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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
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).
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
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
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)
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)
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
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).
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
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
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).
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
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
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
Mendeliome v1.3124 PTGS1 Zornitza Stark Phenotypes for gene: PTGS1 were changed from Platelet dysfunction; bleeding to Platelet-type bleeding disorder 12 MONDO:0011588
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
Mendeliome v1.3122 PTCD1 Zornitza Stark Phenotypes for gene: PTCD1 were changed from Cardiomyopathy to Cardiomyopathy MONDO:0004994, PTCD1-related
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
Mendeliome v1.3120 SRP72 Zornitza Stark Publications for gene: SRP72 were set to 22541560; 31254415
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
Mendeliome v1.3119 TOM1 Zornitza Stark Publications for gene: TOM1 were set to 31263572; 40936361
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
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
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).
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
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
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
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
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).
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
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).
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
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
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).
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
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).
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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).
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).
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).
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.
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
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
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
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
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).
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).
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
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
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
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
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
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).
Mendeliome v1.3036 POLR3H Zornitza Stark Phenotypes for gene: POLR3H were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR3H-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
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
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).
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
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
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).
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).
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
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
Mendeliome v1.3016 POLR2C Zornitza Stark Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR2C-related
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).
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).
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).
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
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
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
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
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.
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
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).
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
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
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
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
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
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).
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
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
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
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
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
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).
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
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).
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
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
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
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
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
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
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
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
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
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
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
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.
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.
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.
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
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
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
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
Mendeliome v1.2972 KLHL9 Zornitza Stark Publications for gene: KLHL9 were set to 20554658
Mendeliome v1.2971 KLHL9 Zornitza Stark reviewed gene: KLHL9: Rating: AMBER; Mode of pathogenicity: None; Publications: 40818927; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2971 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982; 36458887
Mendeliome v1.2970 UHRF1 Zornitza Stark Classified gene: UHRF1 as Amber List (moderate evidence)
Mendeliome v1.2970 UHRF1 Zornitza Stark Gene: uhrf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2969 UHRF1 Zornitza Stark edited their review of gene: UHRF1: Added comment: Second family reported with homozygous missense variant.; Changed rating: AMBER; Changed publications: 29574422, 28976982, 40825131; Changed phenotypes: Imprinting disorder
Mendeliome v1.2969 RNF2 Zornitza Stark Publications for gene: RNF2 were set to 33864376
Mendeliome v1.2968 RNF2 Zornitza Stark Classified gene: RNF2 as Green List (high evidence)
Mendeliome v1.2968 RNF2 Zornitza Stark Gene: rnf2 has been classified as Green List (High Evidence).
Mendeliome v1.2967 RNF2 Zornitza Stark edited their review of gene: RNF2: Added comment: PMID 40831499 is a preprint which identifies additional individuals with de novo variants. p.S82R is recurrent. Functional data to support gene-disease association.; Changed rating: GREEN; Changed publications: 40831499
Mendeliome v1.2967 CCDC93 Zornitza Stark Marked gene: CCDC93 as ready
Mendeliome v1.2967 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Mendeliome v1.2967 CCDC93 Zornitza Stark Classified gene: CCDC93 as Red List (low evidence)
Mendeliome v1.2967 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Mendeliome v1.2966 COX18 Zornitza Stark Publications for gene: COX18 were set to PMID:37468577
Mendeliome v1.2965 COX18 Zornitza Stark Classified gene: COX18 as Green List (high evidence)
Mendeliome v1.2965 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Mendeliome v1.2964 SPNS1 Sangavi Sivagnanasundram changed review comment from: Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature; to: Patient 1 and 2 - Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature
Mendeliome v1.2964 SPNS1 Sangavi Sivagnanasundram gene: SPNS1 was added
gene: SPNS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPNS1 were set to 40608416
Phenotypes for gene: SPNS1 were set to Lysosomal disorder, SPNS1-related, MONDO:0002561
Review for gene: SPNS1 was set to AMBER
Added comment: Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature
Mendeliome v1.2964 MIS18BP1 Krithika Murali Marked gene: MIS18BP1 as ready
Mendeliome v1.2964 MIS18BP1 Krithika Murali Gene: mis18bp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2964 WDR18 Krithika Murali Marked gene: WDR18 as ready
Mendeliome v1.2964 WDR18 Krithika Murali Gene: wdr18 has been classified as Red List (Low Evidence).
Mendeliome v1.2964 WDR18 Krithika Murali gene: WDR18 was added
gene: WDR18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR18 were set to PMID: 40677927
Phenotypes for gene: WDR18 were set to Cornelia de Lange syndrome (MONDO:0016033)
Review for gene: WDR18 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2963 MIS18BP1 Krithika Murali gene: MIS18BP1 was added
gene: MIS18BP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIS18BP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIS18BP1 were set to PMID: 40677927
Phenotypes for gene: MIS18BP1 were set to Cornelia de Lange syndrome (MONDO:0016033)
Review for gene: MIS18BP1 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2962 MED29 Zornitza Stark Marked gene: MED29 as ready
Mendeliome v1.2962 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2962 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Mendeliome v1.2962 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2961 GLYAT Zornitza Stark Marked gene: GLYAT as ready
Mendeliome v1.2961 GLYAT Zornitza Stark Gene: glyat has been classified as Red List (Low Evidence).
Mendeliome v1.2961 GLYAT Zornitza Stark gene: GLYAT was added
gene: GLYAT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GLYAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLYAT were set to 40747359
Phenotypes for gene: GLYAT were set to Neurodevelopmental disorder, MONDO:0700092, GLYAT-related
Review for gene: GLYAT was set to RED
Added comment: Single individual reported with homozygous LoF variant, p.Q108Ter. The individual was treated with pantothenic acid and a mitochondrial cocktail consisting of coenzyme Q10, vitamins B1, B2, B6, B12, C, folate, and carnitine, together with a low-protein diet, which led to the alleviation of oedema and hypotonia and an improvement in her motor function and social interactions. Her serum glycine level was also normalized.
Sources: Literature
Mendeliome v1.2960 TDRD12 Zornitza Stark Marked gene: TDRD12 as ready
Mendeliome v1.2960 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2960 TDRD12 Zornitza Stark Classified gene: TDRD12 as Amber List (moderate evidence)
Mendeliome v1.2960 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2959 TDRD12 Zornitza Stark gene: TDRD12 was added
gene: TDRD12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TDRD12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD12 were set to 40750267
Phenotypes for gene: TDRD12 were set to Spermatogenic failure, MONDO:0004983, TDRD12-related
Review for gene: TDRD12 was set to AMBER
Added comment: Two novel homozygous TDRD12 variants (c.3378dupG and c.2463C>G) reported in two unrelated infertile men, respectively. Patient 1 had a TDRD12 frameshift mutation (c.3378dupG), resulting in a truncated protein lacking the cysteine-rich domain. This individual presented with teratozoospermia, characterized by abnormal sperm morphology, including defects in the head and flagellum. Patient 2 had a TDRD12 nonsense mutation (c.2463C>G), resulting in complete degradation of the protein. This individual exhibited azoospermia, characterized by germ cell maturation arrest at the spermatocyte stage.
Sources: Literature
Mendeliome v1.2958 CCDC189 Zornitza Stark Marked gene: CCDC189 as ready
Mendeliome v1.2958 CCDC189 Zornitza Stark Gene: ccdc189 has been classified as Red List (Low Evidence).
Mendeliome v1.2958 CCDC189 Zornitza Stark gene: CCDC189 was added
gene: CCDC189 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: CCDC189.
Mode of inheritance for gene: CCDC189 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC189 were set to 40759592
Phenotypes for gene: CCDC189 were set to Spermatogenic failure, MONDO:0004983, CCDC189-related
Review for gene: CCDC189 was set to RED
Added comment: Single individual with biallelic variants. Limited functional data.

