was set to RED
Added comment: Single family reported with three affected siblings and bi-allelic LoF variant. Newly published functional data but no further reports.
Sources: Literature
Microcephaly v1.335 DMRTA2 Zornitza Stark Marked gene: DMRTA2 as ready
Microcephaly v1.335 DMRTA2 Zornitza Stark Gene: dmrta2 has been classified as Red List (Low Evidence).
Microcephaly v1.335 DMRTA2 Zornitza Stark gene: DMRTA2 was added
gene: DMRTA2 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: DMRTA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRTA2 were set to 40541527; 26757254
Phenotypes for gene: DMRTA2 were set to Microcephaly, MONDO:0001149, DMRTA2-related
Review for gene: DMRTA2 was set to RED
Added comment: Single family reported with three affected siblings and bi-allelic LoF variant. Newly published functional data but no further reports.
Sources: Literature
Congenital hypothyroidism v0.48 TRPC4AP Chris Richmond gene: TRPC4AP was added
gene: TRPC4AP was added to Congenital hypothyroidism. Sources: Expert Review,Literature
Mode of inheritance for gene: TRPC4AP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPC4AP were set to 32428920; 26786105
Phenotypes for gene: TRPC4AP were set to Thyroid hypoplasia
Review for gene: TRPC4AP was set to AMBER
Added comment: De novo TRPC4AP variant has been identified on WES in a child with thyroid dyshormonogenesis. Next, 179 patients with CHTD sequenced using a panel of target genes identifying four variants in TRPC4AP. During development, Choukair et al. showed that Trpc4ap is expressed in the brain, the thyroid bud, and the kidney of the African clawed frog (Xenopus laevis). This team showed that disabling Trpc4ap in the African clawed frog leads to thyroid hypoplasia during development. It was also shown that TRPC4AP interacted with IKBKG which activates the NF-κB signaling pathway and regulates the genes involved in the growth and survival of thyrocytes. Furthermore, the NF-kB would control the expression of NKX2-1, PAX8, TPO, NIS, and TG.18 The authors conclude that TRPC4AP would be a new candidate gene for TDs.

Insufficient clinical cases for green. Candidate gene. Propose amber.
Sources: Expert Review, Literature
Congenital hypothyroidism v0.48 JAG1 Chris Richmond gene: JAG1 was added
gene: JAG1 was added to Congenital hypothyroidism. Sources: Expert Review,Literature
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to 26760175; 28653287
Phenotypes for gene: JAG1 were set to Alagille syndrome 1
Review for gene: JAG1 was set to GREEN
Added comment: Het LoF cause Alagille. Notch pathway involved in thyroid development. Disruption causes hypothyroidism in zebrafish. PMID 28653287

Thyroid function in 21 patients with JAG1 mutations was analyzed and genetic analysis of JAG1 was carried out in an Italian cohort of 100 CH patients. De Filippis et al. reported the predominance of CH in 6/21 patients with Alagille syndrome, two of which had thyroid hypoplasia. PMID 26760175
Sources: Expert Review, Literature
Congenital hypothyroidism v0.48 NTN1 Chris Richmond gene: NTN1 was added
gene: NTN1 was added to Congenital hypothyroidism. Sources: Literature
Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NTN1 were set to 35774517; 25353184
Phenotypes for gene: NTN1 were set to Thyroid ectopia with hypothyroidism
Review for gene: NTN1 was set to AMBER
Added comment: Only 1x family (de novo NTN1 deletion) with animal model. Propose Amber.

NTN1 codes for Netrin 1, which is involved in regulating various developmental processes, such as angiogenesis, the migration of non-neuronal cells, and epithelial morphogenesis. Known to be associated with congenital mirror movts (OMIM 618264)

A patient with a congenital heart defect and TD (ectopia) has been described with a de novo deletion of NTN1. Embryos of the zebrafish with the ntn1a gene disabled have abnormal morphogenesis of the thyroid, probablydue to abnormal vascularisation not enabling the thyroid progenitor cells
Sources: Literature
Angelman Rett like syndromes v1.13 DYRK1A Zornitza Stark Marked gene: DYRK1A as ready
Angelman Rett like syndromes v1.13 DYRK1A Zornitza Stark Gene: dyrk1a has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.101 ICK Zornitza Stark Marked gene: ICK as ready
Ectodermal Dysplasia v0.101 ICK Zornitza Stark Gene: ick has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.101 ICK Zornitza Stark Phenotypes for gene: ICK were changed from Cranioectodermal dysplasia MONDO:0009032 to Cranioectodermal dysplasia 6, MIM# 621337
Ectodermal Dysplasia v0.100 ICK Zornitza Stark reviewed gene: ICK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cranioectodermal dysplasia 6, MIM# 621337; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Ciliopathies and Nephronophthisis v1.37 ICK Zornitza Stark Publications for gene: ICK were set to 19185282; 27069622
Renal Ciliopathies and Nephronophthisis v1.36 ICK Zornitza Stark Phenotypes for gene: ICK were changed from Endocrine-cerebroosteodysplasia, MIM# 612651 to Endocrine-cerebroosteodysplasia, MIM# 612651; Cranioectodermal dysplasia 6, MIM# 621337
Ciliopathies v1.85 ICK Zornitza Stark Phenotypes for gene: ICK were changed from Endocrine-cerebroosteodysplasia (MIM#612651) to Endocrine-cerebroosteodysplasia (MIM#612651); Cranioectodermal dysplasia 6, MIM# 621337
Ciliopathies v1.84 ICK Zornitza Stark edited their review of gene: ICK: Added comment: 5 children from two families homozygous for the same 2bp deletion. Uncertain if this is a distinct disorder or represents spectrum of abnormalities within the ciliopathies.; Changed rating: GREEN; Changed publications: 40615527; Changed phenotypes: Cranioectodermal dysplasia 6, MIM# 621337; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3075 RCC1 Zornitza Stark Phenotypes for gene: RCC1 were changed from Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related to Infection-induced acute-onset axonal neuropathy, MIM# 621333
Mendeliome v1.3074 RCC1 Zornitza Stark edited their review of gene: RCC1: Changed phenotypes: Infection-induced acute-onset axonal neuropathy, MIM# 621333
Hereditary Neuropathy_CMT - isolated v1.62 RCC1 Zornitza Stark Phenotypes for gene: RCC1 were changed from Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related to Infection-induced acute-onset axonal neuropathy, MIM# 621333
Hereditary Neuropathy_CMT - isolated v1.61 RCC1 Zornitza Stark edited their review of gene: RCC1: Changed phenotypes: Infection-induced acute-onset axonal neuropathy, MIM# 621333
Angelman Rett like syndromes v1.13 DYRK1A Chirag Patel Classified gene: DYRK1A as Green List (high evidence)
Angelman Rett like syndromes v1.13 DYRK1A Chirag Patel Gene: dyrk1a has been classified as Green List (High Evidence).
Angelman Rett like syndromes v1.13 DYRK1A Chirag Patel Classified gene: DYRK1A as Green List (high evidence)
Angelman Rett like syndromes v1.13 DYRK1A Chirag Patel Gene: dyrk1a has been classified as Green List (High Evidence).
Angelman Rett like syndromes v1.12 DYRK1A Chirag Patel gene: DYRK1A was added
gene: DYRK1A was added to Angelman Rett like syndromes. Sources: Expert list
Mode of inheritance for gene: DYRK1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DYRK1A were set to PMID: 26677511
Phenotypes for gene: DYRK1A were set to DYRK1A-related intellectual disability syndrome MONDO:0013578
Review for gene: DYRK1A was set to GREEN
Added comment: Established gene-disease association.
Presentation overlaps Angelman-Rett like syndromes with: intellectual disability, autism spectrum disorder, stereotypic behaviour problems, microcephaly, epilepsy, hypertonia, gait disturbances, feeding problems, short stature, ophthalmologic anomalies, urogenital anomalies, cardiac anomalies, dental anomalies, foot anomalies, and typical facial gestalt.
Sources: Expert list
Ciliopathies v1.84 ICK Chirag Patel reviewed gene: ICK: Rating: ; Mode of pathogenicity: None; Publications: PMID: 40615527; Phenotypes: Cranioectodermal dysplasia MONDO:0009032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Ciliopathies and Nephronophthisis v1.35 ICK Chirag Patel Classified gene: ICK as Amber List (moderate evidence)
Renal Ciliopathies and Nephronophthisis v1.35 ICK Chirag Patel Gene: ick has been classified as Amber List (Moderate Evidence).
Renal Ciliopathies and Nephronophthisis v1.35 ICK Chirag Patel Classified gene: ICK as Amber List (moderate evidence)
Renal Ciliopathies and Nephronophthisis v1.35 ICK Chirag Patel Gene: ick has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.100 ICK Chirag Patel Classified gene: ICK as Amber List (moderate evidence)
Ectodermal Dysplasia v0.100 ICK Chirag Patel Gene: ick has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.99 ICK Chirag Patel gene: ICK was added
gene: ICK was added to Ectodermal Dysplasia. Sources: Literature
Mode of inheritance for gene: ICK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ICK were set to PMID: 40615527, 24797473
Phenotypes for gene: ICK were set to Cranioectodermal dysplasia MONDO:0009032
Review for gene: ICK was set to AMBER
Added comment: 5 individuals from 2 families (from the same city - Tal Afar) with disproportionately short stature, skeletal abnormalities (short limbs, relative macrocephaly, digit anomalies), ectodermal dysplasia (dental/nail/hair issues), renal issues (hyperechogenic kidneys, dilated renal pelvis, CKD/kidney failure), and liver complications (abnormal enzymes, liver failure). All the patients survived into childhood. Exome sequencing identified the same homozygous frameshift variant (p.(Tyr555Cysfs*48) in ICK (CILK1) gene in the distal part of the non-catalytic domain.

Functional data from patient-derived cells and the C. elegans model indicate that the variant reduces cilia number, increases cilia length, and disrupts the localization of IFT components. In contrast, the ciliary localization of CILK1 bearing the variant itself remains unaffected. They rescued the majority of these abnormalities by reintroducing CILK1 into patient-derived cells.

Note ICK gene is green on multiple panels for Endocrine-cerebro-osteodysplasia syndrome MONDO:0012980 (3 families reported, homozygous missense variants in catalytic domain, supportive functional studies and animal models).

PMID: 24797473 - Ick deficient mice showed ciliary defects. Authors concluded that ICK is required for normal ciliogenesis.
Sources: Literature
Renal Ciliopathies and Nephronophthisis v1.34 ICK Chirag Patel reviewed gene: ICK: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 40615527, 24797473; Phenotypes: Cranioectodermal dysplasia MONDO:0009032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3074 ICK Chirag Patel reviewed gene: ICK: Rating: ; Mode of pathogenicity: None; Publications: PMID: 40615527; Phenotypes: Cranioectodermal dysplasia MONDO:0009032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.292 MTERF3 Zornitza Stark Marked gene: MTERF3 as ready
Intellectual disability syndromic and non-syndromic v1.292 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.292 MTERF3 Zornitza Stark Classified gene: MTERF3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.292 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.291 MTERF3 Zornitza Stark gene: MTERF3 was added
gene: MTERF3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MTERF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTERF3 were set to 40543543
Phenotypes for gene: MTERF3 were set to Mitochondrial disease (MONDO:0044970), MTERF3-related
Review for gene: MTERF3 was set to AMBER
Added comment: Two individuals reported from unrelated families, presenting with DD/ID, intermittent hypoglycaemia and metabolic acidosis. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C > T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A > Gp.(Met315Val) in Patient 2. Patient's fibroblasts and MTERF3 knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type MTERF3 expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction.
Sources: Literature
Mendeliome v1.3074 MTERF3 Zornitza Stark Marked gene: MTERF3 as ready
Mendeliome v1.3074 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3074 MTERF3 Zornitza Stark Classified gene: MTERF3 as Amber List (moderate evidence)
Mendeliome v1.3074 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3073 MTERF3 Zornitza Stark gene: MTERF3 was added
gene: MTERF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTERF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTERF3 were set to 40543543
Phenotypes for gene: MTERF3 were set to Mitochondrial disease (MONDO:0044970), MTERF3-related
Review for gene: MTERF3 was set to AMBER
Added comment: Two individuals reported from unrelated families, presenting with DD/ID, intermittent hypoglycaemia and metabolic acidosis. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C > T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A > Gp.(Met315Val) in Patient 2. Patient's fibroblasts and MTERF3 knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type MTERF3 expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction.
Sources: Literature
Mitochondrial disease v0.1004 MTERF3 Zornitza Stark Marked gene: MTERF3 as ready
Mitochondrial disease v0.1004 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1004 MTERF3 Zornitza Stark Classified gene: MTERF3 as Amber List (moderate evidence)
Mitochondrial disease v0.1004 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1003 MTERF3 Zornitza Stark gene: MTERF3 was added
gene: MTERF3 was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: MTERF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTERF3 were set to 40543543
Phenotypes for gene: MTERF3 were set to Mitochondrial disease (MONDO:0044970), MTERF3-related
Review for gene: MTERF3 was set to AMBER
Added comment: Two individuals reported from unrelated families, presenting with DD/ID, intermittent hypoglycaemia and metabolic acidosis. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C > T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A > Gp.(Met315Val) in Patient 2. Patient's fibroblasts and MTERF3 knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type MTERF3 expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction.
Sources: Literature
Mendeliome v1.3072 KCNJ15 Zornitza Stark Marked gene: KCNJ15 as ready
Mendeliome v1.3072 KCNJ15 Zornitza Stark Gene: kcnj15 has been classified as Red List (Low Evidence).
Mendeliome v1.3072 KCNJ15 Zornitza Stark gene: KCNJ15 was added
gene: KCNJ15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNJ15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ15 were set to 40566643
Phenotypes for gene: KCNJ15 were set to Parkinson disease, MONDO:0005180, KCNJ15-related
Review for gene: KCNJ15 was set to RED
Added comment: Single multiplex family reported with a missense variant and functional data.
Sources: Literature
Early-onset Parkinson disease v2.38 KCNJ15 Zornitza Stark Marked gene: KCNJ15 as ready
Early-onset Parkinson disease v2.38 KCNJ15 Zornitza Stark Gene: kcnj15 has been classified as Red List (Low Evidence).
Early-onset Parkinson disease v2.38 KCNJ15 Zornitza Stark gene: KCNJ15 was added
gene: KCNJ15 was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: KCNJ15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ15 were set to 40566643
Phenotypes for gene: KCNJ15 were set to Parkinson disease, MONDO:0005180, KCNJ15-related
Review for gene: KCNJ15 was set to RED
Added comment: Single multiplex family reported with a missense variant and functional data.
Sources: Literature
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Marked gene: TFCP2L1 as ready
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Classified gene: TFCP2L1 as Amber List (moderate evidence)
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3070 TFCP2L1 Zornitza Stark gene: TFCP2L1 was added
gene: TFCP2L1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TFCP2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFCP2L1 were set to 40569305; 33097957
Phenotypes for gene: TFCP2L1 were set to CAKUT, MONDO:0019719, TFGP2L1-related
Review for gene: TFCP2L1 was set to AMBER
Added comment: PMID 40569305: consanguineous preterm male infant with a clinical picture of advanced kidney dysfunction and severe renal salt-wasting, highly suggestive of prenatal onset Bartter syndrome. Patient's follow-up was characterized by severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. Homozygous variant in the TFCP2L1 gene identified. TFCP2L1 is a transcription factor required for normal kidney development, that regulates acid-base and salt-water homeostasis.

PMID 33097957: infant who developed CKD by the age of 2 months and had episodes of severe hypochloraemic, hyponatraemic and hypokalaemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. Homozygous LoF variant.

TFCP2L1 is localized throughout kidney development particularly in the distal nephron. TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient's mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.
Sources: Literature
Renal Tubulopathies and related disorders v1.20 TFCP2L1 Zornitza Stark Marked gene: TFCP2L1 as ready
Renal Tubulopathies and related disorders v1.20 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Renal Tubulopathies and related disorders v1.20 TFCP2L1 Zornitza Stark Classified gene: TFCP2L1 as Amber List (moderate evidence)
Renal Tubulopathies and related disorders v1.20 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Renal Tubulopathies and related disorders v1.19 TFCP2L1 Zornitza Stark gene: TFCP2L1 was added
gene: TFCP2L1 was added to Renal Tubulopathies and related disorders. Sources: Literature
Mode of inheritance for gene: TFCP2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFCP2L1 were set to 40569305; 33097957
Phenotypes for gene: TFCP2L1 were set to CAKUT, MONDO:0019719, TFGP2L1-related
Review for gene: TFCP2L1 was set to AMBER
Added comment: PMID 40569305: consanguineous preterm male infant with a clinical picture of advanced kidney dysfunction and severe renal salt-wasting, highly suggestive of prenatal onset Bartter syndrome. Patient's follow-up was characterized by severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. Homozygous variant in the TFCP2L1 gene identified. TFCP2L1 is a transcription factor required for normal kidney development, that regulates acid-base and salt-water homeostasis.