New HGNC approved name CFAP119.
Sources: Literature
Mendeliome v1.2957 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Mendeliome v1.2957 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Mendeliome v1.2957 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Mendeliome v1.2957 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Mendeliome v1.2956 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C1orf109 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf109 were set to 40760247
Phenotypes for gene: C1orf109 were set to Neurodevelopmental disorder, MONDO:0700092, C1orf109-related
Review for gene: C1orf109 was set to GREEN
Added comment: Cohort of 11 unrelated families, encompassing 18 individuals with bi-allelic variants in C1orf109, 17 liveborn. Affected individuals presented with moderate-to-severe or severe global developmental delay/intellectual disability (17 of 17) and never achieved developmental milestones. Microcephaly and seizures were other common features. Reduced ribosome activity demonstrated during early brain development.
Sources: Literature
Mendeliome v1.2955 ASAP2 Zornitza Stark Marked gene: ASAP2 as ready
Mendeliome v1.2955 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2955 ASAP2 Zornitza Stark Classified gene: ASAP2 as Amber List (moderate evidence)
Mendeliome v1.2955 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2954 ASAP2 Zornitza Stark gene: ASAP2 was added
gene: ASAP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASAP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ASAP2 were set to 40770811; 28191890; 33057194; 35982160
Phenotypes for gene: ASAP2 were set to Neurodevelopmental disorder, MONDO:0700092, ASAP2-related
Review for gene: ASAP2 was set to AMBER
Added comment: One individual reported with compound het missense variants. Identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811. Another individual with biallelic variants identified in the DDD cohort. Several others found with de novo variants through retrospective literature review of large cohort studies reporting multiple gene candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of ASAP2 in brain development. Rated AMBER as only two families with bi-allelic variants and minimal information on the cases with mono-allelic variants.
Sources: Literature
Mendeliome v1.2953 RTF1 Zornitza Stark changed review comment from: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates.
Sources: Literature; to: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 in brain development.
Sources: Literature
Mendeliome v1.2953 RTF1 Zornitza Stark Marked gene: RTF1 as ready
Mendeliome v1.2953 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Mendeliome v1.2953 RTF1 Zornitza Stark Classified gene: RTF1 as Green List (high evidence)
Mendeliome v1.2953 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Mendeliome v1.2952 RTF1 Zornitza Stark gene: RTF1 was added
gene: RTF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RTF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RTF1 were set to 40770811; 33057194; 35982160; 31038196
Phenotypes for gene: RTF1 were set to Neurodevelopmental disorder, MONDO:0700092, RTF1-related
Review for gene: RTF1 was set to GREEN
Added comment: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates.
Sources: Literature
Mendeliome v1.2951 PIK3C3 Krithika Murali Marked gene: PIK3C3 as ready
Mendeliome v1.2951 PIK3C3 Krithika Murali Gene: pik3c3 has been classified as Red List (Low Evidence).
Mendeliome v1.2951 PIK3C3 Krithika Murali gene: PIK3C3 was added
gene: PIK3C3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIK3C3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3C3 were set to PMID:40677927
Phenotypes for gene: PIK3C3 were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: PIK3C3 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2950 ARID3A Krithika Murali Marked gene: ARID3A as ready
Mendeliome v1.2950 ARID3A Krithika Murali Gene: arid3a has been classified as Red List (Low Evidence).
Mendeliome v1.2950 ARID3A Krithika Murali gene: ARID3A was added
gene: ARID3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARID3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID3A were set to PMID: 40677927
Phenotypes for gene: ARID3A were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: ARID3A was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2949 DDX39A Krithika Murali Marked gene: DDX39A as ready
Mendeliome v1.2949 DDX39A Krithika Murali Gene: ddx39a has been classified as Red List (Low Evidence).
Mendeliome v1.2949 DDX39A Krithika Murali gene: DDX39A was added
gene: DDX39A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX39A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX39A were set to PMID: 40726340
Phenotypes for gene: DDX39A were set to Neurodevelopmental disorder, MONDO:0700092, DDX39A-related
Review for gene: DDX39A was set to RED
Added comment: PMID: 40726340 Ahmed et al 2025 (Clinical Genetics) report a 7 month old F with GDD, seizures, microcephaly, hypotonia, corpus callosum thinning and homozygous missense variant (p.Lys137Gln) in DDX39A on trio WES with both non-consanguineous parents confirmed to be heterozygous carriers. DDX39A is involved in mRNA splicing and export. Patient-derived fibroblast studies showed that mutant protein resulted in aberrant nuclear clumping and failure to interact with the TREX complex.

Of note, closely-related paralogue DDX39B is also a component of the TREX complex and has a definitive monoallelic association with neurodevelopmental disorder.
Sources: Literature
Mendeliome v1.2948 HYPK Krithika Murali Marked gene: HYPK as ready
Mendeliome v1.2948 HYPK Krithika Murali Gene: hypk has been classified as Red List (Low Evidence).
Mendeliome v1.2948 HYPK Krithika Murali gene: HYPK was added
gene: HYPK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HYPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HYPK were set to Clinical Genetics Early View
Phenotypes for gene: HYPK were set to Neurodevelopmental disorder, MONDO:0700092, HYPK-related
Review for gene: HYPK was set to RED
Added comment: Single case report - Patel, R. et al 2025 Clinical Genetics Early View

Male proband with developmental delay, autism and facial dysmorphism with a de novo missense HYPK variant (p. R70I). Variant-specific biochemical analyses demonstrates enhanced inhibitory activity of HYPK on NatA-mediated N-terminal protein acetylation.

GestaltMatcher analysis indicates that the proband's facial phenotype closely resembles Ogden syndrome (NAA10) and some resemblance to NAA15-NDS - both associated genes are also involved in the N-terminal acetylation pathway.
Sources: Literature
Mendeliome v1.2947 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED29 were set to PMID: 40745490
Phenotypes for gene: MED29 were set to Pontocerebellar hypoplasia, MONDO:0020135, MED29-related
Review for gene: MED29 was set to AMBER
Added comment: MED29 encodes part of the mediator (MED) complex which has role in RNA polymerase II (Poll II) gene transcription.

PMID: 40745490 describes 2 siblings from one consanguineous family affected with pontocerebellar hypoplasia, profound GDD, severe microcephaly, cataracts and variable seizures.
Both shared the same homozygous missense variant with presumed LOF mechanism.

No homozygous LOF variants in gnomAD v4.

Extensive functional studies performed with morpholino knockdown of MED29 having marked reduction of GABAergic neurons and abnormal touch response.
Studies of hippocampal neurons from mice with knockdown MED29 showed impaired development.
Mouse embryos that had knockdown of MED29 during development demonstrated abnormal neuronal migration.
Sources: Literature
Mendeliome v1.2947 COX18 Sangavi Sivagnanasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 40830826; Phenotypes: Mitochondrial disease (MONDO:0044970), COX18-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2947 CCDC93 Sarah Milton reviewed gene: CCDC93: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 40601774; Phenotypes: Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2947 CCDC93 Sarah Milton Deleted their review
Mendeliome v1.2947 CCDC93 Sarah Milton gene: CCDC93 was added
gene: CCDC93 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC93 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC93 were set to PMID: 40601774
Phenotypes for gene: CCDC93 were set to Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related
Review for gene: CCDC93 was set to AMBER
Added comment: CCDC93 encodes the coiled coil domain containing subunit of commander complex involved in recycling of integral membrane proteins.

PMID: 40601774 describes 1 affected individual with compound heterozygous variants in CCDC93 who presented with Ritscher Schinzel like phenotype. Features included hypoplasia of cerebellar hemispheres, hypoplasia of the brainstem and of the corpus callosum, distinctive facial features and multiple small renal cysts.
Variants were missense and nonsense.

No homozygous LOF variants in gnomAD v4.