PMID 33097957: infant who developed CKD by the age of 2 months and had episodes of severe hypochloraemic, hyponatraemic and hypokalaemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. Homozygous LoF variant.

TFCP2L1 is localized throughout kidney development particularly in the distal nephron. TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient's mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.
Sources: Literature
Prepair 1000+ v2.13 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Fetal anomalies v1.411 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Heterotaxy v1.41 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Ciliary Dyskinesia v1.55 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Mendeliome v1.3069 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Mendeliome v1.3069 BCAS2 Zornitza Stark Marked gene: BCAS2 as ready
Mendeliome v1.3069 BCAS2 Zornitza Stark Gene: bcas2 has been classified as Red List (Low Evidence).
Mendeliome v1.3069 BCAS2 Zornitza Stark gene: BCAS2 was added
gene: BCAS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BCAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCAS2 were set to 40585763
Phenotypes for gene: BCAS2 were set to Hyper IgM syndrome, MONDO:0003947, BCAS2-related
Review for gene: BCAS2 was set to RED
Added comment: Extensive functional work, however a single individual reported with non-coding variant, 3'UTR.
Sources: Literature
Predominantly Antibody Deficiency v1.4 BCAS2 Zornitza Stark Marked gene: BCAS2 as ready
Predominantly Antibody Deficiency v1.4 BCAS2 Zornitza Stark Gene: bcas2 has been classified as Red List (Low Evidence).
Predominantly Antibody Deficiency v1.4 BCAS2 Zornitza Stark gene: BCAS2 was added
gene: BCAS2 was added to Predominantly Antibody Deficiency. Sources: Literature
Mode of inheritance for gene: BCAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCAS2 were set to 40585763
Phenotypes for gene: BCAS2 were set to Hyper IgM syndrome, MONDO:0003947, BCAS2-related
Review for gene: BCAS2 was set to RED
Added comment: Extensive functional work, however a single individual reported with non-coding variant, 3'UTR.
Sources: Literature
Polydactyly v0.291 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Polydactyly v0.291 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Polydactyly v0.291 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Polydactyly v0.291 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Polydactyly v0.290 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Polydactyly. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Clefting disorders v0.270 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Clefting disorders v0.270 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Clefting disorders v0.270 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Clefting disorders v0.270 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Clefting disorders v0.269 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Clefting disorders. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Mendeliome v1.3068 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Mendeliome v1.3068 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Mendeliome v1.3068 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Mendeliome v1.3068 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Mendeliome v1.3067 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Fetal anomalies v1.411 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Fetal anomalies v1.411 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Fetal anomalies v1.411 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Fetal anomalies v1.411 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Fetal anomalies v1.410 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Fetal anomalies v1.410 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Fetal anomalies v1.409 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Mendeliome v1.3066 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Mendeliome v1.3066 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Mendeliome v1.3065 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Heterotaxy v1.41 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Heterotaxy v1.41 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Heterotaxy v1.40 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Congenital Heart Defect v0.457 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Congenital Heart Defect v0.457 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Macrocephaly_Megalencephaly v0.150 PPP2R1A Lucy Spencer reviewed gene: PPP2R1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Houge-Janssens syndrome 2 MIM#616362; Mode of inheritance: None
Mendeliome v1.3065 PPP1R12A Lucy Spencer reviewed gene: PPP1R12A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Genitourinary and/or/brain malformation syndrome MIM#618820; Mode of inheritance: None
Mendeliome v1.3065 PPM1F Lucy Spencer reviewed gene: PPM1F: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis MONDO:0001751, PPM1F-related; Mode of inheritance: None
Fetal anomalies v1.409 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Fetal anomalies v1.409 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Fetal anomalies v1.408 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Ciliopathies v1.84 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Ciliopathies v1.84 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Ciliopathies v1.84 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Ciliopathies v1.84 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Ciliopathies v1.83 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Ciliopathies. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Mendeliome v1.3065 ICK Zornitza Stark Marked gene: ICK as ready
Mendeliome v1.3065 ICK Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is CILK1
Mendeliome v1.3065 ICK Zornitza Stark Gene: ick has been classified as Green List (High Evidence).
Mendeliome v1.3065 ICK Zornitza Stark Tag new gene name tag was added to gene: ICK.
Ciliopathies v1.82 ICK Zornitza Stark Marked gene: ICK as ready
Ciliopathies v1.82 ICK Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is CILK1
Ciliopathies v1.82 ICK Zornitza Stark Gene: ick has been classified as Green List (High Evidence).
Ciliopathies v1.82 ICK Zornitza Stark Tag new gene name tag was added to gene: ICK.
Heterotaxy v1.40 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Heterotaxy v1.40 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.407 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Fetal anomalies v1.407 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.407 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Fetal anomalies v1.407 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.406 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Congenital Heart Defect v0.455 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Heterotaxy v1.40 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Heterotaxy v1.40 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Heterotaxy v1.40 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Heterotaxy v1.40 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3065 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Mendeliome v1.3065 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3065 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Mendeliome v1.3065 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3064 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Heterotaxy v1.39 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Heterotaxy. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Mendeliome v1.3063 ZNF319 Zornitza Stark Marked gene: ZNF319 as ready
Mendeliome v1.3063 ZNF319 Zornitza Stark Gene: znf319 has been classified as Red List (Low Evidence).
Mendeliome v1.3063 ZNF319 Zornitza Stark gene: ZNF319 was added
gene: ZNF319 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF319 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF319 were set to 40820230
Phenotypes for gene: ZNF319 were set to Leukodystrophy, MONDO:0019046, ZNF319-related
Review for gene: ZNF319 was set to RED
Added comment: Single individual with homozygous missense variant reported, p.Phe267Ser.

18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the variant disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319's role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy.
Sources: Literature
Leukodystrophy - adult onset v0.151 ZNF319 Zornitza Stark Marked gene: ZNF319 as ready
Leukodystrophy - adult onset v0.151 ZNF319 Zornitza Stark Gene: znf319 has been classified as Red List (Low Evidence).
Leukodystrophy - adult onset v0.151 ZNF319 Zornitza Stark gene: ZNF319 was added
gene: ZNF319 was added to Leukodystrophy - adult onset. Sources: Literature
Mode of inheritance for gene: ZNF319 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF319 were set to 40820230
Phenotypes for gene: ZNF319 were set to Leukodystrophy, MONDO:0019046, ZNF319-related
Review for gene: ZNF319 was set to RED
Added comment: Single individual with homozygous missense variant reported, p.Phe267Ser.

18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the variant disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319's role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy.
Sources: Literature
Congenital Disorders of Glycosylation v1.73 POMT1 Zornitza Stark Phenotypes for gene: POMT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308; Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 1 613155 to Myopathy caused by variation in POMT1 MONDO:0700070
Congenital Disorders of Glycosylation v1.72 POMT1 Zornitza Stark edited their review of gene: POMT1: Added comment: Lumped by ClinGen.; Changed phenotypes: Myopathy caused by variation in POMT1 MONDO:0700070
Mendeliome v1.3062 POMT1 Zornitza Stark Phenotypes for gene: POMT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 1 613155; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308 to Myopathy caused by variation in POMT1 MONDO:0700070
Mendeliome v1.3061 POMT1 Zornitza Stark edited their review of gene: POMT1: Changed phenotypes: Myopathy caused by variation in POMT1 MONDO:0700070
Congenital Disorders of Glycosylation v1.72 POMGNT2 Zornitza Stark Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 618135 to Myopathy caused by variation in POMGNT2 MONDO:0700069
Congenital Disorders of Glycosylation v1.71 POMGNT2 Zornitza Stark edited their review of gene: POMGNT2: Added comment: Lumped by ClinGen.; Changed phenotypes: Myopathy caused by variation in POMGNT2 MONDO:0700069
Mendeliome v1.3061 POMGNT2 Zornitza Stark Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, MIM# 614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, MIM# 618135 to Myopathy caused by variation in POMGNT2 MONDO:0700069
Congenital Disorders of Glycosylation v1.71 POMGNT1 Zornitza Stark Phenotypes for gene: POMGNT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3, 253280; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B3, 613151; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3 613157 to Myopathy caused by variation in POMGNT1 MONDO:0700068
Congenital Disorders of Glycosylation v1.70 POMGNT1 Zornitza Stark edited their review of gene: POMGNT1: Added comment: Lumped by ClinGen.; Changed phenotypes: Myopathy caused by variation in POMGNT1 MONDO:0700068
Mendeliome v1.3060 POMGNT1 Zornitza Stark Phenotypes for gene: POMGNT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 MIM#614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 MIM#618135; Retinitis pigmentosa 76 617123 to Myopathy caused by variation in POMGNT1 MONDO:0700068; Retinitis pigmentosa 76 617123
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.151 NR6A1 Zornitza Stark Publications for gene: NR6A1 were set to 39606382
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.150 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Added comment: PMID: 40774958 - Additional 10x individuals identified from a CAKUT cohort with kidney, eye, and other congenital anomalies.; Changed publications: 40774958
Mendeliome v1.3059 NR6A1 Zornitza Stark Publications for gene: NR6A1 were set to 39606382
Mendeliome v1.3058 ARID3A Zornitza Stark Phenotypes for gene: ARID3A were changed from Cornelia de Lange syndrome - MONDO:0016033 to Congenital anomaly of kidney and urinary tract, MONDO:0019719, ARID3A-related; Cornelia de Lange syndrome - MONDO:0016033
Mendeliome v1.3057 ARID3A Zornitza Stark Publications for gene: ARID3A were set to PMID: 40677927
Mendeliome v1.3056 ARID3A Zornitza Stark Classified gene: ARID3A as Amber List (moderate evidence)
Mendeliome v1.3056 ARID3A Zornitza Stark Gene: arid3a has been classified as Amber List (Moderate Evidence).
Corneal Dystrophy v1.13 MIR184 Zornitza Stark Marked gene: MIR184 as ready
Corneal Dystrophy v1.13 MIR184 Zornitza Stark Gene: mir184 has been classified as Green List (High Evidence).
Corneal Dystrophy v1.13 MIR184 Zornitza Stark Classified gene: MIR184 as Green List (high evidence)
Corneal Dystrophy v1.13 MIR184 Zornitza Stark Gene: mir184 has been classified as Green List (High Evidence).
Mendeliome v1.3055 MED14 Zornitza Stark Marked gene: MED14 as ready
Mendeliome v1.3055 MED14 Zornitza Stark Gene: med14 has been classified as Red List (Low Evidence).
Mendeliome v1.3055 MED14 Zornitza Stark Classified gene: MED14 as Red List (low evidence)
Mendeliome v1.3055 MED14 Zornitza Stark Gene: med14 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.30 NXT2 Zornitza Stark Marked gene: NXT2 as ready
Infertility and Recurrent Pregnancy Loss v1.30 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.30 NXT2 Zornitza Stark Classified gene: NXT2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.30 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3054 NXT2 Zornitza Stark Marked gene: NXT2 as ready
Mendeliome v1.3054 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3054 NXT2 Zornitza Stark Classified gene: NXT2 as Amber List (moderate evidence)
Mendeliome v1.3054 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 ARID3A Zornitza Stark Marked gene: ARID3A as ready
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 ARID3A Zornitza Stark Gene: arid3a has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 ARID3A Zornitza Stark Classified gene: ARID3A as Amber List (moderate evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 ARID3A Zornitza Stark Gene: arid3a has been classified as Amber List (Moderate Evidence).
Dystonia - complex v0.285 ATP5A1 Zornitza Stark Marked gene: ATP5A1 as ready
Dystonia - complex v0.285 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Dystonia - complex v0.285 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Dystonia - complex v0.285 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Dystonia - complex v0.284 ATP5A1 Zornitza Stark gene: ATP5A1 was added
gene: ATP5A1 was added to Dystonia - complex. Sources: Literature
new gene name tags were added to gene: ATP5A1.
Mode of inheritance for gene: ATP5A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5A1 were set to 34483339; 34954817; 40859057
Phenotypes for gene: ATP5A1 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358), AD
Review for gene: ATP5A1 was set to GREEN
Added comment: At least 12 individuals reported with de novo missense variants in this gene, several recurrent.

PMIDs: 34483339, 34954817: 6xde novo patients 4 with Arg207His, 1 Arg182Gln 1 Ser346Phe. All Arg207His patients were neonates with failure to thrive, hyperammonemia, lactic acidosis, and respiratory defects in fibroblasts, major symptoms remitted with treatment by late infancy, and at age 14mo to 3yrs growth and development were normal. Other 2 patients are 17yo with ID, ataxia, spastic paraparesis and dystonia, and a 12yo with psychomotor retardation, spastic tetraparesis, generalised dystonia, absent speech, swallowing problems, and increased blood lactate concentrations.

And an internal VCGS patient Arg182Gln (variant also seen in a different patient above) with ID, muscular hypotonia, clinodactyly of the 5th finger, and dysmorphic facial features, proteomics showed decreased ATP5F1A and a complex V deficiency. There is also an alternative change at this residue in the DECIPHER cohort Arg182Pro de novo in an individual with a neurodevelopmental disorder.

PMID: 40672495: 6x de novo individuals - 4 variants p.Arg182Gln, p.Ser346Phe, p.Pro331Leu, and p.Leu109Ser - with complex but overlapping neurological phenotypes including developmental delays, intellectual disability, pyramidal tract dysfunction, and dystonia.

In vivo functional studies in C. elegans were performed for three of the variants, showing growth defects and disruption of mitochondrial function (measured by mitochondrial stress). Authors suggest a dominant negative mechanism.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Tag new gene name tag was added to gene: ATP5A1.
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Marked gene: ATP5A1 as ready
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.289 ATP5A1 Zornitza Stark gene: ATP5A1 was added
gene: ATP5A1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATP5A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5A1 were set to 34483339; 34954817; 40859057
Phenotypes for gene: ATP5A1 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358), AD
Review for gene: ATP5A1 was set to GREEN
Added comment: At least 12 individuals reported with de novo missense variants in this gene, several recurrent.

PMIDs: 34483339, 34954817: 6xde novo patients 4 with Arg207His, 1 Arg182Gln 1 Ser346Phe. All Arg207His patients were neonates with failure to thrive, hyperammonemia, lactic acidosis, and respiratory defects in fibroblasts, major symptoms remitted with treatment by late infancy, and at age 14mo to 3yrs growth and development were normal. Other 2 patients are 17yo with ID, ataxia, spastic paraparesis and dystonia, and a 12yo with psychomotor retardation, spastic tetraparesis, generalised dystonia, absent speech, swallowing problems, and increased blood lactate concentrations.

And an internal VCGS patient Arg182Gln (variant also seen in a different patient above) with ID, muscular hypotonia, clinodactyly of the 5th finger, and dysmorphic facial features, proteomics showed decreased ATP5F1A and a complex V deficiency. There is also an alternative change at this residue in the DECIPHER cohort Arg182Pro de novo in an individual with a neurodevelopmental disorder.

PMID: 40672495: 6x de novo individuals - 4 variants p.Arg182Gln, p.Ser346Phe, p.Pro331Leu, and p.Leu109Ser - with complex but overlapping neurological phenotypes including developmental delays, intellectual disability, pyramidal tract dysfunction, and dystonia.

In vivo functional studies in C. elegans were performed for three of the variants, showing growth defects and disruption of mitochondrial function (measured by mitochondrial stress). Authors suggest a dominant negative mechanism.
Sources: Literature
Mendeliome v1.3053 ATP5A1 Zornitza Stark Phenotypes for gene: ATP5A1 were changed from Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228
Mendeliome v1.3052 ATP5A1 Zornitza Stark Publications for gene: ATP5A1 were set to 23599390, 34954817, 34483339
Mendeliome v1.3051 ATP5A1 Zornitza Stark Mode of inheritance for gene: ATP5A1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3050 ATP5A1 Zornitza Stark changed review comment from: Two unrelated families.; to: Two unrelated families with biallelic disease. Evidence for bi-allelic disease is limited. In one of the families, PMID 23599390, only a paternally inherited variant was identified, maternal variant presumed based on functional studies but not actually identified. In the other family, PMID 23596069, the variant identified is a homozygous missense.
Genetic Epilepsy v1.199 ATP5A1 Zornitza Stark Phenotypes for gene: ATP5A1 were changed from Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A MIM#620358; Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228
Genetic Epilepsy v1.198 ATP5A1 Zornitza Stark Publications for gene: ATP5A1 were set to 23599390
Genetic Epilepsy v1.197 ATP5A1 Zornitza Stark Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v1.196 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed publications: 23599390, 23596069
Genetic Epilepsy v1.196 ATP5A1 Zornitza Stark changed review comment from: Two unrelated families.; to: Two unrelated families. Evidence for bi-allelic disease is limited. In one of the families, PMID 23599390, only a paternally inherited variant was identified, maternal variant presumed based on functional studies but not actually identified. In the other family, PMID 23596069, the variant identified is a homozygous missense.
Mitochondrial disease v0.1002 ATP5A1 Zornitza Stark Phenotypes for gene: ATP5A1 were changed from Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228; Mitochondrial disorder, autosomal dominant to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228; Mitochondrial disorder, autosomal dominant
Mitochondrial disease v0.1001 ATP5A1 Zornitza Stark Publications for gene: ATP5A1 were set to 23599390; 34483339
Mitochondrial disease v0.1000 ATP5A1 Zornitza Stark Mode of inheritance for gene: ATP5A1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed rating: RED
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed publications: 23599390, 23596069
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark changed review comment from: One family described with each of these mitochondrial conditions.; to: One family described with each of these mitochondrial conditions. Evidence for bi-allelic disease is limited. In one of the families, PMID 23599390, only a paternally inherited variant was identified, maternal variant presumed based on functional studies but not actually identified. In the other family, PMID 23596069, the variant identified is a homozygous missense.
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Mendeliome v1.3050 POMT2 Lucy Spencer reviewed gene: POMT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMT2 MONDO:0700071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMT1 Lucy Spencer reviewed gene: POMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMT1 MONDO:0700070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMGNT2 Lucy Spencer reviewed gene: POMGNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMGNT2 MONDO:0700069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMGNT1 Lucy Spencer reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMGNT1 MONDO:0700068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 NR6A1 Rylee Peters reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40774958; Phenotypes: Oculovertebral syndrome MIM# 621277; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.125 ARID3A Rylee Peters gene: ARID3A was added
gene: ARID3A was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic. Sources: Literature
Mode of inheritance for gene: ARID3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID3A were set to 40774958
Phenotypes for gene: ARID3A were set to Congenital anomaly of kidney and urinary tract, MONDO:0019719, ARID3A-related
Review for gene: ARID3A was set to AMBER
Added comment: PMID: 40774958: 7x individuals from a CAKUT cohort - 5 individuals with unilateral renal agenesis and two individuals with hydronephrosis, extra-renal anomalies were also identified.

Variants identified include 3x stopgain, 1xframeshift, 3x splice site – inheritance includes 2x de novo, 4x unknown inheritance, 1x maternally inherited (unknown clinical status).
Sources: Literature
Mendeliome v1.3050 ARID3A Rylee Peters reviewed gene: ARID3A: Rating: AMBER; Mode of pathogenicity: None; Publications: 40774958; Phenotypes: Congenital anomaly of kidney and urinary tract, MONDO:0019719, ARID3A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Corneal Dystrophy v1.12 MIR184 Rylee Peters gene: MIR184 was added
gene: MIR184 was added to Corneal Dystrophy. Sources: Literature
Mode of inheritance for gene: MIR184 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIR184 were set to 40852795; 21996275; 22131394; 25373792; 24138095
Phenotypes for gene: MIR184 were set to EDICT syndrome (MIM#614303)
Review for gene: MIR184 was set to GREEN
Added comment: PMID: 40852795: Four individuals with Fuchs Endothelial Corneal Dystrophy (FECD) – three harboured n.58G>A and one with n.73G>T. No segregation testing was performed in this cohort.

At least 5 other families reported for EDICT syndrome (autosomal dominant syndromal anterior segment dysgenesis characterised by endothelial dystrophy, iris hypoplasia, congenital cataract, and thinning of the corneal stroma). Three had the same variant, (+57C>T). However, it has been suggested that his arose independently rather than being a founder variant (PMIDs: 21996275, 22131394, 25373792, 24138095).
Sources: Literature
Mendeliome v1.3050 MED14 Rylee Peters gene: MED14 was added
gene: MED14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED14 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MED14 were set to PMID: 40597352
Phenotypes for gene: MED14 were set to Neurodevelopmental disorder (MONDO:0700092), MED14-related
Review for gene: MED14 was set to RED
Added comment: PMID: 40597352: 1x male with clinical VLCAD, developmental delay, microcephaly, hypotonia and brain anomalies. Identified a hemizygous, maternally inherited splice variant c.2365+2T>C, classified as VUS. RNA studies show that the variant results in an out-of-frame loss of the C-terminal end of exon 18 due to novel splice donor use in 1.72 percent of reads.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.29 NXT2 Rylee Peters gene: NXT2 was added
gene: NXT2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NXT2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NXT2 were set to PMID: 40624043; 35013161
Phenotypes for gene: NXT2 were set to Spermatogenic failure, MONDO:0004983, NXT2-related
Review for gene: NXT2 was set to AMBER
Added comment: PMID: 40624043
- 1x hemi male with maternally inherited p.(Asp119*) – (p.Asp64* in MANE transcript) – absent from v4. Variant also present in two infertile brothers with azoospermia; absent in fertile father and brother. Over expression of the variant in HEK293T cells resulted in the complete absence of the truncated protein according to Western blot analysis.
- 1x hemi male with p.(Ala90Ser) – (p.Ala35Ser in MANE transcript) – 85 hets, 42 hemis in v4. Variant is located near the start of an exon, minigene assay showed exon 4 skipping resulting in a PTC, but no quantification of aberrant transcript expression was performed. Over expression of the variant in HEK293T cells showed comparable protein expression to WT, and NXT2 staining was present in SOX9-positive Sertoli cells in the patient’s testis.
- Above article also refers to an individual described in PMID: 35013161 – 1x male individual with a de novo 42 kb large deletion on the X chromosome encompassing the entire NXT2 gene.
Sources: Literature
Mendeliome v1.3050 NXT2 Rylee Peters gene: NXT2 was added
gene: NXT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NXT2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NXT2 were set to PMID: 40624043; 35013161
Phenotypes for gene: NXT2 were set to Spermatogenic failure, MONDO:0004983, NXT2-related
Review for gene: NXT2 was set to AMBER
Added comment: PMID: 40624043
- 1x hemi male with maternally inherited p.(Asp119*) – (p.Asp64* in MANE transcript) – absent from v4. Variant also present in two infertile brothers with azoospermia; absent in fertile father and brother. Over expression of the variant in HEK293T cells resulted in the complete absence of the truncated protein according to Western blot analysis.
- 1x hemi male with p.(Ala90Ser) – (p.Ala35Ser in MANE transcript) – 85 hets, 42 hemis in v4. Variant is located near the start of an exon, minigene assay showed exon 4 skipping resulting in a PTC, but no quantification of aberrant transcript expression was performed. Over expression of the variant in HEK293T cells showed comparable protein expression to WT, and NXT2 staining was present in SOX9-positive Sertoli cells in the patient’s testis.
- Above article also refers to an individual described in PMID: 35013161 – 1x male individual with a de novo 42 kb large deletion on the X chromosome encompassing the entire NXT2 gene.
Sources: Literature
Mendeliome v1.3050 ATP5A1 Rylee Peters reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40672495; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disease v0.998 ATP5A1 Rylee Peters reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40672495; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3050 LDHD Zornitza Stark Marked gene: LDHD as ready
Mendeliome v1.3050 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Mendeliome v1.3050 LDHD Zornitza Stark Classified gene: LDHD as Green List (high evidence)
Mendeliome v1.3050 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Miscellaneous Metabolic Disorders v1.51 LDHD Zornitza Stark Marked gene: LDHD as ready
Miscellaneous Metabolic Disorders v1.51 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Miscellaneous Metabolic Disorders v1.51 LDHD Zornitza Stark Classified gene: LDHD as Green List (high evidence)
Miscellaneous Metabolic Disorders v1.51 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Marked gene: CREB3 as ready
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Tag founder tag was added to gene: CREB3.
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Classified gene: CREB3 as Amber List (moderate evidence)
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Cone-rod Dystrophy v0.56 CREB3 Zornitza Stark reviewed gene: CREB3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa v0.176 CREB3 Zornitza Stark Marked gene: CREB3 as ready
Retinitis pigmentosa v0.176 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa v0.176 CREB3 Zornitza Stark Classified gene: CREB3 as Amber List (moderate evidence)
Retinitis pigmentosa v0.176 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa v0.175 CREB3 Zornitza Stark Tag founder tag was added to gene: CREB3.
Retinitis pigmentosa v0.175 CREB3 Zornitza Stark reviewed gene: CREB3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3049 CREB3 Zornitza Stark Marked gene: CREB3 as ready
Mendeliome v1.3049 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3049 CREB3 Zornitza Stark Classified gene: CREB3 as Amber List (moderate evidence)
Mendeliome v1.3049 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3048 CREB3 Zornitza Stark Tag founder tag was added to gene: CREB3.
Mendeliome v1.3048 CREB3 Zornitza Stark reviewed gene: CREB3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3048 XPO1 Zornitza Stark Marked gene: XPO1 as ready
Mendeliome v1.3048 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Mendeliome v1.3048 XPO1 Zornitza Stark Classified gene: XPO1 as Green List (high evidence)
Mendeliome v1.3048 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.288 XPO1 Zornitza Stark Marked gene: XPO1 as ready
Intellectual disability syndromic and non-syndromic v1.288 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.288 XPO1 Zornitza Stark Classified gene: XPO1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.288 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Atrial Fibrillation v1.4 NPPA Zornitza Stark Publications for gene: NPPA were set to 18614783; 20064500; 31034774; 31077706
Atrial Fibrillation v1.3 NPPA Zornitza Stark Mode of inheritance for gene: NPPA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Atrial Fibrillation v1.2 NPPA Zornitza Stark edited their review of gene: NPPA: Added comment: PMID 40838933: young adult with AF and homozygous missense variant in this gene p.Arg150Gln. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.; Changed rating: AMBER; Changed publications: 23275345, 40838933; Changed phenotypes: Atrial fibrillation, familial, 6, (MIM#612201); Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3047 NPPA Zornitza Stark Publications for gene: NPPA were set to 18614783; 20064500; 31034774; 31077706
Mendeliome v1.3046 NPPA Zornitza Stark Mode of inheritance for gene: NPPA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3045 NPPA Zornitza Stark changed review comment from: PMID 40838933: young adult with AF and homozygous missense variant in this gene. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.; to: PMID 40838933: young adult with AF and homozygous missense variant in this gene p.Arg150Gln. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.
Mendeliome v1.3045 NPPA Zornitza Stark edited their review of gene: NPPA: Added comment: PMID 40838933: young adult with AF and homozygous missense variant in this gene. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.; Changed publications: 18614783, 20064500, 31034774, 31077706, 40838933, 23275345; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Diarrhoea v1.23 PNLIP Zornitza Stark Marked gene: PNLIP as ready
Congenital Diarrhoea v1.23 PNLIP Zornitza Stark Gene: pnlip has been classified as Amber List (Moderate Evidence).
Congenital Diarrhoea v1.23 PNLIP Zornitza Stark Classified gene: PNLIP as Amber List (moderate evidence)
Congenital Diarrhoea v1.23 PNLIP Zornitza Stark Gene: pnlip has been classified as Amber List (Moderate Evidence).
Congenital Diarrhoea v1.22 PNLIP Zornitza Stark gene: PNLIP was added
gene: PNLIP was added to Congenital Diarrhoea. Sources: Expert Review
Mode of inheritance for gene: PNLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNLIP were set to 31977950; 25862608; 24262094; 27604308; 40840699
Phenotypes for gene: PNLIP were set to Pancreatic lipase deficiency MIM#614338
Review for gene: PNLIP was set to AMBER
Added comment: PMID 40840699: Six children from four Amish families with novel homozygous PNLIP variant, c.869G>A (p.S290N) and CPLD symptoms. Computational modeling showed that p.Ser290 is highly conserved across species and the variant causes steric hindrance resulting in protein misfolding. Functional assays revealed that the PNLIP variant had a complete loss of activity compared to the wild type (WT), with defects in catalytic function and secretion. Immunoblotting showed reduced PNLIP variant in the medium and increased accumulation in the detergent-insoluble fraction consistent with protein misfolding. Variant-expressing cells had elevated levels of BiP, an ER stress marker, and increased Xbp1 mRNA splicing, suggesting an elevated ER stress and unfolded protein response (UPR).

Previous reports: 4 cases from 2 unrelated families, with supporting biochemical assays in patient cells and cellular-based assays. The cases have decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health.