Some supportive functional data.
Sources: Literature
Mendeliome v1.2947 ATP13A3 Zornitza Stark Mode of inheritance for gene: ATP13A3 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 v1.2946 ATP13A3 Zornitza Stark edited their review of gene: ATP13A3: Added comment: Biallelic variants reported in childhood onset. DEFINITIVE by ClinGen.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2946 DLGAP5 Zornitza Stark Marked gene: DLGAP5 as ready
Mendeliome v1.2946 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Mendeliome v1.2946 DLGAP5 Zornitza Stark Classified gene: DLGAP5 as Green List (high evidence)
Mendeliome v1.2946 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Mendeliome v1.2945 DLGAP5 Zornitza Stark gene: DLGAP5 was added
gene: DLGAP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DLGAP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLGAP5 were set to 40796344
Phenotypes for gene: DLGAP5 were set to Infertility disorder, MONDO:0005047, DLGAP5-related
Review for gene: DLGAP5 was set to GREEN
Added comment: 3 individuals with biallelic variants identified as part of a large cohort (N=488) of women experiencing recurrent early embryonic arrest. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3.
Sources: Literature
Mendeliome v1.2944 CREB3 Sarah Milton gene: CREB3 was added
gene: CREB3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CREB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CREB3 were set to PMID: 40674075
Phenotypes for gene: CREB3 were set to Retinal degeneration, MONDO:0004580, CREB3-related
Review for gene: CREB3 was set to GREEN
Added comment: CREB3 encodes Cyclic AMP response element binding protein-3 which is an endoplasmic reticulum–membrane-bound transcription factor.

PMID: 40674075 describes 13 individuals from 4 families with the same homozygous nonsense variant (CREB:c.881G>A|p.Trp294). Affected individuals had retinal degeneration presenting initially with slowly progressive decreased visual acuity – significant variability in age of onset and severity – age 8-65.
2 different haplotypes identified on which the variant was found.

Homozygous LOF variants not present in CREB3 in gnomad v4.

Functional studies performed only demonstrated that mRNA transcript doesn't undergo NMD and that protein is expressed in retina. No variant specific or downstream effects investigated.
Sources: Literature
Mendeliome v1.2944 ISPD Zornitza Stark Marked gene: ISPD as ready
Mendeliome v1.2944 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Mendeliome v1.2944 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Mendeliome v1.2944 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Mendeliome v1.2944 TRIM72 Zornitza Stark Marked gene: TRIM72 as ready
Mendeliome v1.2944 TRIM72 Zornitza Stark Gene: trim72 has been classified as Red List (Low Evidence).
Mendeliome v1.2944 TRIM72 Zornitza Stark gene: TRIM72 was added
gene: TRIM72 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM72 were set to 40804694
Phenotypes for gene: TRIM72 were set to Limb girdle muscular dystrophy MONDO:0016971, TRIM72-related
Review for gene: TRIM72 was set to RED
Added comment: Single affected individual, homozygous LoF variant, c.891delT; p.Ala298ArgfsTer64. However note two homozygous individuals are present in gnomAD.
Sources: Literature
Mendeliome v1.2943 TRIM74 Zornitza Stark Marked gene: TRIM74 as ready
Mendeliome v1.2943 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Mendeliome v1.2943 TRIM74 Zornitza Stark Classified gene: TRIM74 as Red List (low evidence)
Mendeliome v1.2943 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Mendeliome v1.2942 ZNF496 Zornitza Stark Marked gene: ZNF496 as ready
Mendeliome v1.2942 ZNF496 Zornitza Stark Gene: znf496 has been classified as Red List (Low Evidence).
Mendeliome v1.2942 ZNF496 Zornitza Stark gene: ZNF496 was added
gene: ZNF496 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF496 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF496 were set to 40806714
Phenotypes for gene: ZNF496 were set to Neurodevelopmental disorder, MONDO:0700092, ZNF496-related
Review for gene: ZNF496 was set to RED
Added comment: Single individual with NDD and de novo LoF variant, no other supportive data.
Sources: Literature
Mendeliome v1.2941 SCN3B Sarah Milton gene: SCN3B was added
gene: SCN3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCN3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN3B were set to PMID: 40879121
Phenotypes for gene: SCN3B were set to Neurodevelopmental disorder, MONDO:0700092, SCN3B-related
Review for gene: SCN3B was set to AMBER
Added comment: SCN3B Encodes b3 auxiliary subunit of the sodium channel.

4 affected individuals from 2 consanguineous families reported in PMID: 40879121 with biallelic variants in this gene with neurodevelopmental phenotypes. Presentation included GDD, ID of variable severity, autism, seizures.
One variant was nonsense, one canonical splice site in the penultimate exon.

No homozygous LOF variants in gnomAD v4.

Some functional studies performed with loss of function of channel demonstrated for one variant.
Sources: Literature
Mendeliome v1.2941 XPO1 Sangavi Sivagnanasundram gene: XPO1 was added
gene: XPO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: XPO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: XPO1 were set to 40819229
Phenotypes for gene: XPO1 were set to Neurodevelopmental disorder, XPO1-related, MONDO:0700092
Review for gene: XPO1 was set to GREEN
Added comment: Established gene-disease association
22 probands with de novo XPO1 variants presenting with phenotypes associated with NDD (DD, ID, motor delay, behavioral problems, facial dysmorphisms, microcephaly and organ anomalies) along with supportive Drosophila knockdown model reported.
Sources: Literature
Mendeliome v1.2941 MKL1 Zornitza Stark Phenotypes for gene: MKL1 were changed from Neutropaenia with combined immune deficiency to Inborn error of immunity, MONDO:0003778, MKL1-related
Mendeliome v1.2940 MKL1 Zornitza Stark Publications for gene: MKL1 were set to 32128589; 26224645
Mendeliome v1.2939 MKL1 Zornitza Stark Classified gene: MKL1 as Green List (high evidence)
Mendeliome v1.2939 MKL1 Zornitza Stark Gene: mkl1 has been classified as Green List (High Evidence).
Mendeliome v1.2938 MKL1 Zornitza Stark edited their review of gene: MKL1: Added comment: Third individual reported with compound het LoF variants and some supportive functional data. Neutrophils from the affected individual showed impaired F-actin polymerization, decreased migration ability, reduced ROS production, increased apoptosis, diminished NETs formation, and decreased MPO levels. Transcriptome profiling revealed neutrophil-specific downregulation of cytoskeletal genes with concomitant upregulation of antimicrobial peptide/inflammatory pathways, while PBMCs presented upregulated adhesion/migration-related genes.; Changed rating: GREEN; Changed publications: 32128589, 26224645, 40808667; Changed phenotypes: Inborn error of immunity, MONDO:0003778, MKL1-related
Mendeliome v1.2938 MARS Zornitza Stark Publications for gene: MARS were set to 23729695; 24354524; 29655802; 24103465; 25913036; 33909043; 24482476; 34585293
Mendeliome v1.2937 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Second individual with homozygous variant and trichothiodystorphy reported in PMID 40820264; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036, 24482476, 34585293, 40820264, 33909043
Mendeliome v1.2937 TECTB Zornitza Stark Marked gene: TECTB as ready
Mendeliome v1.2937 TECTB Zornitza Stark Gene: tectb has been classified as Red List (Low Evidence).
Mendeliome v1.2937 TECTB Zornitza Stark gene: TECTB was added
gene: TECTB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TECTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TECTB were set to 40832383
Phenotypes for gene: TECTB were set to Hearing loss disorder, MONDO:0005365, TECTB-related
Review for gene: TECTB was set to RED
Added comment: Single multigenerational family segregating a missense variant and a mouse model.
Sources: Literature
Mendeliome v1.2936 TRIM74 Sangavi Sivagnanasundram gene: TRIM74 was added
gene: TRIM74 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TRIM74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM74 were set to 40735933
Phenotypes for gene: TRIM74 were set to Neurodevelopmental disorder, TRIM74-related, MONDO:0700092
Review for gene: TRIM74 was set to RED
Added comment: Only one reported case with supportive functional assay

PMID: 40735933
5yr M presenting from non consanguineous parents with global developmental delay, hypotonia, seizures, and diffuse cerebral atrophy with mega cisterna magna. Parents of the proband were found to be carriers of the variant.
Homozygous variant c.562C > T (p.Pro121Leu) - NFE AF 0.0188% - rare enough for AR

Supportive functional analysis on human fibroblast showed protein function disruption leading to protein aggregation, proteostasis collapse, and cell death.
Sources: Other
Mendeliome v1.2936 BAZ2B Zornitza Stark Classified gene: BAZ2B as Amber List (moderate evidence)
Mendeliome v1.2936 BAZ2B Zornitza Stark Gene: baz2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2935 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: Added comment: Classified as LIMITED by ClinGen.; Changed rating: AMBER; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Mendeliome v1.2935 BAZ2B Zornitza Stark Phenotypes for gene: BAZ2B were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Mendeliome v1.2934 BBS2 Sarah Milton reviewed gene: BBS2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: BBS2-related ciliopathy, MONDO:1040048; Mode of inheritance: None
Mendeliome v1.2934 BAZ2B Sarah Milton reviewed gene: BAZ2B: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related; Mode of inheritance: None
Mendeliome v1.2934 TRAP1 Zornitza Stark Phenotypes for gene: TRAP1 were changed from CAKUT; VACTERL to Syndromic disease, MONDO:0002254, TRAP1-related
Mendeliome v1.2933 TRAP1 Zornitza Stark edited their review of gene: TRAP1: Changed phenotypes: Syndromic disease, MONDO:0002254, TRAP1-related
Mendeliome v1.2933 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from ADULT syndrome, OMIM #103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292; Hay-Wells syndrome, OMIM #106260; Limb-mammary syndrome, OMIM #603543; Orofacial cleft 8, OMIM #618149; Rapp-Hodgkin syndrome, OMIM #129400; Split-hand/foot malformation 4, OMIM #605289 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Premature ovarian failure 21, MIM#620311
Mendeliome v1.2932 TP63 Zornitza Stark edited their review of gene: TP63: Added comment: DEFINITIVE by ClinGen.

Lumped EEC3 syndrome (MIM:604292), ADULT syndrome (MIM:103285), AEC syndrome (MIM:106260), Rapp-Hodgkin syndrome (MIM:129400), Limb-mammary syndrome (MIM:603543), Split-hand/foot malformation 4 (MIM:605289), and Orofacial cleft 8 (MIM:618149).

Association with POF considered separate.; Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001, Premature ovarian failure 21, MIM#620311
Mendeliome v1.2932 TOMM70 Zornitza Stark Phenotypes for gene: TOMM70 were changed from Severe anaemia, lactic acidosis, developmental delay; White matter abnormalities, developmental delay, regression, movement disorder to Mitochondrial disease, MONDO:0044970, TOMM70-related; Leukodystrophy, MONDO:0019046, TOMM70-related
Mendeliome v1.2931 TOMM70 Zornitza Stark edited their review of gene: TOMM70: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TOMM70-related, Leukodystrophy, MONDO:0019046, TOMM70-related
Mendeliome v1.2931 ARNTL Zornitza Stark Marked gene: ARNTL as ready
Mendeliome v1.2931 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Mendeliome v1.2931 ARNTL Zornitza Stark Classified gene: ARNTL as Green List (high evidence)
Mendeliome v1.2931 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Mendeliome v1.2930 ARNTL Zornitza Stark Tag new gene name tag was added to gene: ARNTL.
Mendeliome v1.2930 CSMD3 Zornitza Stark Marked gene: CSMD3 as ready
Mendeliome v1.2930 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Mendeliome v1.2930 CSMD3 Zornitza Stark Classified gene: CSMD3 as Green List (high evidence)
Mendeliome v1.2930 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Mendeliome v1.2929 TMPRSS7 Zornitza Stark Marked gene: TMPRSS7 as ready
Mendeliome v1.2929 TMPRSS7 Zornitza Stark Gene: tmprss7 has been classified as Red List (Low Evidence).
Mendeliome v1.2929 TMPRSS7 Zornitza Stark gene: TMPRSS7 was added
gene: TMPRSS7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMPRSS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS7 were set to 40796295
Phenotypes for gene: TMPRSS7 were set to Neurodevelopmental disorder, TMPRSS7-related
Review for gene: TMPRSS7 was set to RED
Added comment: PMID 40796295: individual with compound het variants, p.R479H and p.S685Kfs*26 and neurodevelopmental disorder. Tmprss7 homozygous knockout (KO) mice exhibited dysregulated synaptic dendritic spine density, function, and dendritic elongation in the cerebral cortex and hippocampus. In addition, the KO animals displayed neurobehavioral deficits, including impairments in spatial learning, anxiety-like behavior, and a reduced preference for social novelty. Multi-omics analysis discovered enrichment of pathways related to synaptic signaling disruptions in both the cerebral cortex and hippocampus.
Sources: Literature
Mendeliome v1.2928 PPP1R2 Zornitza Stark gene: PPP1R2 was added
gene: PPP1R2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP1R2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R2 were set to 40597352; 26558779
Phenotypes for gene: PPP1R2 were set to Neurodevelopmental disorder, PPP1R2-related
Review for gene: PPP1R2 was set to RED
Added comment: Single individual reported with homozygous splicing variant c.403 + 3 A >T. Abnormal splicing demonstrated but leaky. Clinical features included pre and postnatal growth restriction, ventricular septal defect, dysmorphic features (proptosis, long eye lashes, thick eyebrows, low-set ears), microcephaly, sensorineural hearing loss, cortical cataracts, retinal defects, intellectual disability with limited speech, and autism spectrum disorder. Note mouse model is embryonically lethal, leading the authors to speculate survival may be due to fraction of normally spliced transcripts.
Sources: Literature
Mendeliome v1.2927 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Mendeliome v1.2927 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Mendeliome v1.2927 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Mendeliome v1.2927 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Mendeliome v1.2926 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Mendeliome v1.2925 CSMD3 Sarah Milton gene: CSMD3 was added
gene: CSMD3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD3 were set to PMID: 40632521
Phenotypes for gene: CSMD3 were set to Epilepsy, MONDO:0005027, CSMD3-related
Review for gene: CSMD3 was set to GREEN
Added comment: CSMD3 encodes a synaptic membrane proteins and play a role in neuronal maturation/growth dendrites. A related protein CSMD1 has been previously associated with a complex neurodevelopmental disorder.

PMID: 40632521 describes 8 individuals with seizures. 4 with focal epilepsy, 3 with febrile seizures and 1 individual with infantile spasms. 1 individual described had a de novo missense variant with remainder having comp het/biallelic variants. Mild ID in 1 individual only.

Variant type mostly missense variants with 1 nonsense, all appropriately rare in gnomAD v4 for recessive disorder.

No variant specific functional studies performed, no clear discussion in paper about postulated mechanism for disease. No discussion around difference in mechanism for de novo monoallelic variant.

Previous studies showed homozygous knockout mice display abnormal neuronal proliferation and growth retardation.
Sources: Literature
Mendeliome v1.2925 MMD2 Zornitza Stark Marked gene: MMD2 as ready
Mendeliome v1.2925 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2925 MMD2 Zornitza Stark Classified gene: MMD2 as Amber List (moderate evidence)
Mendeliome v1.2925 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2924 MMD2 Zornitza Stark gene: MMD2 was added
gene: MMD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MMD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMD2 were set to 40663042
Phenotypes for gene: MMD2 were set to Periodontitis, MONDO:0005076, MMD2-related
Review for gene: MMD2 was set to AMBER
Added comment: Two multigenerational families with aggressive periodontitis segregating missense variants, plus supportive functional data. Abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients' neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 variants.
Sources: Literature
Mendeliome v1.2923 ARNTL Sarah Milton gene: ARNTL was added
gene: ARNTL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARNTL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARNTL were set to PMID: 40720646
Phenotypes for gene: ARNTL were set to Neurodevelopmental disorder, MONDO:0700092, BMAL1-related
Review for gene: ARNTL was set to GREEN
Added comment: Note has new HGNC approved name - BMAL1

BMAL1 encodes a transcription factor that plays a role in the mammalian molecular clock, binds to promoter of PER and CRY family genes to promote transcription. Other circardian genes have sleep phase disorder assoc but not neurodevelopmental phenotype.