AMBER rating as not quite as severe as the other conditions included in this panel.
Sources: Expert Review
Dyslipidaemia v0.46 PNLIP Zornitza Stark Classified gene: PNLIP as Green List (high evidence)
Dyslipidaemia v0.46 PNLIP Zornitza Stark Gene: pnlip has been classified as Green List (High Evidence).
Dyslipidaemia v0.45 PNLIP Zornitza Stark reviewed gene: PNLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 40840699; Phenotypes: Pancreatic lipase deficiency MIM#614338; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3045 PNLIP Zornitza Stark Publications for gene: PNLIP were set to 31977950; 25862608; 24262094; 27604308
Mendeliome v1.3044 PNLIP Zornitza Stark Classified gene: PNLIP as Green List (high evidence)
Mendeliome v1.3044 PNLIP Zornitza Stark Gene: pnlip has been classified as Green List (High Evidence).
Mendeliome v1.3043 PNLIP Zornitza Stark reviewed gene: PNLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 40840699; Phenotypes: Pancreatic lipase deficiency MIM#614338; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3043 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Mendeliome v1.3043 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Mendeliome v1.3042 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Added comment: PMID 40859057: 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. Functional data.; Changed rating: GREEN; Changed publications: 23599390, 40859057
Mendeliome v1.3042 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Disorders of immune dysregulation v1.25 PLCG1 Zornitza Stark Publications for gene: PLCG1 were set to PMID: 37422272
Disorders of immune dysregulation v1.24 PLCG1 Zornitza Stark Classified gene: PLCG1 as Green List (high evidence)
Disorders of immune dysregulation v1.24 PLCG1 Zornitza Stark Gene: plcg1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.23 PLCG1 Zornitza Stark edited their review of gene: PLCG1: Added comment: PMID 40862571: seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] presenting with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). Further functional work in Drosophila on some of the variants investigating GoF effect.; Changed rating: GREEN; Changed publications: 37422272, 40862571
Mendeliome v1.3042 PLCG1 Zornitza Stark Publications for gene: PLCG1 were set to 37422272
Mendeliome v1.3041 PLCG1 Zornitza Stark Classified gene: PLCG1 as Green List (high evidence)
Mendeliome v1.3041 PLCG1 Zornitza Stark Gene: plcg1 has been classified as Green List (High Evidence).
Mendeliome v1.3040 PLCG1 Zornitza Stark edited their review of gene: PLCG1: Added comment: PMID 40862571: seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] presenting with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). Further functional work in Drosophila on some of the variants investigating GoF effect.; Changed rating: GREEN; Changed publications: 37422272, 40862571
Mendeliome v1.3040 KNG1 Zornitza Stark Classified gene: KNG1 as Green List (high evidence)
Mendeliome v1.3040 KNG1 Zornitza Stark Gene: kng1 has been classified as Green List (High Evidence).
Mendeliome v1.3039 KNG1 Zornitza Stark edited their review of gene: KNG1: Added comment: PMID 40848077: Two more individuals reported with LoF variants as part of a large angioedema cohort.; Changed rating: GREEN; Changed publications: 31087670, 33114181, 40848077
Hereditary angioedema v1.11 KNG1 Zornitza Stark Classified gene: KNG1 as Green List (high evidence)
Hereditary angioedema v1.11 KNG1 Zornitza Stark Gene: kng1 has been classified as Green List (High Evidence).
Hereditary angioedema v1.10 KNG1 Zornitza Stark edited their review of gene: KNG1: Changed rating: GREEN
Hereditary angioedema v1.10 KNG1 Zornitza Stark Publications for gene: KNG1 were set to 31087670; 33114181
Hereditary angioedema v1.9 KNG1 Zornitza Stark edited their review of gene: KNG1: Added comment: PMID 40848077: Two more individuals reported with LoF variants as part of a large angioedema cohort.; Changed publications: 31087670, 33114181, 40848077
Mendeliome v1.3039 MYOF Zornitza Stark Classified gene: MYOF as Amber List (moderate evidence)
Mendeliome v1.3039 MYOF Zornitza Stark Gene: myof has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3038 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: PMID 40848077: four more missense variants reported as part of a cohort, no further supportive data. Upgrade to Amber.; Changed rating: AMBER; Changed publications: 32542751, 40797221, 40848077
Hereditary angioedema v1.9 MYOF Zornitza Stark Publications for gene: MYOF were set to 32542751; 40797221
Hereditary angioedema v1.8 MYOF Zornitza Stark Classified gene: MYOF as Amber List (moderate evidence)
Hereditary angioedema v1.8 MYOF Zornitza Stark Gene: myof has been classified as Amber List (Moderate Evidence).
Hereditary angioedema v1.7 MYOF Zornitza Stark edited their review of gene: MYOF: Changed rating: AMBER
Hereditary angioedema v1.7 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: PMID 40848077: four more missense variants reported as part of a cohort, no further supportive data. Upgrade to Amber.; Changed publications: 32542751, 40797221, 40848077
Hereditary angioedema v1.7 HS3ST6 Zornitza Stark Publications for gene: HS3ST6 were set to 33508266
Hereditary angioedema v1.6 HS3ST6 Zornitza Stark edited their review of gene: HS3ST6: Added comment: PMID 40848077: reports additional patient with missense variant but no further supportive data.; Changed publications: 33508266, 40848077
Mendeliome v1.3038 ETS1 Zornitza Stark Phenotypes for gene: ETS1 were changed from Neurodevelopmental disorder, MONDO:0700092, ETS1-related to Neurodevelopmental disorder, MONDO:0700092, ETS1-related; Familial dilated cardiomyopathy, MONDO:0016333, ETS1-related
Mendeliome v1.3037 ETS1 Zornitza Stark edited their review of gene: ETS1: Added comment: PMID 40870883: Single multiplex family reported with LoF variant and DCM.; Changed publications: 31160359, 40870883; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ETS1-related, Familial dilated cardiomyopathy, MONDO:0016333, ETS1-related
Dilated Cardiomyopathy v1.44 ETS1 Zornitza Stark Marked gene: ETS1 as ready
Dilated Cardiomyopathy v1.44 ETS1 Zornitza Stark Gene: ets1 has been classified as Red List (Low Evidence).
Dilated Cardiomyopathy v1.44 ETS1 Zornitza Stark gene: ETS1 was added
gene: ETS1 was added to Dilated Cardiomyopathy. Sources: Literature
Mode of inheritance for gene: ETS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ETS1 were set to 40870883
Phenotypes for gene: ETS1 were set to Familial dilated cardiomyopathy, MONDO:0016333, ETS1-related
Review for gene: ETS1 was set to RED
Added comment: Single multiplex family reported with LoF variant and DCM.
Sources: Literature
Mendeliome v1.3037 SCN3B Zornitza Stark Marked gene: SCN3B as ready
Mendeliome v1.3037 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3037 SCN3B Zornitza Stark Classified gene: SCN3B as Amber List (moderate evidence)
Mendeliome v1.3037 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.287 SCN3B Zornitza Stark Marked gene: SCN3B as ready
Intellectual disability syndromic and non-syndromic v1.287 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.287 SCN3B Zornitza Stark Classified gene: SCN3B as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.287 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.355 POLR3H Zornitza Stark Phenotypes for gene: POLR3H were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR3H-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.354 POLR3H Zornitza Stark reviewed gene: POLR3H: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR3H-related; Mode of inheritance: None
Mendeliome v1.3036 POLR3H Zornitza Stark Phenotypes for gene: POLR3H were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR3H-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.354 POU5F1 Zornitza Stark Phenotypes for gene: POU5F1 were changed from Premature ovarian failure to Primary ovarian insufficiency MONDO:0005387, POU5F1-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.353 POU5F1 Zornitza Stark edited their review of gene: POU5F1: Changed phenotypes: Primary ovarian insufficiency MONDO:0005387, POU5F1-related
Mendeliome v1.3035 POU5F1 Zornitza Stark Phenotypes for gene: POU5F1 were changed from Premature ovarian failure to Primary ovarian insufficiency MONDO:0005387, POU5F1-related
Mendeliome v1.3034 PPARA Zornitza Stark Phenotypes for gene: PPARA were changed from {Hyperapobetalipoproteinemia, susceptibility to} to Cholesterol metabolism disease MONDO:0045008, PPARA-related
Mendeliome v1.3033 TCFL5 Zornitza Stark Marked gene: TCFL5 as ready
Mendeliome v1.3033 TCFL5 Zornitza Stark Gene: tcfl5 has been classified as Red List (Low Evidence).
Mendeliome v1.3033 TCFL5 Zornitza Stark Phenotypes for gene: TCFL5 were changed from Oligoasthenoteratozoospermia MONDO:0850098 to Oligoasthenoteratozoospermia MONDO:0850098, TCFL5-related
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Marked gene: ADAMTS6 as ready
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Gene: adamts6 has been classified as Green List (High Evidence).
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Phenotypes for gene: ADAMTS6 were changed from Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453 to Connective tissue disorder MONDO:0003900, ADAMTS6-related
Aortopathy_Connective Tissue Disorders v1.99 ADAMTS6 Zornitza Stark Marked gene: ADAMTS6 as ready
Aortopathy_Connective Tissue Disorders v1.99 ADAMTS6 Zornitza Stark Gene: adamts6 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.99 ADAMTS6 Zornitza Stark Phenotypes for gene: ADAMTS6 were changed from Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453 to Connective tissue disorder MONDO:0003900, ADAMTS6-related
Congenital Heart Defect v0.454 ADAMTS6 Zornitza Stark Marked gene: ADAMTS6 as ready
Congenital Heart Defect v0.454 ADAMTS6 Zornitza Stark Gene: adamts6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.454 ADAMTS6 Zornitza Stark Phenotypes for gene: ADAMTS6 were changed from Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453 to Connective tissue disorder MONDO:0003900, ADAMTS6-related
Mitochondrial disease v0.998 MT-TT Zornitza Stark Phenotypes for gene: MT-TT were changed from Mitochondrial disease (MONDO:0044970), MT-TT-related to Mitochondrial disease (MONDO:0044970), MT-TT-related
Mitochondrial disease v0.998 MT-TT Zornitza Stark Phenotypes for gene: MT-TT were changed from to Mitochondrial disease (MONDO:0044970), MT-TT-related
Mitochondrial disease v0.997 MT-TT Zornitza Stark Classified gene: MT-TT as Amber List (moderate evidence)
Mitochondrial disease v0.997 MT-TT Zornitza Stark Gene: mt-tt has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.286 UPF1 Zornitza Stark Classified gene: UPF1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.286 UPF1 Zornitza Stark Gene: upf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.285 UPF1 Zornitza Stark edited their review of gene: UPF1: Added comment: Additional reports identified:

PMID:28135719 (2017) reported four unrelated patients with de novo heterozygous missense variants in UPF1 gene from the Deciphering Developmental Disorders Study cohort, for which no detailed phenotypic information was available in the publication. Three patients were reported with global developmental delay (mild in one) and the fourth patient was reported with neurodevelopmental delay as one of the presenting phenotypes in the Decipher database (https://www.deciphergenomics.org/gene/UPF1/patient-overlap/snvs)

PMID:28539120 (2017) reported a patient with significant intellectual disability (ID) and gross motor delay and with a heterozygous likely pathogenic variant in UPF1 gene (c.1576_1577delinsAA/ p.Ala526Asn). However, this patient also harboured a heterozygous likely pathogenic variant in SQSTM1 gene. As reviewed below by Ivone Leong, the authors suggested that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

PMID:39571789 (2024) reported two unrelated paediatric patients with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. They both had language and motor delays and were identified with de novo heterozygous variants in UPF1 gene (c.949_951del/ p.Asp317del & c.1984G>A/ p.Asp662Asn). The p.Asp662Asn variant has also been previously reported in a patient from PMID:28135719.

PMID:39993774 (2025) reported a 17‐year‐old male patient with moderate intellectual disability, atypical autism, ADHD, and aggressivity. He was identified with a de novo missense variant in UPF1 gene - c.1576G>A/ p.Ala526Thr.; Changed rating: GREEN; Changed publications: 33057194, 28135719, 28539120, 39571789, 39993774; Changed phenotypes: neurodevelopmental disorder, MONDO:0700092, UPF1-related
Mendeliome v1.3031 UPF1 Zornitza Stark Phenotypes for gene: UPF1 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092, UPF1-related
Mendeliome v1.3030 UPF1 Zornitza Stark Publications for gene: UPF1 were set to 33057194
Mendeliome v1.3029 UPF1 Zornitza Stark Classified gene: UPF1 as Green List (high evidence)
Mendeliome v1.3029 UPF1 Zornitza Stark Gene: upf1 has been classified as Green List (High Evidence).
Mendeliome v1.3028 UPF1 Achchuthan Shanmugasundram reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 28539120, 39571789, 39993774; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia edited their review of gene: GAMT: Changed publications: PMID: 36856349, PMID: 28055022, PMID: 28055022, https://doi.org/10.1016/j.ymgme.2024.108362.
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia edited their review of gene: GAMT: Changed publications: PMID: 36856349, PMID: 28055022, PMID: 28055022
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia changed review comment from: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023.

The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014.

There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc.

Only in RED in Cerebral Palsy, Fetal anomalies.

Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship.

There is a biochemical test to confirm patogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine.

There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting.; to: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023.

The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014.

There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc.

Only in RED in Cerebral Palsy, Fetal anomalies.

Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship.

There is a biochemical test to confirm pathogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine.

There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting.
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia edited their review of gene: GAMT: Added comment: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023.

The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014.

There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc.

Only in RED in Cerebral Palsy, Fetal anomalies.

Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship.

There is a biochemical test to confirm patogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine.

There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting.; Changed publications: PMID: 36856349, PMID: 28055022; Changed phenotypes: Creberal creatine deficiency syndrome 2 (MIM 612736), global developmental delay, intellectual disability, epilepsy, behavioral disturbance, movement disorder, markedly low brain creatine and elevated guanidinoacetate.
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia gene: GAMT was added
gene: GAMT was added to Genomic newborn screening: ICoNS. Sources: Expert Review
Mode of inheritance for gene: GAMT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GAMT were set to Creberal creatine deficiency syndrome 2 (MIM 612736)
Penetrance for gene: GAMT were set to Complete
Review for gene: GAMT was set to GREEN
gene: GAMT was marked as current diagnostic
Added comment: Sources: Expert Review
Mitochondrial disease v0.996 MT-TT Chern Lim reviewed gene: MT-TT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL; Current diagnostic: yes
Mendeliome v1.3028 COMMD9 Krithika Murali Marked gene: COMMD9 as ready
Mendeliome v1.3028 COMMD9 Krithika Murali Gene: commd9 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.285 COMMD9 Krithika Murali Marked gene: COMMD9 as ready
Intellectual disability syndromic and non-syndromic v1.285 COMMD9 Krithika Murali Gene: commd9 has been classified as Red List (Low Evidence).
Mendeliome v1.3028 COMMD9 Krithika Murali gene: COMMD9 was added
gene: COMMD9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COMMD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD9 were set to PMID: 40601774
Phenotypes for gene: COMMD9 were set to Neurodevelopmental disorder, MONDO:0700092, COMMD9-related
Review for gene: COMMD9 was set to RED
Added comment: PMID: 40601774 report a cohort ascertained through GeneMatcher with phenotypic features overlapping with Ritscher-Schinzel syndrome.

Homozygous fs variant in COMMD9 [NM_014186.3:c.208_209del, p.Leu70Glyfs*5] identified in a 4 yo M with dev delay, dysmorphism, skeletal changes including brachydactyly and radioulnar dysostosis, hypotonia, MRI-B anomalies - dysgyria, dilated
lateral ventricles, deep white matter periventricular demyelination, thin corpus callosum, cerebellar vermis hypoplasia and malrotation.

Consanguineous parents confirmed to be heterozygous carriers. No information provided regarding segregation of these variants in unaffected siblings.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.285 COMMD9 Krithika Murali gene: COMMD9 was added
gene: COMMD9 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: COMMD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD9 were set to PMID: 40601774
Phenotypes for gene: COMMD9 were set to Neurodevelopmental disorder, MONDO:0700092, COMMD9-related
Review for gene: COMMD9 was set to RED
Added comment: PMID: 40601774 report a cohort ascertained through GeneMatcher with phenotypic features overlapping with Ritscher-Schinzel syndrome.

Homozygous fs variant in COMMD9 [NM_014186.3:c.208_209del, p.Leu70Glyfs*5] identified in a 4 yo M with dev delay, dysmorphism, skeletal changes including brachydactyly and radioulnar dysostosis, hypotonia, MRI-B anomalies - dysgyria, dilated
lateral ventricles, deep white matter periventricular demyelination, thin corpus callosum, cerebellar vermis hypoplasia and malrotation.