10 affected individuals described in PMID: 40455867 with variable developmental delay/ID from average IQ to severe ID, seizures in 50%, autism, some had sleep disturbance and marfanoid habitus.
Variants were LOF & missense and very rare or absent in gnomAD v4.
5 confirmed de novo, 2 confirmed inherited (one from apparently unaffected mother).

Functional studies using luciferase reporter assay of downstream target PER showed reduced luminescence for most variants with presumed LOF mechanism. One variant p.(Ile201Thr) led to increased luminescence with author's postulating GOF mechanism for this variant. Drosophilia studies for 2 of the variants demonstrated altered circadian rhythm. ?needs more studies to further define mechanism.
Sources: Literature
Mendeliome v1.2923 FAM136A Zornitza Stark Marked gene: FAM136A as ready
Mendeliome v1.2923 FAM136A Zornitza Stark Gene: fam136a has been classified as Red List (Low Evidence).
Mendeliome v1.2923 FAM136A Zornitza Stark gene: FAM136A was added
gene: FAM136A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM136A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FAM136A were set to 40714634
Phenotypes for gene: FAM136A were set to Meniere's disease
Review for gene: FAM136A was set to RED
Added comment: Single family reported with high impact variant, supportive functional data.
Sources: Literature
Mendeliome v1.2922 NCOA7 Zornitza Stark Marked gene: NCOA7 as ready
Mendeliome v1.2922 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Mendeliome v1.2922 NCOA7 Zornitza Stark Classified gene: NCOA7 as Green List (high evidence)
Mendeliome v1.2922 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Mendeliome v1.2921 NCOA7 Zornitza Stark gene: NCOA7 was added
gene: NCOA7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCOA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NCOA7 were set to 40745099
Phenotypes for gene: NCOA7 were set to Inherited premature ovarian failure MONDO:0019852, NCOA7-related
Review for gene: NCOA7 was set to GREEN
Added comment: 7 individuals with POI and heterozygous variants in this gene. Two of the variants led to NMD; 3 were missense. Functional data supports role in cell senescence.
Sources: Literature
Mendeliome v1.2920 DNAH6 Zornitza Stark Phenotypes for gene: DNAH6 were changed from Spermatogenic failure, MONDO:0004983, DNAH6-related; situs inversus, MONDO:0010029 to Spermatogenic failure, MONDO:0004983, DNAH6-related
Mendeliome v1.2919 DNAH6 Zornitza Stark Publications for gene: DNAH6 were set to PMID: 26918822
Mendeliome v1.2918 DNAH6 Zornitza Stark Classified gene: DNAH6 as Green List (high evidence)
Mendeliome v1.2918 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Green List (High Evidence).
Mendeliome v1.2917 DNAH6 Zornitza Stark Deleted their comment
Mendeliome v1.2917 DNAH6 Zornitza Stark edited their review of gene: DNAH6: Added comment: More than 5 unrelated individuals reported with spermatogenic failure and bi-allelic variants in this gene.; Changed rating: GREEN; Changed publications: 37594300, 39192248, 37424858, 31676830, 29356036, 40592014
Mendeliome v1.2917 DNAH6 Zornitza Stark Phenotypes for gene: DNAH6 were changed from Heterotaxy, Azoospermia to Spermatogenic failure, MONDO:0004983, DNAH6-related; situs inversus, MONDO:0010029
Mendeliome v1.2916 DNAH6 Zornitza Stark reviewed gene: DNAH6: Rating: AMBER; Mode of pathogenicity: None; Publications: 40592014; Phenotypes: Spermatogenic failure, MONDO:0004983, DNAH6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2916 PAX4 Zornitza Stark edited their review of gene: PAX4: Changed phenotypes: Maturity-onset diabetes of the young, type IX MIM#612225, Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related
Mendeliome v1.2916 PAX4 Zornitza Stark Phenotypes for gene: PAX4 were changed from Maturity-onset diabetes of the young, type IX MIM#612225; Diabetes mellitus, type 2, MIM# 125853 to Maturity-onset diabetes of the young, type IX MIM#612225; Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related
Mendeliome v1.2915 PAX4 Zornitza Stark Publications for gene: PAX4 were set to 17426099; 14561778; 25951767; 21263211
Mendeliome v1.2914 PAX4 Zornitza Stark Mode of inheritance for gene: PAX4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2913 PAX4 Zornitza Stark edited their review of gene: PAX4: Added comment: Homozygous PAX4 loss-of-function variants in 2 individuals with transient NDM: a p.(Arg126∗) stop-gain variant and a c.-352_104del deletion affecting the first 4 PAX4 exons. This is a separate association to the refuted association with MODY but maintaining the RED rating overall.; Changed rating: RED; Changed publications: 17426099, 14561778, 25951767, 21263211, 40614820; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2913 MAN2A2 Zornitza Stark Publications for gene: MAN2A2 were set to 36357165
Mendeliome v1.2912 MAN2A2 Zornitza Stark Classified gene: MAN2A2 as Amber List (moderate evidence)
Mendeliome v1.2912 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2911 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Added comment: PMID 40628855: second unrelated individual reported, presenting with ID/autism and with bi-allelic variants, one missense and the other LoF. Abnormal glycosylation patterns observed consistent with CDG.; Changed rating: AMBER; Changed publications: 36357165, 40628855
Mendeliome v1.2911 CCDC186 Zornitza Stark Phenotypes for gene: CCDC186 were changed from Epileptic encephalopathy to Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Mendeliome v1.2910 CCDC186 Zornitza Stark Publications for gene: CCDC186 were set to 33259146
Mendeliome v1.2909 CCDC186 Zornitza Stark Classified gene: CCDC186 as Green List (high evidence)
Mendeliome v1.2909 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Changed rating: GREEN
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Added comment: PMID 40633195: Individual with another bi-allelic LoF variant reported, NM_018017.4:c.535C>T (p.Arg179Ter), presenting with seizures, ID and microcephaly.; Changed publications: 33259146, 37569695, 40633195
Mendeliome v1.2908 CCDC186 Zornitza Stark changed review comment from: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter; to: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter. EE was part of the phenotype, although the phenotype was broader.
Mendeliome v1.2908 CCDC186 Zornitza Stark changed review comment from: One individual reported with bi-allelic truncating variant and EE.
Sources: Literature; to: One individual reported with bi-allelic truncating variant p.(Ser256Ter) and EE.
Sources: Literature
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Added comment: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter; Changed publications: 33259146, 37569695
Mendeliome v1.2908 VWA8 Zornitza Stark Publications for gene: VWA8 were set to PMID: 37012052
Mendeliome v1.2907 VWA8 Zornitza Stark Classified gene: VWA8 as Green List (high evidence)
Mendeliome v1.2907 VWA8 Zornitza Stark Gene: vwa8 has been classified as Green List (High Evidence).
Mendeliome v1.2906 VWA8 Zornitza Stark edited their review of gene: VWA8: Added comment: PMID 40638000: additional individual reported with LoF variant and RP, upgrade to Green.; Changed rating: GREEN; Changed publications: 37012052, 40638000
Mendeliome v1.2906 PCLO Zornitza Stark Publications for gene: PCLO were set to 25832664
Mendeliome v1.2905 PCLO Zornitza Stark Classified gene: PCLO as Green List (high evidence)
Mendeliome v1.2905 PCLO Zornitza Stark Gene: pclo has been classified as Green List (High Evidence).
Mendeliome v1.2904 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 40661989: additional case report of a Thai patient with PCH and compound het LoF variants in this gene.
PMID 32122952: rat model consistent with human phenotype.
PMID 30287594: additional family with 5 affected sibs, compound het for LoF variants and PCH. Upgrade to GREEN.; Changed rating: GREEN; Changed publications: 25832664, 40661989, 32122952, 30287594
Mendeliome v1.2904 LSR Zornitza Stark Phenotypes for gene: LSR were changed from transient neonatal cholestasis; intellectual disability; short stature to Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related; transient neonatal cholestasis; intellectual disability; short stature
Mendeliome v1.2903 LSR Zornitza Stark Publications for gene: LSR were set to 30250217; 32303357
Mendeliome v1.2902 LSR Zornitza Stark Classified gene: LSR as Green List (high evidence)
Mendeliome v1.2902 LSR Zornitza Stark Gene: lsr has been classified as Green List (High Evidence).
Mendeliome v1.2901 LSR Zornitza Stark edited their review of gene: LSR: Added comment: PMID 40846272: further two patients with homozygous missense variants.
PMID 40679108: additional case report, compound het LoF and missense variant in a 4yo with cholestasis and mild liver fibrosis.
We are aware of a further case internally, upgrade to GREEN.; Changed rating: GREEN; Changed publications: 32303357, 30250217, 40679108, 40846272; Changed phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related, transient neonatal cholestasis, intellectual disability, short stature
Mendeliome v1.2901 TAF13 Zornitza Stark Phenotypes for gene: TAF13 were changed from Mental retardation, autosomal recessive 60, MIM# 617432 to Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Mendeliome v1.2900 TAF13 Zornitza Stark Publications for gene: TAF13 were set to 28257693
Mendeliome v1.2899 TAF13 Zornitza Stark edited their review of gene: TAF13: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Mendeliome v1.2899 TAF13 Zornitza Stark edited their review of gene: TAF13: Added comment: Two more families reported, but with same homozygous missense variant as previous, c.119T>A p.Met40Lys, suggestive of founder effect. In addition to ID and microcephaly, DSD reported.; Changed publications: 28257693, 40679298
Mendeliome v1.2899 IGSF10 Zornitza Stark Phenotypes for gene: IGSF10 were changed from delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency to Disorder of sex differentiation, MONDO:0002145, IGSF10-related
Mendeliome v1.2898 IGSF10 Zornitza Stark Publications for gene: IGSF10 were set to 27137492; 31042289
Mendeliome v1.2897 IGSF10 Zornitza Stark Mode of inheritance for gene: IGSF10 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2896 IGSF10 Zornitza Stark reviewed gene: IGSF10: Rating: AMBER; Mode of pathogenicity: None; Publications: 27137492, 31042289, 40700020; Phenotypes: Disorder of sex differentiation, MONDO:0002145, IGSF10-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2896 TXNRD2 Zornitza Stark Classified gene: TXNRD2 as Green List (high evidence)
Mendeliome v1.2896 TXNRD2 Zornitza Stark Gene: txnrd2 has been classified as Green List (High Evidence).
Mendeliome v1.2895 TXNRD2 Zornitza Stark edited their review of gene: TXNRD2: Added comment: PMID 40726908: further family reported with compound het missense variants, some supportive data (reduced protein levels).

Two further case reports identified in PMIDs 38011841 and 39097530. Upgrade to GREEN.; Changed rating: GREEN; Changed publications: 34258490, 40726908, 38011841, 39097530
Mendeliome v1.2895 FAAH2 Zornitza Stark Phenotypes for gene: FAAH2 were changed from autism spectrum disorder MONDO:0005258 to Neurodevelopmental disorder, MONDO:0700092, FAAH2-related
Mendeliome v1.2894 FAAH2 Zornitza Stark Publications for gene: FAAH2 were set to 34645488; 25885783
Mendeliome v1.2893 FAAH2 Zornitza Stark edited their review of gene: FAAH2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2893 FAAH2 Zornitza Stark reviewed gene: FAAH2: Rating: RED; Mode of pathogenicity: None; Publications: 40744325; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, FAAH2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2893 TNFSF12 Zornitza Stark Phenotypes for gene: TNFSF12 were changed from Recurrent infections, poor antibody responses, decreased immunoglobulins to Inborn error of immunity, MONDO:0003778, TNFSF12-related
Mendeliome v1.2892 TNFSF12 Zornitza Stark edited their review of gene: TNFSF12: Changed phenotypes: Inborn error of immunity, MONDO:0003778, TNFSF12-related
Mendeliome v1.2892 NDC1 Zornitza Stark Phenotypes for gene: NDC1 were changed from triple-A syndrome MONDO:0009279 to Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328
Mendeliome v1.2891 NDC1 Zornitza Stark reviewed gene: NDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2891 SEPHS1 Zornitza Stark Phenotypes for gene: SEPHS1 were changed from Neurodevelopmental disorder, MONDO:0700092, SEPHS1-related to Ververi-Brady syndrome 2, MIM# 621325
Mendeliome v1.2890 SEPHS1 Zornitza Stark edited their review of gene: SEPHS1: Changed phenotypes: Ververi-Brady syndrome 2, MIM# 621325
Mendeliome v1.2890 TNFRSF21 Zornitza Stark Phenotypes for gene: TNFRSF21 were changed from high myopia to Myopia, MONDO:0001384, TNFRSF21-related
Mendeliome v1.2889 TNFRSF21 Zornitza Stark reviewed gene: TNFRSF21: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopia, MONDO:0001384, TNFRSF21-related; Mode of inheritance: None
Mendeliome v1.2889 TMTC2 Zornitza Stark Classified gene: TMTC2 as Red List (low evidence)
Mendeliome v1.2889 TMTC2 Zornitza Stark Gene: tmtc2 has been classified as Red List (Low Evidence).
Mendeliome v1.2888 TMTC2 Zornitza Stark Tag disputed tag was added to gene: TMTC2.
Mendeliome v1.2888 TMTC2 Zornitza Stark edited their review of gene: TMTC2: Added comment: Note the homozygous variant reported in PMID 27311106 is present in a high number of homozygotes in gnomAD.; Changed rating: RED
Mendeliome v1.2888 TMEM65 Zornitza Stark Phenotypes for gene: TMEM65 were changed from Mitochondrial encephalomyopathy to Mitochondrial disease, MONDO:0044970, TMEM65-related
Mendeliome v1.2887 TMEM65 Zornitza Stark edited their review of gene: TMEM65: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TMEM65-related
Mendeliome v1.2887 POLE2 Zornitza Stark Phenotypes for gene: POLE2 were changed from Combined immunodeficiency; Lymphopaenia; Lack of TRECS, absent proliferation in response to antigens; Hypoglobulinaemia; Recurrent infections, disseminated BCG infections; Autoimmunity; Facial dysmorphism to Combined immunodeficiency MONDO:0015131, POLE2-related
Mendeliome v1.2886 PNPLA6 Zornitza Stark Phenotypes for gene: PNPLA6 were changed from Boucher-Neuhauser syndrome, 215470; ?Laurence-Moon syndrome, 245800; Oliver-McFarlane syndrome, 275400; Spastic paraplegia 39, autosomal recessive, 612020 to Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155; Spastic paraplegia 39, autosomal recessive MIM#612020
Mendeliome v1.2885 PNPLA4 Zornitza Stark Phenotypes for gene: PNPLA4 were changed from to Mitochondrial disease (MONDO:0044970), PNPLA4-related
Mendeliome v1.2884 PNPLA3 Zornitza Stark Phenotypes for gene: PNPLA3 were changed from Susceptibility to nonalcoholic fatty liver disease to Metabolic dysfunction-associated steatotic liver disease MONDO:0013209, PNPLA3-related
Mendeliome v1.2883 POLE2 Lucy Spencer reviewed gene: POLE2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined immunodeficiency MONDO:0015131, POLE2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PNPLA6 Lucy Spencer reviewed gene: PNPLA6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155, Spastic paraplegia 39, autosomal recessive MIM#612020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PNPLA4 Lucy Spencer reviewed gene: PNPLA4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial disease (MONDO:0044970), PNPLA4-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2883 PNPLA3 Lucy Spencer reviewed gene: PNPLA3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metabolic dysfunction-associated steatotic liver disease MONDO:0013209, PNPLA3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2883 TMEM173 Zornitza Stark Marked gene: TMEM173 as ready
Mendeliome v1.2883 TMEM173 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is STING1
Mendeliome v1.2883 TMEM173 Zornitza Stark Gene: tmem173 has been classified as Green List (High Evidence).
Mendeliome v1.2883 TMEM173 Zornitza Stark Tag new gene name tag was added to gene: TMEM173.
Mendeliome v1.2883 PMM2 Lucy Spencer changed review comment from: Adding HIPKD MONDO term specific for this gene; to: Adding HIPKD MONDO term specific for this gene
Mendeliome v1.2883 PMM2 Lucy Spencer reviewed gene: PMM2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinaemic Hypoglycaemia with polycystic kidney disease MONDO:1030000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PMFBP1 Lucy Spencer reviewed gene: PMFBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 31 MIM#618112; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PLXNC1 Lucy Spencer reviewed gene: PLXNC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral cortical dysplasia MONDO:0017094, PLXNC1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2883 PLXNA3 Lucy Spencer reviewed gene: PLXNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0018555, PLXNA3-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2883 TIMM22 Zornitza Stark Phenotypes for gene: TIMM22 were changed from mitochondrial myopathy; hypotonia; gastroesophageal reflux disease to Mitochondrial disease, MONDO:0044970, TIMM22-related
Mendeliome v1.2882 TIMM22 Zornitza Stark edited their review of gene: TIMM22: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TIMM22-related
Mendeliome v1.2882 THOC1 Zornitza Stark Phenotypes for gene: THOC1 were changed from Nonsyndromic hearing loss to Hearing loss disorder, MONDO:0005365, THOC1-related
Mendeliome v1.2881 THOC1 Zornitza Stark reviewed gene: THOC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hearing loss disorder, MONDO:0005365, THOC1-related; Mode of inheritance: None