Consanguineous parents confirmed to be heterozygous carriers. No information provided regarding segregation of these variants in unaffected siblings.
Sources: Literature
Autism v0.215 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Autism v0.215 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Autism v0.214 TBCB Krithika Murali Marked gene: TBCB as ready
Autism v0.214 TBCB Krithika Murali Gene: tbcb has been classified as Red List (Low Evidence).
Autism v0.214 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Autism. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Callosome v0.558 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Callosome v0.558 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Callosome v0.557 TBCB Krithika Murali Marked gene: TBCB as ready
Callosome v0.557 TBCB Krithika Murali Gene: tbcb has been classified as Red List (Low Evidence).
Leukodystrophy - paediatric v0.327 TBCB Krithika Murali Marked gene: TBCB as ready
Leukodystrophy - paediatric v0.327 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.284 TBCB Krithika Murali Marked gene: TBCB as ready
Intellectual disability syndromic and non-syndromic v1.284 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia v1.95 TBCB Krithika Murali Marked gene: TBCB as ready
Hereditary Spastic Paraplegia v1.95 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Leukodystrophy - paediatric v0.327 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Leukodystrophy - paediatric v0.327 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia v1.95 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Hereditary Spastic Paraplegia v1.95 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.284 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.284 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Callosome v0.557 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Callosome. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Leukodystrophy - paediatric v0.326 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Hereditary Spastic Paraplegia v1.94 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.283 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Mendeliome v1.3027 TBCB Krithika Murali Marked gene: TBCB as ready
Mendeliome v1.3027 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3027 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Mendeliome v1.3027 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3026 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Mendeliome v1.3025 NPSR1 Zornitza Stark Phenotypes for gene: NPSR1 were changed from {Asthma, susceptibility to, 2} 608584 to Short sleep, familial natural, 3, MIM# 621336; {Asthma, susceptibility to, 2} 608584
Mendeliome v1.3024 NPSR1 Zornitza Stark Publications for gene: NPSR1 were set to
Mendeliome v1.3023 NPSR1 Zornitza Stark reviewed gene: NPSR1: Rating: RED; Mode of pathogenicity: None; Publications: 31619542; Phenotypes: Short sleep, familial natural, 3, MIM# 621336; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3023 KRT32 Bryony Thompson Marked gene: KRT32 as ready
Mendeliome v1.3023 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Mendeliome v1.3023 KRT32 Bryony Thompson Classified gene: KRT32 as Green List (high evidence)
Mendeliome v1.3023 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Mendeliome v1.3022 KRT32 Bryony Thompson gene: KRT32 was added
gene: KRT32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KRT32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT32 were set to 40814173; 39048559
Phenotypes for gene: KRT32 were set to loose anagen syndrome MONDO:0010908; Pityriasis rubra pilaris MONDO:0100017
Review for gene: KRT32 was set to GREEN
Added comment: Sufficient evidence for Pityriasis rubra pilaris association, but limited for association with loose anagen syndrome.
PMID: 39048559 - Significant enrichment of KRT32 variants (p=3.06e-4) in 58 PRP cases vs 364 healthy controls (4 variants - individual 1: c.344G>A (p.Arg115Gln - 10 hets gnomAD v4.1), individual 2: c.477_478del (p.Thr160fs), individual 3: c.607C>T (p.Arg203Cys - 71 hets gnomAD v4.1), and individual 4: c.685T>C (p.Cys229Arg - 18 hets gnomAD v4.1). Validation cohort of 44 PRP cases vs 436 healthy controls identified an additional 2 variants (individual 5: c.907G>A (p.Glu303Lys - 3 hets gnomAD v4.1), individual 6: c.937A>G (p.Ile313Val - 30 hets gnomAD v4.1). A combined analysis of the KRT32 gene in both the discovery and validation cohorts revealed a significant p value of 1.73 e-6. The KRT32 expression patterns (location of protein expression) were altered in PRP cases with the KRT32 variants. In vitro analysis demonstrated that the 6 variants (all located in the IF rod domain) exhibited varying degrees of attenuation in inhibiting the NF-κB signaling pathway. A Krt32 knockout mouse model recapitulates the human PRP-like phenotype.
PMID: 40814173 - a single family with loose anagen hair syndrome co-segregating (c.296C>T; p.Thr99Ile) in a large family; however, the AF in the European population is 0.3% in gnomAD v4.1 (6 homozygotes), which is higher than expected for a dominant condition. In vitro functional assay showing the variant alters interaction with KRT82, however, only WT & the variant were assessed (no positive control).
Sources: Literature
Palmoplantar Keratoderma and Erythrokeratoderma v0.136 KRT32 Bryony Thompson Marked gene: KRT32 as ready
Palmoplantar Keratoderma and Erythrokeratoderma v0.136 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Palmoplantar Keratoderma and Erythrokeratoderma v0.136 KRT32 Bryony Thompson Classified gene: KRT32 as Green List (high evidence)
Palmoplantar Keratoderma and Erythrokeratoderma v0.136 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Palmoplantar Keratoderma and Erythrokeratoderma v0.135 KRT32 Bryony Thompson gene: KRT32 was added
gene: KRT32 was added to Palmoplantar Keratoderma and Erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: KRT32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT32 were set to 39048559
Phenotypes for gene: KRT32 were set to Pityriasis rubra pilaris MONDO:0100017
Review for gene: KRT32 was set to GREEN
Added comment: Significant enrichment of KRT32 variants (p=3.06e-4) in 58 PRP cases vs 364 healthy controls (4 variants - individual 1: c.344G>A (p.Arg115Gln - 10 hets gnomAD v4.1), individual 2: c.477_478del (p.Thr160fs), individual 3: c.607C>T (p.Arg203Cys - 71 hets gnomAD v4.1), and individual 4: c.685T>C (p.Cys229Arg - 18 hets gnomAD v4.1). Validation cohort of 44 PRP cases vs 436 healthy controls identified an additional 2 variants (individual 5: c.907G>A (p.Glu303Lys - 3 hets gnomAD v4.1), individual 6: c.937A>G (p.Ile313Val - 30 hets gnomAD v4.1). A combined analysis of the KRT32 gene in both the discovery and validation cohorts revealed a significant p value of 1.73 e-6. The KRT32 expression patterns (location of protein expression) were altered in PRP cases with the KRT32 variants. In vitro analysis demonstrated that the 6 variants (all located in the IF rod domain) exhibited varying degrees of attenuation in inhibiting the NF-κB signaling pathway. A Krt32 knockout mouse model recapitulates the human PRP-like phenotype.
Sources: Literature
Hair disorders v0.81 KRT32 Bryony Thompson Marked gene: KRT32 as ready
Hair disorders v0.81 KRT32 Bryony Thompson Gene: krt32 has been classified as Red List (Low Evidence).
Hair disorders v0.81 KRT32 Bryony Thompson gene: KRT32 was added
gene: KRT32 was added to Hair disorders. Sources: Literature
Mode of inheritance for gene: KRT32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT32 were set to 40814173
Phenotypes for gene: KRT32 were set to loose anagen syndrome MONDO:0010908
Review for gene: KRT32 was set to RED
Added comment: A single family with loose anagen hair syndrome co-segregating (c.296C>T; p.Thr99Ile) in a large family; however, the AF in the European population is 0.3% in gnomAD v4.1 (6 homozygotes), which is higher than expected for a dominant condition and it would be expected that this phenotype has been reported in association with the variant/gene previously. In vitro functional assay showing the variant alters interaction with KRT82; however, only WT & the variant were assessed (no positive control).
Sources: Literature
Mendeliome v1.3021 CCDC89 Bryony Thompson Marked gene: CCDC89 as ready
Mendeliome v1.3021 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.29 CCDC89 Bryony Thompson Marked gene: CCDC89 as ready
Infertility and Recurrent Pregnancy Loss v1.29 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.29 CCDC89 Bryony Thompson Classified gene: CCDC89 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.29 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.28 CCDC89 Bryony Thompson gene: CCDC89 was added
gene: CCDC89 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CCDC89 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC89 were set to 40591933
Phenotypes for gene: CCDC89 were set to spermatogenic failure MONDO:0004983
Review for gene: CCDC89 was set to AMBER
Added comment: 2 missense identified in 3 males with non-obstructive azoospermia (2 homozygous for c.903G>T p.E301D, NFE AF 0.7% in gnomAD v4.1 & 1 chet for c.903G>T & c.1024G>A p.D342N - NFE AF 0.0086%). A homozygous knock-in mouse model for p.E301D (Ccdc89E297D/E297D) was fertile, their testis weights and germ cell content were reduced, and male knockouts (Ccdc89−/−) were sub-fertile.
Sources: Literature
Mendeliome v1.3021 CCDC89 Bryony Thompson Classified gene: CCDC89 as Amber List (moderate evidence)
Mendeliome v1.3021 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3020 CCDC89 Bryony Thompson gene: CCDC89 was added
gene: CCDC89 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC89 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC89 were set to 40591933
Phenotypes for gene: CCDC89 were set to spermatogenic failure MONDO:0004983
Review for gene: CCDC89 was set to AMBER
Added comment: 2 missense identified in 3 males with non-obstructive azoospermia (2 homozygous for c.903G>T p.E301D, NFE AF 0.7% in gnomAD v4.1 & 1 chet for c.903G>T & c.1024G>A p.D342N - NFE AF 0.0086%). A homozygous knock-in mouse model for p.E301D (Ccdc89E297D/E297D) was fertile, their testis weights and germ cell content were reduced, and male knockouts (Ccdc89−/−) were sub-fertile.
Sources: Literature
Mendeliome v1.3019 TULP2 Bryony Thompson Marked gene: TULP2 as ready
Mendeliome v1.3019 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.27 TULP2 Bryony Thompson Marked gene: TULP2 as ready
Infertility and Recurrent Pregnancy Loss v1.27 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.27 TULP2 Bryony Thompson Classified gene: TULP2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.27 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.26 TULP2 Bryony Thompson gene: TULP2 was added
gene: TULP2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TULP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TULP2 were set to 35619658: 33763418; 40613306
Phenotypes for gene: TULP2 were set to male infertility MONDO:0005372
Review for gene: TULP2 was set to AMBER
Added comment: Tulp2 -/- mouse model is sterile. Only one individual with asthenoteratozoospermia reported with a homozygous missense variant (c.832C>T p.R278W) that present in at AF of ~1% in the East Asian population in gnomAD v4.1 (455/44,880 alleles, 4 homozygotes). This AF doesn’t rule it out as a possible cause of male sterility.
Sources: Literature
Mendeliome v1.3019 TULP2 Bryony Thompson Classified gene: TULP2 as Amber List (moderate evidence)
Mendeliome v1.3019 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3018 TULP2 Bryony Thompson gene: TULP2 was added
gene: TULP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TULP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TULP2 were set to 35619658: 33763418; 40613306
Phenotypes for gene: TULP2 were set to male infertility MONDO:0005372
Review for gene: TULP2 was set to AMBER
Added comment: Tulp2 -/- mouse model is sterile. Only one individual with asthenoteratozoospermia reported with a homozygous missense variant (c.832C>T p.R278W) that present in at AF of ~1% in the East Asian population in gnomAD v4.1 (455/44,880 alleles, 4 homozygotes). This AF doesn’t rule it out as a possible cause of male sterility.
Sources: Literature
Leukodystrophy - paediatric v0.325 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694 to POLR3A-related disorder MONDO:0700276
Leukodystrophy - paediatric v0.324 POLR3A Zornitza Stark edited their review of gene: POLR3A: Changed phenotypes: POLR3A-related disorder MONDO:0700276
Dystonia - complex v0.283 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694; Striatal abnormalities; Dystonia to POLR3A-related disorder MONDO:0700276
Dystonia - complex v0.282 POLR3A Zornitza Stark edited their review of gene: POLR3A: Changed phenotypes: POLR3A-related disorder MONDO:0700276
Ataxia v1.49 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Autosomal Recessive Ataxia; Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism; Hypomyelinating leukodystrophy 7 with or without oligodontia and/or hypogonadotrophic hypogonadism, 607694 to POLR3A-related disorder MONDO:0700276
Ataxia v1.48 POLR3A Zornitza Stark edited their review of gene: POLR3A: Changed phenotypes: POLR3A-related disorder MONDO:0700276
Differences of Sex Development v1.16 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM#607694 to POLR3A-related disorder MONDO:0700276
Differences of Sex Development v1.15 POLR3A Zornitza Stark reviewed gene: POLR3A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: POLR3A-related disorder MONDO:0700276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v2.37 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694; POLR3A Leukoencephalopathy; Parkinsonism; Ocular and dental abnormality; Hypogonadism to POLR3A-related disorder MONDO:0700276
Early-onset Parkinson disease v2.36 POLR3A Zornitza Stark edited their review of gene: POLR3A: Changed phenotypes: POLR3A-related disorder MONDO:0700276
Mendeliome v1.3017 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694; Wiedemann-Rautenstrauch syndrome, MIM# 264090; Susceptibility to severe VZV infection; POLR3A-related spastic ataxia to POLR3A-related disorder MONDO:0700276; Susceptibility to severe VZV infection; POLR3A-related spastic ataxia
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.353 POLR2C Zornitza Stark Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR2C-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 POLR2C Zornitza Stark reviewed gene: POLR2C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR2C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3016 POLR2C Zornitza Stark Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR2C-related
Growth failure v1.81 ZPR1 Zornitza Stark Phenotypes for gene: ZPR1 were changed from Growth restriction, hypoplastic kidneys, alpecia, and distinctive facies, MIM# 619321 to Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, MIM# 619321
Growth failure v1.80 ZPR1 Zornitza Stark Classified gene: ZPR1 as Amber List (moderate evidence)
Growth failure v1.80 ZPR1 Zornitza Stark Gene: zpr1 has been classified as Amber List (Moderate Evidence).
Growth failure v1.79 ZPR1 Zornitza Stark edited their review of gene: ZPR1: Changed rating: AMBER
Growth failure v1.79 ZPR1 Zornitza Stark changed review comment from: PMID 40776660: new family reported with two sibs, same homozygous founder variant.; to: PMID 40776660: new family reported with two sibs, same homozygous founder variant.

This paper also summarizes functional studies from the previous paper PMID: 29851065 - cultured skin fibroblasts from the patient homozygous for c.587 T>C showed significantly fewer cells in late S and G2/M phases of the cell cycle compared to control fibroblasts suggesting a disruption of cell-cycle progression past the G1 phase. ZPR1 protein was undetectable in fibroblasts from the affected individual.
Mendeliome v1.3015 ZPR1 Zornitza Stark Classified gene: ZPR1 as Amber List (moderate evidence)
Mendeliome v1.3015 ZPR1 Zornitza Stark Gene: zpr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.282 COMMD4 Zornitza Stark Marked gene: COMMD4 as ready
Intellectual disability syndromic and non-syndromic v1.282 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.282 COMMD4 Zornitza Stark Classified gene: COMMD4 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v1.282 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Callosome v0.556 COMMD4 Zornitza Stark Marked gene: COMMD4 as ready
Callosome v0.556 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Callosome v0.556 COMMD4 Zornitza Stark Classified gene: COMMD4 as Red List (low evidence)
Callosome v0.556 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Mendeliome v1.3014 COMMD4 Zornitza Stark Marked gene: COMMD4 as ready
Mendeliome v1.3014 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Mendeliome v1.3014 COMMD4 Zornitza Stark Classified gene: COMMD4 as Red List (low evidence)
Mendeliome v1.3014 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.453 ADAMTS6 Chirag Patel Classified gene: ADAMTS6 as Green List (high evidence)
Congenital Heart Defect v0.453 ADAMTS6 Chirag Patel Gene: adamts6 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.98 ADAMTS6 Chirag Patel Classified gene: ADAMTS6 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.98 ADAMTS6 Chirag Patel Gene: adamts6 has been classified as Green List (High Evidence).
Mendeliome v1.3013 ADAMTS6 Chirag Patel Classified gene: ADAMTS6 as Green List (high evidence)
Mendeliome v1.3013 ADAMTS6 Chirag Patel Gene: adamts6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.452 ADAMTS6 Chirag Patel gene: ADAMTS6 was added
gene: ADAMTS6 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ADAMTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTS6 were set to PMID: 40657314
Phenotypes for gene: ADAMTS6 were set to Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453
Review for gene: ADAMTS6 was set to GREEN
Added comment: 4 unrelated individuals with thoracic aortic dilatation/aneurysm (3/4), congenital heart defect (3/4), high palate (3/4), hypertelorism (3/4), flat feet (3/4). learning issues/ID (2/4).

WES/WGS identified 4 rare predicted deleterious missense variants in ADAMTS6 gene [p.(Leu814Arg), p.(Asp319Asn), p.(Ala147Thr), p.(Ile810Leu)]. 2/4 variants were de novo, 1/4 was inherited (no parental phenotype info), 1/4 unknown status. Note: THSD4 gene, encoding ADAMTSL6, is associated with aortopathy disorder.

Functional studies (patient-derived fibroblasts) demonstrated that the variants impair ADAMTS6 secretion or function resulting in increased deposition of FBN1 and FBN2, and therefore extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signalling pathways and altered cell adhesion. Adamts6 (S149R/S149R) mice showed ventricular septal defects and accumulation of FBN1 and FBN2 in the outflow tracts.

Proposed name of condition: CHAN syndrome (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental) syndrome.
Sources: Literature
Mendeliome v1.3012 ADAMTS6 Chirag Patel gene: ADAMTS6 was added
gene: ADAMTS6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAMTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTS6 were set to PMID: 40657314
Phenotypes for gene: ADAMTS6 were set to Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453
Review for gene: ADAMTS6 was set to GREEN
Added comment: 4 unrelated individuals with thoracic aortic dilatation/aneurysm (3/4), congenital heart defect (3/4), high palate (3/4), hypertelorism (3/4), flat feet (3/4). learning issues/ID (2/4).

WES/WGS identified 4 rare predicted deleterious missense variants in ADAMTS6 gene [p.(Leu814Arg), p.(Asp319Asn), p.(Ala147Thr), p.(Ile810Leu)]. 2/4 variants were de novo, 1/4 was inherited (no parental phenotype info), 1/4 unknown status. Note: THSD4 gene, encoding ADAMTSL6, is associated with aortopathy disorder.

Functional studies (patient-derived fibroblasts) demonstrated that the variants impair ADAMTS6 secretion or function resulting in increased deposition of FBN1 and FBN2, and therefore extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signalling pathways and altered cell adhesion. Adamts6 (S149R/S149R) mice showed ventricular septal defects and accumulation of FBN1 and FBN2 in the outflow tracts.

Proposed name of condition: CHAN syndrome (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental) syndrome.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.97 ADAMTS6 Chirag Patel gene: ADAMTS6 was added
gene: ADAMTS6 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ADAMTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTS6 were set to PMID: 40657314
Phenotypes for gene: ADAMTS6 were set to Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453
Review for gene: ADAMTS6 was set to GREEN
Added comment: 4 unrelated individuals with thoracic aortic dilatation/aneurysm (3/4), congenital heart defect (3/4), high palate (3/4), hypertelorism (3/4), flat feet (3/4). learning issues/ID (2/4).

WES/WGS identified 4 rare predicted deleterious missense variants in ADAMTS6 gene [p.(Leu814Arg), p.(Asp319Asn), p.(Ala147Thr), p.(Ile810Leu)]. 2/4 variants were de novo, 1/4 was inherited (no parental phenotype info), 1/4 unknown status. Note: THSD4 gene, encoding ADAMTSL6, is associated with aortopathy disorder.

Functional studies (patient-derived fibroblasts) demonstrated that the variants impair ADAMTS6 secretion or function resulting in increased deposition of FBN1 and FBN2, and therefore extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signalling pathways and altered cell adhesion. Adamts6 (S149R/S149R) mice showed ventricular septal defects and accumulation of FBN1 and FBN2 in the outflow tracts.