Mendeliome v1.2881 TDGF1 Zornitza Stark Phenotypes for gene: TDGF1 were changed from Forebrain abnormalities to Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Mendeliome v1.2880 TDGF1 Zornitza Stark Tag disputed tag was added to gene: TDGF1.
Mendeliome v1.2880 TDGF1 Zornitza Stark edited their review of gene: TDGF1: Changed phenotypes: Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Mendeliome v1.2880 TCF7L2 Zornitza Stark Phenotypes for gene: TCF7L2 were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system to Neurodevelopmental disorder, MONDO:0700092, TCF7L2-related
Mendeliome v1.2879 TCF7L2 Zornitza Stark edited their review of gene: TCF7L2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TCF7L2-related
Mendeliome v1.2879 TCF7L1 Zornitza Stark Phenotypes for gene: TCF7L1 were changed from Congenital hypopituitarism to Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related
Mendeliome v1.2878 TCF7L1 Zornitza Stark reviewed gene: TCF7L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2878 NIT1 Zornitza Stark Phenotypes for gene: NIT1 were changed from Cerebrovascular disorder, NIT1-related (MONDO:0011057) to Brain small vessel disease 4, MIM# 621313
Mendeliome v1.2877 NIT1 Zornitza Stark reviewed gene: NIT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 4, MIM# 621313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2877 PLEKHG5 Zornitza Stark Phenotypes for gene: PLEKHG5 were changed from Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376; Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067 to hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related
Mendeliome v1.2876 PLEKHN1 Zornitza Stark Phenotypes for gene: PLEKHN1 were changed from Sensory Neuropathy to Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related
Mendeliome v1.2875 CYP3A4 Zornitza Stark Publications for gene: CYP3A4 were set to 29461981
Mendeliome v1.2874 SYP Zornitza Stark Phenotypes for gene: SYP were changed from Mental retardation, X-linked 96 MIM#300802 to Intellectual developmental disorder, X-linked 96, MIM# 300802
Mendeliome v1.2873 SYP Zornitza Stark reviewed gene: SYP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 96, MIM# 300802; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2873 SYNCRIP Zornitza Stark Phenotypes for gene: SYNCRIP were changed from Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology to Neurodevelopmental disorder, MONDO:0700092, SYNCRIP-related
Mendeliome v1.2872 SYNCRIP Zornitza Stark edited their review of gene: SYNCRIP: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SYNCRIP-related
Mendeliome v1.2872 SYCP2 Zornitza Stark Phenotypes for gene: SYCP2 were changed from Male infertility to Spermatogenic failure 1, MIM# 258150
Mendeliome v1.2871 SYCP2 Zornitza Stark edited their review of gene: SYCP2: Changed phenotypes: Spermatogenic failure 1, MIM# 258150
Mendeliome v1.2871 SUFU Zornitza Stark Phenotypes for gene: SUFU were changed from Joubert syndrome 32, MIM#617757; SUFU-related neurodevelopmental syndrome; Basal cell nevus syndrome, MIM# 109400 to Joubert syndrome 32, MIM#617757; Neurodevelopmental disorder, MONDO:0700092, SUFU-related; Basal cell nevus syndrome, MIM# 109400
Mendeliome v1.2870 SUFU Zornitza Stark edited their review of gene: SUFU: Changed phenotypes: Joubert syndrome 32, MIM#617757, Neurodevelopmental disorder, MONDO:0700092, SUFU-related, Basal cell nevus syndrome, MIM# 109400
Mendeliome v1.2870 SUCO Zornitza Stark Phenotypes for gene: SUCO were changed from Osteogenesis imperfecta to Osteogenesis imperfecta, MONDO:0019019, SUCO-related
Mendeliome v1.2869 SUCO Zornitza Stark reviewed gene: SUCO: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteogenesis imperfecta, MONDO:0019019, SUCO-related; Mode of inheritance: None
Mendeliome v1.2869 STXBP3 Zornitza Stark Phenotypes for gene: STXBP3 were changed from Very Early Onset Inflammatory Bowel Disease; Bilateral Sensorineural Hearing Loss; Immune Dysregulation to Inborn error of immunity, MONDO:0003778, STXBP3-related
Mendeliome v1.2868 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
Mendeliome v1.2868 SRGAP1 Zornitza Stark Phenotypes for gene: SRGAP1 were changed from CAKUT to CAKUT, MONDO:0019719, SRGAP1-related
Mendeliome v1.2867 SRGAP1 Zornitza Stark edited their review of gene: SRGAP1: Changed rating: AMBER; Changed phenotypes: CAKUT, MONDO:0019719, SRGAP1-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2867 COPZ1 Zornitza Stark Marked gene: COPZ1 as ready
Mendeliome v1.2867 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2867 COPZ1 Zornitza Stark Classified gene: COPZ1 as Amber List (moderate evidence)
Mendeliome v1.2867 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2866 COPZ1 Zornitza Stark gene: COPZ1 was added
gene: COPZ1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COPZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPZ1 were set to 39642330
Phenotypes for gene: COPZ1 were set to Severe congenital neutropenia, autosomal recessive, MONDO:0028226, COPZ1-related
Review for gene: COPZ1 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported. A pair of siblings with homozygous LoF variant and a more severe phenotype, comprising other immune defects, neurological and skeletal features. An additional individual with homozygous missense variant and a milder phenotype of isolated neutropenia. Some supportive functional data. AMBER rating as only two families and homozygous variants.
Sources: Literature
Mendeliome v1.2865 CYP3A4 Chirag Patel Classified gene: CYP3A4 as Amber List (moderate evidence)
Mendeliome v1.2865 CYP3A4 Chirag Patel Gene: cyp3a4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2864 CYP3A4 Chirag Patel reviewed gene: CYP3A4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38179381, 29461981, 36656330; Phenotypes: Vitamin D-dependent rickets, type 3, MIM#619073; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2864 PLEKHN1 Lucy Spencer reviewed gene: PLEKHN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2864 PLEKHG5 Lucy Spencer changed review comment from: ClinGen has now lumped the 2 OMIM conditions under the general term "neuromuscular disease MONDO:0019056" however, "hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related" is a better description of the condition; to: ClinGen has now lumped the 2 OMIM conditions under the general term "neuromuscular disease MONDO:0019056" however, "hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related" is a better description of the condition
Mendeliome v1.2864 PLEKHG5 Lucy Spencer reviewed gene: PLEKHG5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2864 TRIM33 Zornitza Stark Phenotypes for gene: TRIM33 were changed from to Developmental dysplasia of the hip 4, MIM# 621311
Mendeliome v1.2863 TRIM33 Zornitza Stark Publications for gene: TRIM33 were set to