Proposed name of condition: CHAN syndrome (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental) syndrome.
Sources: Literature
Mendeliome v1.3011 TCFL5 Chirag Patel gene: TCFL5 was added
gene: TCFL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCFL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCFL5 were set to PMID: 40711600
Phenotypes for gene: TCFL5 were set to Oligoasthenoteratozoospermia MONDO:0850098
Review for gene: TCFL5 was set to RED
Added comment: 2 brothers from non-consanguineous family with oligoasthenoteratozoospermia (OAT). WES identified missense variant in TCFL5 gene (c.1207G>A, p.E403K). Western blotting and immunofluorescence showed no significant effect on the expression of 'mutant' TCFL5. Dual-luciferase reporter assay revealed a serious impact on its transcriptional regulatory function.
The variant disrupted the normal transcription of crucial genes involved in spermatogenesis (DMRT1, DAZL, SYCE1, SPACA1, CNTROB, IFT88, HOOK1 and SPATA6). Tcfl5+/- male mice manifest infertile due to OAT, while Tcfl5-/- mice can not be generated.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.25 TCFL5 Chirag Patel gene: TCFL5 was added
gene: TCFL5 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TCFL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCFL5 were set to PMID: 40711600
Phenotypes for gene: TCFL5 were set to Oligoasthenoteratozoospermia MONDO:0850098
Review for gene: TCFL5 was set to RED
Added comment: 2 brothers from non-consanguineous family with oligoasthenoteratozoospermia (OAT). WES identified missense variant in TCFL5 gene (c.1207G>A, p.E403K). Western blotting and immunofluorescence showed no significant effect on the expression of 'mutant' TCFL5. Dual-luciferase reporter assay revealed a serious impact on its transcriptional regulatory function.
The variant disrupted the normal transcription of crucial genes involved in spermatogenesis (DMRT1, DAZL, SYCE1, SPACA1, CNTROB, IFT88, HOOK1 and SPATA6). Tcfl5+/- male mice manifest infertile due to OAT, while Tcfl5-/- mice can not be generated.
Sources: Literature
Heterotaxy v1.38 NPHP4 Chirag Patel Classified gene: NPHP4 as Red List (low evidence)
Heterotaxy v1.38 NPHP4 Chirag Patel Gene: nphp4 has been classified as Red List (Low Evidence).
Mendeliome v1.3010 PPARA Lucy Spencer reviewed gene: PPARA: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholesterol metabolism disease MONDO:0045008, PPARA-related; Mode of inheritance: None
Mendeliome v1.3010 POU5F1 Lucy Spencer reviewed gene: POU5F1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POU5F1-related; Mode of inheritance: None
Mendeliome v1.3010 POPDC2 Lucy Spencer reviewed gene: POPDC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39006410, 32535041; Phenotypes: Cardiac conduction defect MONDO:0100042, POPDC2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3010 POLR3H Lucy Spencer reviewed gene: POLR3H: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR3H-related; Mode of inheritance: None
Mendeliome v1.3010 POLR3A Lucy Spencer reviewed gene: POLR3A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: POLR3A-related disorder MONDO:0700276; Mode of inheritance: None
Mendeliome v1.3010 POLR2C Lucy Spencer reviewed gene: POLR2C: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR2C-related; Mode of inheritance: None
Mendeliome v1.3010 ZPR1 Lucy Spencer reviewed gene: ZPR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 40776660; Phenotypes: Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies MIM#619321; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.281 COMMD4 Lucy Spencer gene: COMMD4 was added
gene: COMMD4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: COMMD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD4 were set to 40601774
Phenotypes for gene: COMMD4 were set to Ritscher-Schinzel syndrome, MONDO:0019078, COMMD4-related
Review for gene: COMMD4 was set to RED
Added comment: PMID: 40601774 3 siblings with Ritscher-Schinzel syndrome and a homozygous missense in COMMD4 NM_017828.5:c.122T>G; p.Leu41Arg. All three individuals died in infancy and the authors suggest there could be a dual diagnosis to explain the severity.

This variant was expressed in a H4 neuroglioma cell line with COMMD4 knocked out, and showed an enhanced degradative turnover compared to WT when treated with cyclohexamide. Western blot in HEK293T cells showed a decrease in the steady-state abundance of COMMD4.

Knock out of COMMD4 protein leads to destabilization of the Commander complex.
Sources: Literature
Callosome v0.555 COMMD4 Lucy Spencer gene: COMMD4 was added
gene: COMMD4 was added to Callosome. Sources: Literature
Mode of inheritance for gene: COMMD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD4 were set to 40601774
Phenotypes for gene: COMMD4 were set to Ritscher-Schinzel syndrome, MONDO:0019078, COMMD4-related
Review for gene: COMMD4 was set to RED
Added comment: PMID: 40601774 3 siblings with Ritscher-Schinzel syndrome and a homozygous missense in COMMD4 NM_017828.5:c.122T>G; p.Leu41Arg. All three individuals died in infancy and the authors suggest there could be a dual diagnosis to explain the severity.

This variant was expressed in a H4 neuroglioma cell line with COMMD4 knocked out, and showed an enhanced degradative turnover compared to WT when treated with cyclohexamide. Western blot in HEK293T cells showed a decrease in the steady-state abundance of COMMD4.

Knock out of COMMD4 protein leads to destabilization of the Commander complex.
Sources: Literature
Mendeliome v1.3010 COMMD4 Lucy Spencer gene: COMMD4 was added
gene: COMMD4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COMMD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD4 were set to 40601774
Phenotypes for gene: COMMD4 were set to Ritscher-Schinzel syndrome, MONDO:0019078, COMMD4-related
Review for gene: COMMD4 was set to RED
Added comment: PMID: 40601774 3 siblings with Ritscher-Schinzel syndrome and a homozygous missense in COMMD4 NM_017828.5:c.122T>G; p.Leu41Arg. All three individuals died in infancy and the authors suggest there could be a dual diagnosis to explain the severity.

This variant was expressed in a H4 neuroglioma cell line with COMMD4 knocked out, and showed an enhanced degradative turnover compared to WT when treated with cyclohexamide. Western blot in HEK293T cells showed a decrease in the steady-state abundance of COMMD4.

Knock out of COMMD4 protein leads to destabilization of the Commander complex.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.281 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Intellectual disability syndromic and non-syndromic v1.281 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.281 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.281 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Callosome v0.555 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Callosome v0.555 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Callosome v0.555 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Callosome v0.555 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Genetic Epilepsy v1.196 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Genetic Epilepsy v1.196 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Genetic Epilepsy v1.196 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Genetic Epilepsy v1.196 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Mendeliome v1.3010 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Mendeliome v1.3010 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Mendeliome v1.3010 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Mendeliome v1.3010 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Mendeliome v1.3009 C4orf26 Zornitza Stark Marked gene: C4orf26 as ready
Mendeliome v1.3009 C4orf26 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is ODAPH.
Mendeliome v1.3009 C4orf26 Zornitza Stark Gene: c4orf26 has been classified as Green List (High Evidence).
Mendeliome v1.3009 C4orf26 Zornitza Stark Tag new gene name tag was added to gene: C4orf26.
Callosome v0.554 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Callosome. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Genetic Epilepsy v1.195 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.280 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Mendeliome v1.3009 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Hypertrophic cardiomyopathy_HCM v1.9 PHLPP2 Zornitza Stark Marked gene: PHLPP2 as ready
Hypertrophic cardiomyopathy_HCM v1.9 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy_HCM v1.9 PHLPP2 Zornitza Stark Classified gene: PHLPP2 as Red List (low evidence)
Hypertrophic cardiomyopathy_HCM v1.9 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Mendeliome v1.3009 PHLPP2 Zornitza Stark Marked gene: PHLPP2 as ready
Mendeliome v1.3009 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Mendeliome v1.3009 PHLPP2 Zornitza Stark Classified gene: PHLPP2 as Red List (low evidence)
Mendeliome v1.3009 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.201 MYO19 Zornitza Stark Marked gene: MYO19 as ready
Cardiomyopathy_Paediatric v0.201 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.201 MYO19 Zornitza Stark Classified gene: MYO19 as Red List (low evidence)
Cardiomyopathy_Paediatric v0.201 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Mendeliome v1.3008 MYO19 Zornitza Stark Marked gene: MYO19 as ready
Mendeliome v1.3008 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Mendeliome v1.3008 MYO19 Zornitza Stark Classified gene: MYO19 as Red List (low evidence)
Mendeliome v1.3008 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Mendeliome v1.3007 C4orf26 Sangavi Sivagnanasundram reviewed gene: C4orf26: Rating: GREEN; Mode of pathogenicity: Other; Publications: 40680053; Phenotypes: Amelogenesis imperfecta, type IIA4 MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3007 MYO19 Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Cardiomyopathy_Paediatric v0.200 MYO19 Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Mendeliome v1.3007 PHLPP2 Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature
Hypertrophic cardiomyopathy_HCM v1.8 PHLPP2 Lucy Spencer gene: PHLPP2 was added
gene: PHLPP2 was added to Hypertrophic cardiomyopathy_HCM. Sources: Literature
Mode of inheritance for gene: PHLPP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PHLPP2 were set to 40634996; 29628444
Phenotypes for gene: PHLPP2 were set to Hypertrophic cardiomyopathy MONDO:0005045, PHLPP2-related
Review for gene: PHLPP2 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444.
Sources: Literature
Mendeliome v1.3007 PHLPP2 Lucy Spencer gene: PHLPP2 was added
gene: PHLPP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHLPP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PHLPP2 were set to 40634996; 29628444
Phenotypes for gene: PHLPP2 were set to Hypertrophic cardiomyopathy MONDO:0005045, PHLPP2-related
Review for gene: PHLPP2 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature
Cardiomyopathy_Paediatric v0.200 MYO19 Lucy Spencer gene: MYO19 was added
gene: MYO19 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: MYO19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO19 were set to 40634996
Phenotypes for gene: MYO19 were set to Hypertrophic cardiomyopathy MONDO:0005045, MYO19-related
Review for gene: MYO19 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Mendeliome v1.3007 MYO19 Lucy Spencer gene: MYO19 was added
gene: MYO19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYO19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO19 were set to 40634996
Phenotypes for gene: MYO19 were set to Hypertrophic cardiomyopathy MONDO:0005045, MYO19-related
Review for gene: MYO19 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.280 POLR3D Zornitza Stark Marked gene: POLR3D as ready
Intellectual disability syndromic and non-syndromic v1.280 POLR3D Zornitza Stark Gene: polr3d has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.280 POLR3D Zornitza Stark gene: POLR3D was added
gene: POLR3D was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: POLR3D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3D were set to 37915380
Phenotypes for gene: POLR3D were set to Leukodystrophy, MONDO:0019046, POLR3D-related
Review for gene: POLR3D was set to RED
Added comment: PMID 37915380: single individual with compound het variants in POLR3D and childhood onset leukodystrophy manifesting as DD/ID.

Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient's fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation.
Sources: Literature
Mendeliome v1.3007 POLR3D Zornitza Stark Marked gene: POLR3D as ready
Mendeliome v1.3007 POLR3D Zornitza Stark Gene: polr3d has been classified as Red List (Low Evidence).
Mendeliome v1.3007 POLR3D Zornitza Stark gene: POLR3D was added
gene: POLR3D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLR3D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3D were set to 37915380
Phenotypes for gene: POLR3D were set to Leukodystrophy, MONDO:0019046, POLR3D-related
Review for gene: POLR3D was set to RED
Added comment: PMID 37915380: single individual with compound het variants in POLR3D and childhood onset leukodystrophy manifesting as DD/ID.

Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient's fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation.
Sources: Literature
Leukodystrophy - paediatric v0.324 POLR3D Zornitza Stark Marked gene: POLR3D as ready
Leukodystrophy - paediatric v0.324 POLR3D Zornitza Stark Gene: polr3d has been classified as Red List (Low Evidence).
Leukodystrophy - paediatric v0.324 POLR3D Zornitza Stark gene: POLR3D was added
gene: POLR3D was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: POLR3D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3D were set to 37915380
Phenotypes for gene: POLR3D were set to Leukodystrophy, MONDO:0019046, POLR3D-related
Review for gene: POLR3D was set to RED
Added comment: PMID 37915380: single individual with compound het variants in POLR3D and childhood onset leukodystrophy manifesting as DD/ID.

Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient's fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation.
Sources: Literature
Bleeding and Platelet Disorders v1.58 STAB2 Zornitza Stark Marked gene: STAB2 as ready
Bleeding and Platelet Disorders v1.58 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Bleeding and Platelet Disorders v1.58 STAB2 Zornitza Stark Classified gene: STAB2 as Red List (low evidence)
Bleeding and Platelet Disorders v1.58 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Mendeliome v1.3006 STAB2 Zornitza Stark Marked gene: STAB2 as ready
Mendeliome v1.3006 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Mendeliome v1.3006 STAB2 Zornitza Stark Classified gene: STAB2 as Red List (low evidence)
Mendeliome v1.3006 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.50 LDHD Lucy Spencer gene: LDHD was added
gene: LDHD was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: LDHD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LDHD were set to 40678184
Phenotypes for gene: LDHD were set to D-lactic aciduria with susceptibility to gout MIM#245450
Review for gene: LDHD was set to GREEN
Added comment: 8 patients summarized in PMID: 40678184 with D-Lactate Dehydrogenase Deficiency. 5 homozygous missense, 1 homozygous frameshift, 1 compound heterozygous canonical splice and missense, and 1 homozygous deletion encompassing CTRB2, ZFP1 (neither of which have a disease association) and the first 7 exons of LDHD. Three of these patients had additional variants of interest in other genes that were thought to explain extra phenotypes they had out of the typical spectrum for this disorder.

Some patients only have increased plasma urate/gout however 4 also had delayed development, ataxia or epilepsy. 2 of these individuals had other genetic variants that likely explained the neurodevelopmental phenotype (11p deletion syndrome, CACNA1B), and 1 had the deletion that also affected 2 other genes of uncertain significance. So its unclear whether this gene is actually associated with a neurodevelopmental phenotype.

"Patients diagnosed with the disease human D-lactate dehydrogenase deficiency present with elevated plasma D-lactate, causing D-lactic acidosis"
Sources: Literature
Mendeliome v1.3005 LDHD Lucy Spencer gene: LDHD was added
gene: LDHD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LDHD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LDHD were set to 40678184
Phenotypes for gene: LDHD were set to D-lactic aciduria with susceptibility to gout MIM#245450
Review for gene: LDHD was set to GREEN
Added comment: 8 patients summarized in PMID: 40678184 with D-Lactate Dehydrogenase Deficiency. 5 homozygous missense, 1 homozygous frameshift, 1 compound heterozygous canonical splice and missense, and 1 homozygous deletion encompassing CTRB2, ZFP1 (neither of which have a disease association) and the first 7 exons of LDHD. Three of these patients had additional variants of interest in other genes that were thought to explain extra phenotypes they had out of the typical spectrum for this disorder.

Some patients only have increased plasma urate/gout however 4 also had delayed development, ataxia or epilepsy. 2 of these individuals had other genetic variants that likely explained the neurodevelopmental phenotype (11p deletion syndrome, CACNA1B), and 1 had the deletion that also affected 2 other genes of uncertain significance. So its unclear whether this gene is actually associated with a neurodevelopmental phenotype.
Sources: Literature
Mendeliome v1.3005 STAB2 Lucy Spencer changed review comment from: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 100 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature; to: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 1000 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Bleeding and Platelet Disorders v1.57 STAB2 Lucy Spencer gene: STAB2 was added
gene: STAB2 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: STAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STAB2 were set to 40726512
Phenotypes for gene: STAB2 were set to Chronic thromboembolic pulmonary hypertension MONDO:0013024, STAB2-related
Review for gene: STAB2 was set to RED
Added comment: PMID: 40726512 In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 1000 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Mendeliome v1.3005 STAB2 Lucy Spencer gene: STAB2 was added
gene: STAB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STAB2 were set to 40726512
Phenotypes for gene: STAB2 were set to Chronic thromboembolic pulmonary hypertension MONDO:0013024, STAB2-related
Review for gene: STAB2 was set to RED
Added comment: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 100 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Wilms Tumour v1.1 TRIM28 Zornitza Stark Phenotypes for gene: TRIM28 were changed from Wilms tumor, MONDO:0006058; Wilms tumor predisposition, no MIM# to Wilms tumor 7, MIM# 621332
Wilms Tumour v1.0 TRIM28 Zornitza Stark reviewed gene: TRIM28: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Wilms tumor 7, MIM# 621332; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.137 TRIM28 Zornitza Stark Phenotypes for gene: TRIM28 were changed from Wilms tumour, MONDO:0006058, TRIM28-related to Wilms tumor 7, MIM# 621332
Genomic newborn screening: BabyScreen+ v1.136 TRIM28 Zornitza Stark edited their review of gene: TRIM28: Changed phenotypes: Wilms tumor 7, MIM# 621332
Cancer Predisposition_Paediatric v0.132 TRIM28 Zornitza Stark Phenotypes for gene: TRIM28 were changed from Wilms tumour, MONDO:0006058, TRIM28-related to Wilms tumor 7, MIM# 621332
Cancer Predisposition_Paediatric v0.131 TRIM28 Zornitza Stark edited their review of gene: TRIM28: Changed phenotypes: Wilms tumor 7, MIM# 621332
Stroke v1.26 ARHGEF15 Zornitza Stark Marked gene: ARHGEF15 as ready
Stroke v1.26 ARHGEF15 Zornitza Stark Gene: arhgef15 has been classified as Green List (High Evidence).
Stroke v1.26 ARHGEF15 Zornitza Stark Classified gene: ARHGEF15 as Green List (high evidence)
Stroke v1.26 ARHGEF15 Zornitza Stark Gene: arhgef15 has been classified as Green List (High Evidence).
Stroke v1.25 ARHGEF15 Zornitza Stark gene: ARHGEF15 was added
gene: ARHGEF15 was added to Stroke. Sources: Literature
Mode of inheritance for gene: ARHGEF15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGEF15 were set to 36929019
Phenotypes for gene: ARHGEF15 were set to Brain small vessel disease 5 with osteoporosis, MIM# 621331
Review for gene: ARHGEF15 was set to GREEN
Added comment: 7 individuals, ranging from 42 to 60 years of age and from 4 unrelated Chinese families, who presented between 38 and 46 years of age, with cognitive and memory decline, psychiatric disturbances, and small-vessel cerebral infarction and/or intracerebral hemorrhage on brain imaging. Features included irritability, mania, anxiety, depression, and suicidal tendencies. Four different missense variants identified. Supportive functional data, including mouse model.
Sources: Literature
Mendeliome v1.3005 ARHGEF15 Zornitza Stark Phenotypes for gene: ARHGEF15 were changed from to Brain small vessel disease 5 with osteoporosis, MIM# 621331
Mendeliome v1.3004 ARHGEF15 Zornitza Stark Publications for gene: ARHGEF15 were set to
Mendeliome v1.3003 ARHGEF15 Zornitza Stark Mode of inheritance for gene: ARHGEF15 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3002 ARHGEF15 Zornitza Stark Classified gene: ARHGEF15 as Green List (high evidence)
Mendeliome v1.3002 ARHGEF15 Zornitza Stark Gene: arhgef15 has been classified as Green List (High Evidence).
Mendeliome v1.3001 ARHGEF15 Zornitza Stark edited their review of gene: ARHGEF15: Added comment: 7 individuals, ranging from 42 to 60 years of age and from 4 unrelated Chinese families, who presented between 38 and 46 years of age, with cognitive and memory decline, psychiatric disturbances, and small-vessel cerebral infarction and/or intracerebral hemorrhage on brain imaging. Features included irritability, mania, anxiety, depression, and suicidal tendencies.

Four different missense variants identified. Supportive functional data, including mouse model.; Changed rating: GREEN; Changed publications: 36929019; Changed phenotypes: Brain small vessel disease 5 with osteoporosis, MIM# 621331; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v1.24 TDRD9 Bryony Thompson Marked gene: TDRD9 as ready
Infertility and Recurrent Pregnancy Loss v1.24 TDRD9 Bryony Thompson Gene: tdrd9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.24 TDRD9 Bryony Thompson Classified gene: TDRD9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.24 TDRD9 Bryony Thompson Gene: tdrd9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.23 TDRD9 Bryony Thompson gene: TDRD9 was added
gene: TDRD9 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TDRD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD9 were set to 28536242; 40645105; 20059948; 39267058; 39174853; 35172124
Phenotypes for gene: TDRD9 were set to spermatogenic failure MONDO:0004983
Review for gene: TDRD9 was set to GREEN
Added comment: At least 5 families with biallelic variants (homozygous and compound heterozygous) were identified in males with spermatogenic failure (azoospermia and oligoazoospermia). Also, supporting infertile mouse model.
Sources: Literature
Mendeliome v1.3001 TDRD9 Bryony Thompson Classified gene: TDRD9 as Green List (high evidence)
Mendeliome v1.3001 TDRD9 Bryony Thompson Gene: tdrd9 has been classified as Green List (High Evidence).
Mendeliome v1.3000 TDRD9 Bryony Thompson gene: TDRD9 was added
gene: TDRD9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TDRD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD9 were set to 28536242; 40645105; 20059948; 39267058; 39174853; 35172124
Phenotypes for gene: TDRD9 were set to spermatogenic failure MONDO:0004983
Review for gene: TDRD9 was set to GREEN
Added comment: At least 5 families with biallelic variants (homozygous and compound heterozygous) were identified in males with spermatogenic failure (azoospermia and oligoazoospermia). Also, supporting infertile mouse model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.279 HS6ST2 Bryony Thompson Marked gene: HS6ST2 as ready
Intellectual disability syndromic and non-syndromic v1.279 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.279 HS6ST2 Bryony Thompson Classified gene: HS6ST2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.279 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.278 HS6ST2 Bryony Thompson gene: HS6ST2 was added
gene: HS6ST2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HS6ST2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: HS6ST2 were set to 40686562; 30471091; 36993824; 38015989
Phenotypes for gene: HS6ST2 were set to X-linked syndromic intellectual disability MONDO:0020119
Review for gene: HS6ST2 was set to GREEN
Added comment: 4 males with a neurodevelopmental phenotype from 3 families (1 set monozygotic twins) hemizygous for rare missense variants and a supporting mouse model.
PMID: 40686562 - a Chinese male child with a syndromic neurodevelopmental phenotype hemizygous c.764C>A (p.Pro255Glu) and in vitro assays showing the variant alters function. Parents were unaffected and variant was maternally inherited.

PMID: 38015989 - knockout mouse model impairs dendritic spines of hippocampal neurons, and affects memory.

PMID: 36993824 - an Iranian male child with a syndromic neurodevelopmental phenotype hemizygouc.979C>T p.Pro327Ser.

PMID: 30471091 - Italian monozygotic male twins with a syndromic neurodevelopmental phenotype hemizygous c.916G>C (p.G306R - inherited from unaffected mother) and functional assay showing altered enzyme activity.
Sources: Literature
Mendeliome v1.2999 HS6ST2 Bryony Thompson Marked gene: HS6ST2 as ready
Mendeliome v1.2999 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Mendeliome v1.2999 HS6ST2 Bryony Thompson Classified gene: HS6ST2 as Green List (high evidence)
Mendeliome v1.2999 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Mendeliome v1.2998 HS6ST2 Bryony Thompson gene: HS6ST2 was added
gene: HS6ST2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HS6ST2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: HS6ST2 were set to 40686562; 30471091; 36993824; 38015989
Phenotypes for gene: HS6ST2 were set to X-linked syndromic intellectual disability MONDO:0020119
Review for gene: HS6ST2 was set to GREEN
Added comment: 4 males with a neurodevelopmental phenotype from 3 families (1 set monozygotic twins) hemizygous for rare missense variants and a supporting mouse model.
PMID: 40686562 - a Chinese male child with a syndromic neurodevelopmental phenotype hemizygous c.764C>A (p.Pro255Glu) and in vitro assays showing the variant alters function. Parents were unaffected and variant was maternally inherited.

PMID: 38015989 - knockout mouse model impairs dendritic spines of hippocampal neurons, and affects memory.

PMID: 36993824 - an Iranian male child with a syndromic neurodevelopmental phenotype hemizygouc.979C>T p.Pro327Ser.

PMID: 30471091 - Italian monozygotic male twins with a syndromic neurodevelopmental phenotype hemizygous c.916G>C (p.G306R - inherited from unaffected mother) and functional assay showing altered enzyme activity.
Sources: Literature
Ataxia v1.48 ATXN2_SCA2_CAG Bryony Thompson Marked STR: ATXN2_SCA2_CAG as ready
Ataxia v1.48 ATXN2_SCA2_CAG Bryony Thompson Str: atxn2_sca2_cag has been classified as Green List (High Evidence).
Ataxia v1.48 ATXN2_SCA2_CAG Bryony Thompson Classified STR: ATXN2_SCA2_CAG as Green List (high evidence)
Ataxia v1.48 ATXN2_SCA2_CAG Bryony Thompson Str: atxn2_sca2_cag has been classified as Green List (High Evidence).
Ataxia v1.47 ATXN2_SCA2_CAG Bryony Thompson STR: ATXN2_SCA2_CAG was added
STR: ATXN2_SCA2_CAG was added to Ataxia - paediatric. Sources: Literature
Mode of inheritance for STR: ATXN2_SCA2_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: ATXN2_SCA2_CAG were set to 40741828
Phenotypes for STR: ATXN2_SCA2_CAG were set to Spinocerebellar ataxia type 2 MONDO:0008458
Review for STR: ATXN2_SCA2_CAG was set to GREEN
STR: ATXN2_SCA2_CAG was marked as clinically relevant
STR: ATXN2_SCA2_CAG was marked as current diagnostic
Added comment: Cohort of paediatric-onset SCA2 cases. The infantile onset group (n=9) had expansions ≥88 repeats, and the juvenile onset group (n=13) had expansions ≥43 repeats. Paediatric SCA2 phenotype includes developmental delay and seizures (infantile-onset) and cerebellar degeneration similar to adults in the juvenile group.
Sources: Literature
Mendeliome v1.2997 SPNS1 Zornitza Stark Marked gene: SPNS1 as ready
Mendeliome v1.2997 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2997 SPNS1 Zornitza Stark Classified gene: SPNS1 as Amber List (moderate evidence)
Mendeliome v1.2997 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.22 SPNS1 Zornitza Stark Marked gene: SPNS1 as ready
Lysosomal Storage Disorder v1.22 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.22 SPNS1 Zornitza Stark Classified gene: SPNS1 as Amber List (moderate evidence)
Lysosomal Storage Disorder v1.22 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.277 CSMD2 Zornitza Stark Deleted their review
Intellectual disability syndromic and non-syndromic v1.277 CSMD2 Zornitza Stark reviewed gene: CSMD2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Focal epilepsy - MONDO:0005384, CSMD2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.326 SDHD Zornitza Stark Marked gene: SDHD as ready
Incidentalome v0.326 SDHD Zornitza Stark Gene: sdhd has been classified as Green List (High Evidence).
Incidentalome v0.326 SDHD Zornitza Stark Phenotypes for gene: SDHD were changed from to Paragangliomas 1, with or without deafness, MIM# 168000; Pheochromocytoma, MIM# 171300
Incidentalome v0.325 SDHD Zornitza Stark Mode of inheritance for gene: SDHD was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Incidentalome v0.324 SDHAF2 Zornitza Stark Marked gene: SDHAF2 as ready
Incidentalome v0.324 SDHAF2 Zornitza Stark Gene: sdhaf2 has been classified as Green List (High Evidence).
Incidentalome v0.324 SDHAF2 Zornitza Stark Phenotypes for gene: SDHAF2 were changed from to Paragangliomas 2, MIM# 601650
Incidentalome v0.323 SDHAF2 Zornitza Stark Mode of inheritance for gene: SDHAF2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Fetal anomalies v1.405 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Fetal anomalies v1.404 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Ciliopathies and Nephronophthisis v1.34 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Polydactyly v0.289 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Polydactyly v0.289 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Polydactyly v0.289 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Polydactyly v0.288 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2996 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Mendeliome v1.2995 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: Meckel syndrome MONDO:0018921, TMEM17-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliopathies v1.82 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to 40841990
Ciliopathies v1.82 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Incidentalome v0.322 SDHAF2 Anna Le Fevre reviewed gene: SDHAF2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Ciliopathies v1.81 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: Meckel syndrome MONDO:0018921, TMEM17-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2995 TEX44 Zornitza Stark Marked gene: TEX44 as ready
Mendeliome v1.2995 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Incidentalome v0.322 SDHD Anna Le Fevre commented on gene: SDHD: Would you like this gene added to the imprinted gene list?
Note gene in incidentalome.
Mendeliome v1.2995 TEX44 Zornitza Stark Classified gene: TEX44 as Green List (high evidence)
Mendeliome v1.2995 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Mendeliome v1.2994 TEX44 Zornitza Stark gene: TEX44 was added
gene: TEX44 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEX44 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEX44 were set to 40849303
Phenotypes for gene: TEX44 were set to Spermatogenic failure, MONDO:0004983, TEX44-related
Review for gene: TEX44 was set to GREEN
Added comment: Six individuals with biallelic variants, mouse model and other functional data support this gene-disease relationship.
Sources: Literature
Incidentalome v0.322 SDHD Anna Le Fevre reviewed gene: SDHD: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Marked gene: TEX44 as ready
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Marked gene: TEX44 as ready
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Publications for gene: TEX44 were set to
Infertility and Recurrent Pregnancy Loss v1.21 TEX44 Zornitza Stark Classified gene: TEX44 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.21 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.20 TEX44 Zornitza Stark edited their review of gene: TEX44: Changed publications: 40849303
Infertility and Recurrent Pregnancy Loss v1.20 TEX44 Zornitza Stark gene: TEX44 was added
gene: TEX44 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TEX44 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TEX44 were set to Spermatogenic failure, MONDO:0004983, TEX44-related
Review for gene: TEX44 was set to GREEN
Added comment: Six individuals with biallelic variants, mouse model and other functional data support this gene-disease relationship.
Sources: Literature
IBMDx study v0.37 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
IBMDx study v0.37 ADA2 Zornitza Stark Marked gene: ADA2 as ready
IBMDx study v0.37 ADA2 Zornitza Stark Gene: ada2 has been classified as Green List (High Evidence).
IBMDx study v0.37 ADA2 Zornitza Stark Publications for gene: ADA2 were set to
IBMDx study v0.36 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autoinflammatory Disorders v2.15 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285
Autoinflammatory Disorders v2.14 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autoinflammatory Disorders v2.13 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bone Marrow Failure v1.125 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285; 33791889
Bone Marrow Failure v1.124 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bone Marrow Failure v1.123 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Vasculitis v0.89 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Vasculitis v0.88 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285; 33791889
Vasculitis v0.87 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.277 TTC1 Zornitza Stark Marked gene: TTC1 as ready
Intellectual disability syndromic and non-syndromic v1.277 TTC1 Zornitza Stark Gene: ttc1 has been classified as Red List (Low Evidence).
Mendeliome v1.2993 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285; 33791889
Mendeliome v1.2992 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2991 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2991 FSCN1 Zornitza Stark Marked gene: FSCN1 as ready
Mendeliome v1.2991 FSCN1 Zornitza Stark Gene: fscn1 has been classified as Red List (Low Evidence).
Mendeliome v1.2991 FSCN1 Zornitza Stark gene: FSCN1 was added
gene: FSCN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FSCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FSCN1 were set to 40874942
Phenotypes for gene: FSCN1 were set to Neurodevelopmental disorder, MONDO:0700092, FSCN1-related
Review for gene: FSCN1 was set to RED
Added comment: Two individuals reported in an Iranian cohort with same missense variant, c.665C>A; p.Ala222Asp, plus other circumstantial data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.277 FSCN1 Zornitza Stark Marked gene: FSCN1 as ready
Intellectual disability syndromic and non-syndromic v1.277 FSCN1 Zornitza Stark Gene: fscn1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.277 FSCN1 Zornitza Stark gene: FSCN1 was added
gene: FSCN1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FSCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FSCN1 were set to 40874942
Phenotypes for gene: FSCN1 were set to Neurodevelopmental disorder, MONDO:0700092, FSCN1-related
Review for gene: FSCN1 was set to RED
Added comment: Two individuals reported from an Iranian cohort with same missense variant, c.665C>A; p.Ala222Asp plus other circumstantial data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.276 TTC1 Zornitza Stark gene: TTC1 was added
gene: TTC1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC1 were set to 40879651
Phenotypes for gene: TTC1 were set to Pontocerebellar hypoplasia, MONDO:0020135, TTC1-related
Review for gene: TTC1 was set to RED
Added comment: Four individuals from two families reported with the same homozygous missense variant, NM_003314.3: c.784 T > G, p.Phe262Val. No other supporting data.
Sources: Literature
Mendeliome v1.2990 TTC1 Zornitza Stark Marked gene: TTC1 as ready
Mendeliome v1.2990 TTC1 Zornitza Stark Gene: ttc1 has been classified as Red List (Low Evidence).
Mendeliome v1.2990 TTC1 Zornitza Stark gene: TTC1 was added
gene: TTC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC1 were set to 40879651
Phenotypes for gene: TTC1 were set to Pontocerebellar hypoplasia, MONDO:0020135, TTC1-related
Review for gene: TTC1 was set to RED
Added comment: Four individuals from two families reported with the same homozygous missense variant, NM_003314.3: c.784 T > G, p.Phe262Val. No other supporting data.
Sources: Literature
Microcephaly v1.334 MAEA Zornitza Stark Marked gene: MAEA as ready
Microcephaly v1.334 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.87 TTC1 Zornitza Stark Marked gene: TTC1 as ready
Cerebellar and Pontocerebellar Hypoplasia v1.87 TTC1 Zornitza Stark Gene: ttc1 has been classified as Red List (Low Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.87 TTC1 Zornitza Stark gene: TTC1 was added
gene: TTC1 was added to Cerebellar and Pontocerebellar Hypoplasia. Sources: Literature
Mode of inheritance for gene: TTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC1 were set to 40879651
Phenotypes for gene: TTC1 were set to Pontocerebellar hypoplasia, MONDO:0020135, TTC1-related
Review for gene: TTC1 was set to RED
Added comment: Four individuals from two families reported with the same homozygous missense variant, NM_003314.3: c.784 T > G, p.Phe262Val. No other supporting data.
Sources: Literature
Microcephaly v1.334 MAEA Zornitza Stark Classified gene: MAEA as Amber List (moderate evidence)
Microcephaly v1.334 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Microcephaly v1.333 MAEA Zornitza Stark gene: MAEA was added
gene: MAEA was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: MAEA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAEA were set to 40880485
Phenotypes for gene: MAEA were set to Neurodevelopmental disorder, MONDO:0700092, MAEA-related
Review for gene: MAEA was set to AMBER
Added comment: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands. Amber rating as scant detail on the affected individuals.
Sources: Literature
Mendeliome v1.2989 MAEA Zornitza Stark Marked gene: MAEA as ready
Mendeliome v1.2989 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2989 MAEA Zornitza Stark Classified gene: MAEA as Amber List (moderate evidence)
Mendeliome v1.2989 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2988 MAEA Zornitza Stark gene: MAEA was added
gene: MAEA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAEA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAEA were set to 40880485
Phenotypes for gene: MAEA were set to Neurodevelopmental disorder, MONDO:0700092, MAEA-related
Review for gene: MAEA was set to AMBER
Added comment: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands. Amber rating as scant detail on the affected individuals.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark changed review comment from: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands.
Sources: Literature; to: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands. Amber rating as scant detail on the affected individuals.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark Marked gene: MAEA as ready
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark Classified gene: MAEA as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.274 MAEA Zornitza Stark gene: MAEA was added
gene: MAEA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAEA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAEA were set to 40880485
Phenotypes for gene: MAEA were set to Neurodevelopmental disorder, MONDO:0700092, MAEA-related
Review for gene: MAEA was set to AMBER
Added comment: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands.
Sources: Literature
Mendeliome v1.2987 NIN Zornitza Stark Publications for gene: NIN were set to 22933543
Mendeliome v1.2986 NIN Zornitza Stark edited their review of gene: NIN: Added comment: PMID 40751525: second affected individual but homozygous inframe deletion.; Changed publications: 22933543, 40751525
Microcephaly v1.332 NIN Zornitza Stark Publications for gene: NIN were set to 22933543
Microcephaly v1.331 NIN Zornitza Stark edited their review of gene: NIN: Added comment: PMID 40751525: second affected individual but homozygous inframe deletion.; Changed publications: 22933543, 40751525
Mendeliome v1.2986 SYNE2 Zornitza Stark Publications for gene: SYNE2 were set to 32184094; 17761684
Mendeliome v1.2985 SYNE2 Zornitza Stark Mode of inheritance for gene: SYNE2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2984 SYNE2 Zornitza Stark reviewed gene: SYNE2: Rating: RED; Mode of pathogenicity: None; Publications: 40757551; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2984 EMP2 Zornitza Stark Phenotypes for gene: EMP2 were changed from nephrotic syndrome, type 10 MONDO:0014373 to nephrotic syndrome, type 10 MONDO:0014373; Ichthyosis, MONDO:0019269, EMP2-related
Mendeliome v1.2983 EMP2 Zornitza Stark Mode of inheritance for gene: EMP2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2982 EMP2 Zornitza Stark reviewed gene: EMP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 40758889; Phenotypes: Ichthyosis, MONDO:0019269, EMP2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis and Porokeratosis v1.13 EMP2 Zornitza Stark Marked gene: EMP2 as ready
Ichthyosis and Porokeratosis v1.13 EMP2 Zornitza Stark Gene: emp2 has been classified as Amber List (Moderate Evidence).
Ichthyosis and Porokeratosis v1.13 EMP2 Zornitza Stark Classified gene: EMP2 as Amber List (moderate evidence)
Ichthyosis and Porokeratosis v1.13 EMP2 Zornitza Stark Gene: emp2 has been classified as Amber List (Moderate Evidence).
Ichthyosis and Porokeratosis v1.12 EMP2 Zornitza Stark gene: EMP2 was added
gene: EMP2 was added to Ichthyosis. Sources: Literature
Mode of inheritance for gene: EMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMP2 were set to 40758889
Phenotypes for gene: EMP2 were set to Ichthyosis, MONDO:0019269, EMP2-related
Review for gene: EMP2 was set to AMBER
Added comment: Recurrent de novo missense variant associated with progressive symmetric erythrokeratoderma, mechanism appears GoF.
Sources: Literature
Growth failure v1.79 ZPR1 Zornitza Stark Publications for gene: ZPR1 were set to 29851065
Growth failure v1.78 ZPR1 Zornitza Stark edited their review of gene: ZPR1: Added comment: PMID 40776660: new family reported with two sibs, same homozygous founder variant.; Changed publications: 29851065, 40776660
Hypertrophic cardiomyopathy_HCM v1.8 TTL Zornitza Stark Marked gene: TTL as ready
Hypertrophic cardiomyopathy_HCM v1.8 TTL Zornitza Stark Gene: ttl has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy_HCM v1.8 TTL Zornitza Stark gene: TTL was added
gene: TTL was added to Hypertrophic cardiomyopathy_HCM. Sources: Literature
Mode of inheritance for gene: TTL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TTL were set to 40779454
Phenotypes for gene: TTL were set to Hypertrophic cardiomyopathy, MONDO:0005045, TTL-related
Review for gene: TTL was set to RED
Added comment: Single case report, missense variant with functional data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.273 CSMD2 Krithika Murali Marked gene: CSMD2 as ready
Intellectual disability syndromic and non-syndromic v1.273 CSMD2 Krithika Murali Gene: csmd2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.273 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected/affected siblings and segregation testing has been provided

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2982 C4A Zornitza Stark Publications for gene: C4A were set to 22387014; 22737222; 15998580; 10529130; 15294999; 32048120
Mendeliome v1.2981 C4A Zornitza Stark reviewed gene: C4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 40788338; Phenotypes: C4a deficiency MIM#614380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Complement Deficiencies v1.1 C4A Zornitza Stark Publications for gene: C4A were set to 22387014; 22737222; 15998580; 10529130; 15294999; 32048120
Complement Deficiencies v1.0 C4A Zornitza Stark reviewed gene: C4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 40788338; Phenotypes: C4a deficiency MIM#614380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2981 NDNF Zornitza Stark Publications for gene: NDNF were set to 31883645
Mendeliome v1.2980 NDNF Zornitza Stark edited their review of gene: NDNF: Added comment: PMID 40788466: two sisters with compound het variants and CHH. RED for this MOI.; Changed rating: AMBER; Changed publications: 31883645, 40788466
Differences of Sex Development v1.15 NDNF Zornitza Stark Publications for gene: NDNF were set to 31883645
Differences of Sex Development v1.14 NDNF Zornitza Stark changed review comment from: PMID 40788466: two sisters with compound het variants and CHH.; to: PMID 40788466: two sisters with compound het variants and CHH. RED for this MOI.
Differences of Sex Development v1.14 NDNF Zornitza Stark edited their review of gene: NDNF: Changed rating: AMBER
Differences of Sex Development v1.14 NDNF Zornitza Stark edited their review of gene: NDNF: Added comment: PMID 40788466: two sisters with compound het variants and CHH.; Changed publications: 31883645, 40788466
Mendeliome v1.2980 REPS1 Zornitza Stark Publications for gene: REPS1 were set to 29395073
Mendeliome v1.2979 REPS1 Zornitza Stark edited their review of gene: REPS1: Added comment: Additional family reported in PMID 40788509, but homozygous missense variant with no further supporting information.; Changed publications: 29395073, 40788509
Neurodegeneration with brain iron accumulation v1.1 REPS1 Zornitza Stark Publications for gene: REPS1 were set to 29395073
Neurodegeneration with brain iron accumulation v1.0 REPS1 Zornitza Stark edited their review of gene: REPS1: Added comment: Additional family reported in PMID 40788509, but homozygous missense variant with no further supporting information.; Changed publications: 29395073, 40788509; Changed phenotypes: Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Mendeliome v1.2979 MYOF Zornitza Stark Publications for gene: MYOF were set to 32542751
Mendeliome v1.2978 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: Two further families reported but with missense variants, which did not completely segregate with disease. No other supportive information provided.; Changed publications: 32542751, 40797221
Hereditary angioedema v1.6 MYOF Zornitza Stark Publications for gene: MYOF were set to 32542751
Hereditary angioedema v1.5 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: Two further families reported but with missense variants, which did not completely segregate with disease. No other supportive information provided.; Changed publications: 32542751, 40797221
Intellectual disability syndromic and non-syndromic v1.273 CDK6 Zornitza Stark Publications for gene: CDK6 were set to 23918663
Intellectual disability syndromic and non-syndromic v1.272 CDK6 Zornitza Stark edited their review of gene: CDK6: Added comment: Second family reported, but same homozygous missense variant, likely founder.; Changed publications: 23918663, 40801391
Microcephaly v1.331 CDK6 Zornitza Stark Publications for gene: CDK6 were set to 23918663
Microcephaly v1.330 CDK6 Zornitza Stark edited their review of gene: CDK6: Added comment: Report of a second family but same homozygous variant, likely founder.; Changed publications: 23918663, 40801391
Mendeliome v1.2978 CDK6 Zornitza Stark Publications for gene: CDK6 were set to 23918663
Mendeliome v1.2977 CDK6 Zornitza Stark edited their review of gene: CDK6: Added comment: Report of a second family, but same homozygous missense variant, suggestive of founder effect.; Changed publications: 23918663, 40801391
Incidentalome v0.322 DNAJC7 Zornitza Stark Publications for gene: DNAJC7 were set to 31768050
Incidentalome v0.321 DNAJC7 Zornitza Stark edited their review of gene: DNAJC7: Added comment: PMID 40802071: single family with three affected sibs and bi-allelic variants associated with ALS.; Changed publications: 31768050, 40802071
Motor Neurone Disease v1.34 DNAJC7 Zornitza Stark Publications for gene: DNAJC7 were set to 31768050
Motor Neurone Disease v1.33 DNAJC7 Zornitza Stark edited their review of gene: DNAJC7: Added comment: PMID 40802071: report of bi-allelic LoF variants in three sibs with ALS.; Changed publications: 40802071
Genetic Epilepsy v1.195 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected/affected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected/affected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Genetic Epilepsy v1.195 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Intellectual disability syndromic and non-syndromic v1.272 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 31068362; 38649688
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD2-related
Review for gene: CSMD2 was set to RED
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Genetic Epilepsy v1.195 CSMD2 Krithika Murali Marked gene: CSMD2 as ready
Genetic Epilepsy v1.195 CSMD2 Krithika Murali Gene: csmd2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.272 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 31068362; 38649688
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD2-related
Review for gene: CSMD2 was set to RED
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Genetic Epilepsy v1.195 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 31068362; 38649688
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD2-related
Review for gene: CSMD2 was set to RED
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2977 CSMD2 Krithika Murali Marked gene: CSMD2 as ready
Mendeliome v1.2977 CSMD2 Krithika Murali Gene: csmd2 has been classified as Red List (Low Evidence).
Mendeliome v1.2977 CSMD2 Krithika Murali reviewed gene: CSMD2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 40632521, 31068362, 38649688; Phenotypes: Focal epilepsy - MONDO:0005384, CSMD2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.271 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.271 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.270 NSF Zornitza Stark edited their review of gene: NSF: Added comment: Personal communication of additional cases with de novo variants and epilepsy; internal case at VCGS.; Changed rating: GREEN
Genetic Epilepsy v1.194 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Genetic Epilepsy v1.194 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Genetic Epilepsy v1.193 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Genetic Epilepsy v1.193 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Genetic Epilepsy v1.192 NSF Zornitza Stark edited their review of gene: NSF: Added comment: Personal communication of additional cases with de novo variants and epilepsy; internal case at VCGS.; Changed rating: GREEN
Mendeliome v1.2977 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Mendeliome v1.2977 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Mendeliome v1.2976 NSF Zornitza Stark edited their review of gene: NSF: Added comment: Personal communication of additional cases with de novo variants and epilepsy; internal case at VCGS.; Changed rating: GREEN
Mendeliome v1.2976 CSMD2 Krithika Murali Deleted their review
Intellectual disability syndromic and non-syndromic v1.270 HIRA Zornitza Stark Phenotypes for gene: HIRA were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, HIRA-related
Mendeliome v1.2976 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2976 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed a number of them to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence required from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2976 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 38649688; 31068362
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD1-related
Review for gene: CSMD2 was set to AMBER
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed a number of them to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence required from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2975 PTCH2 Zornitza Stark Phenotypes for gene: PTCH2 were changed from Basal cell carcinoma, somatic 605462; Basal cell nevus syndrome, 109400; Medulloblastoma, somatic to Duplication of pituitary gland; Basal cell carcinoma, somatic 605462; Basal cell nevus syndrome, 109400; Medulloblastoma, somatic
Mendeliome v1.2974 PTCH2 Zornitza Stark Publications for gene: PTCH2 were set to 30820324; 23479190; 18285427
Mendeliome v1.2973 PTCH2 Zornitza Stark edited their review of gene: PTCH2: Added comment: PMID 40803816: novel splice site PTCH2 variant, c.1590+1G>A, leading to exon 12 skipping and an in-frame deletion of 44 amino acids identified in individual with duplication of the pituitary gland. Unclear how this relates to previously reported variants and phenotypes.; Changed publications: 30820324, 23479190, 18285427, 40803816; Changed phenotypes: Basal cell nevus syndrome, MIM#109400, Duplication of pituitary gland
Haem degradation and bilirubin metabolism defects v0.19 SLC10A2 Zornitza Stark Marked gene: SLC10A2 as ready
Haem degradation and bilirubin metabolism defects v0.19 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Haem degradation and bilirubin metabolism defects v0.19 SLC10A2 Zornitza Stark Publications for gene: SLC10A2 were set to 9109432
Haem degradation and bilirubin metabolism defects v0.18 SLC10A2 Zornitza Stark Classified gene: SLC10A2 as Amber List (moderate evidence)
Haem degradation and bilirubin metabolism defects v0.18 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Haem degradation and bilirubin metabolism defects v0.17 SLC10A2 Zornitza Stark reviewed gene: SLC10A2: Rating: AMBER; Mode of pathogenicity: None; Publications: 9109432, 40814585; Phenotypes: Bile acid malabsorption, primary, MIM# 613291; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2973 SLC10A2 Zornitza Stark Classified gene: SLC10A2 as Amber List (moderate evidence)
Mendeliome v1.2973 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2972 SLC10A2 Zornitza Stark edited their review of gene: SLC10A2: Added comment: Second individual reported homozygous missense, but quite a specific phenotype so upgrade to Amber.; Changed rating: AMBER; Changed publications: 9109432, 40814585
Congenital Diarrhoea v1.21 SLC10A2 Zornitza Stark Publications for gene: SLC10A2 were set to 9109432
Congenital Diarrhoea v1.20 SLC10A2 Zornitza Stark Classified gene: SLC10A2 as Amber List (moderate evidence)