Mendeliome v1.2862 TRIM33 Zornitza Stark Mode of inheritance for gene: TRIM33 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2861 TRIM33 Zornitza Stark edited their review of gene: TRIM33: Added comment: Four siblings with homozygous single aa insertion reported.; Changed publications: 39054052; Changed phenotypes: Developmental dysplasia of the hip 4, MIM# 621311; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2861 SPOP Zornitza Stark Phenotypes for gene: SPOP were changed from Intellectual disability; dysmorphism; microcephaly; macrocephaly to Nabais Sa-de Vries syndrome, type 1 MIM#618828; Nabais Sa-de Vries syndrome, type 2, MIM#618829
Mendeliome v1.2860 SPOP Zornitza Stark edited their review of gene: SPOP: Changed phenotypes: Nabais Sa-de Vries syndrome, type 1 MIM#618828, Nabais Sa-de Vries syndrome, type 2, MIM#618829
Mendeliome v1.2860 SPATC1L Zornitza Stark Phenotypes for gene: SPATC1L were changed from Deafness to Hearing loss disorder, MONDO:0005365 SPATC1L-related
Mendeliome v1.2859 SPATC1L Zornitza Stark edited their review of gene: SPATC1L: Changed phenotypes: Hearing loss disorder, MONDO:0005365 SPATC1L-related
Mendeliome v1.2859 SOHLH2 Zornitza Stark Phenotypes for gene: SOHLH2 were changed from Premature ovarian failure to Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Mendeliome v1.2858 SOHLH2 Zornitza Stark edited their review of gene: SOHLH2: Changed phenotypes: Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Mendeliome v1.2858 SOD2 Zornitza Stark Phenotypes for gene: SOD2 were changed from {Microvascular complications of diabetes 6} 612634; Lethal neonatal dilated cardiomyopathy to {Microvascular complications of diabetes 6} 612634; Dilated cardiomyopathy MONDO:0005021, lethal neonatal, SOD2-related
Mendeliome v1.2857 SOBP Zornitza Stark Phenotypes for gene: SOBP were changed from Mental retardation, anterior maxillary protrusion, and strabismus, MIM# 613671 to Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2856 SOBP Zornitza Stark edited their review of gene: SOBP: Changed phenotypes: Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2856 SOBP Zornitza Stark edited their review of gene: SOBP: Changed phenotypes: mpaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2856 SNX27 Zornitza Stark Phenotypes for gene: SNX27 were changed from intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, SNX27-related
Mendeliome v1.2855 SNX27 Zornitza Stark edited their review of gene: SNX27: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SNX27-related
Mendeliome v1.2855 SMPDL3A Zornitza Stark Phenotypes for gene: SMPDL3A were changed from Sensory Neuropathy to Sensory Neuropathy MONDO:0002321, SMPDL3A-related
Mendeliome v1.2854 SMPDL3A Zornitza Stark reviewed gene: SMPDL3A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Sensory Neuropathy MONDO:0002321, SMPDL3A-related; Mode of inheritance: None
Mendeliome v1.2854 SMPD4 Zornitza Stark Phenotypes for gene: SMPD4 were changed from Severe neurodevelopmental delay, microcephaly, arthrogryposis to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (MIM#618622)
Mendeliome v1.2853 SMPD4 Zornitza Stark edited their review of gene: SMPD4: Changed phenotypes: Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (MIM#618622)
Mendeliome v1.2853 SMARCD1 Zornitza Stark Phenotypes for gene: SMARCD1 were changed from Intellectual disability; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCD1-related
Mendeliome v1.2852 SMARCD1 Zornitza Stark edited their review of gene: SMARCD1: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCD1-related
Mendeliome v1.2852 SMARCA5 Zornitza Stark Phenotypes for gene: SMARCA5 were changed from Neurodevelopmental disorder; microcephaly; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Mendeliome v1.2851 SMARCA5 Zornitza Stark edited their review of gene: SMARCA5: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Mendeliome v1.2851 SMAD1 Zornitza Stark Phenotypes for gene: SMAD1 were changed from Pulmonary arterial hypertension to Pulmonary arterial hypertension MONDO:0015924, SMAD1-related
Mendeliome v1.2850 SLIT3 Zornitza Stark Phenotypes for gene: SLIT3 were changed from Congenital diaphragmatic hernia to Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Mendeliome v1.2849 SLIT3 Zornitza Stark edited their review of gene: SLIT3: Changed phenotypes: Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Mendeliome v1.2849 SLIT2 Zornitza Stark Phenotypes for gene: SLIT2 were changed from CAKUT to CAKUT MONDO:0019719, SLIT2-related
Mendeliome v1.2848 SLIT2 Zornitza Stark edited their review of gene: SLIT2: Changed phenotypes: CAKUT MONDO:0019719, SLIT2-related
Mendeliome v1.2848 SLIRP Zornitza Stark Phenotypes for gene: SLIRP were changed from Mitochondrial encephalomyopathy with complex I and IV deficiency to Inborn mitochondrial metabolism disorder MONDO:0004069, SLIRP-related
Mendeliome v1.2847 SLIRP Zornitza Stark reviewed gene: SLIRP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn mitochondrial metabolism disorder MONDO:0004069, SLIRP-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2847 SLC6A17 Zornitza Stark Phenotypes for gene: SLC6A17 were changed from Mental retardation, autosomal recessive 48, MIM# 616269 to Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Mendeliome v1.2846 SLC6A17 Zornitza Stark edited their review of gene: SLC6A17: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Mendeliome v1.2846 WNT1 Zornitza Stark Phenotypes for gene: WNT1 were changed from Osteogenesis imperfecta, type XV, MIM# 615220 to Osteogenesis imperfecta, type XV, MIM# 615220; Osteoporosis MONDO:0005298
Mendeliome v1.2845 WNT1 Zornitza Stark Publications for gene: WNT1 were set to 23499309; 23499310; 23656646; 26671912
Mendeliome v1.2844 WNT1 Zornitza Stark edited their review of gene: WNT1: Added comment: Multiple families with milder monoallelic disease reported.; Changed publications: 23499309, 23499310, 23656646, 26671912, 27005318, 25010833, 30246918, 30283887; Changed phenotypes: Osteogenesis imperfecta, type XV, MIM# 615220, Osteoporosis MONDO:0005298; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2844 MAP4K1 Zornitza Stark Marked gene: MAP4K1 as ready
Mendeliome v1.2844 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Mendeliome v1.2844 MAP4K1 Zornitza Stark Classified gene: MAP4K1 as Green List (high evidence)
Mendeliome v1.2844 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Mendeliome v1.2843 MAP4K1 Zornitza Stark gene: MAP4K1 was added
gene: MAP4K1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MAP4K1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP4K1 were set to 40716650
Phenotypes for gene: MAP4K1 were set to Inborn error of immunity, MONDO:0003778, MAP4K1-related
Review for gene: MAP4K1 was set to GREEN
Added comment: Heterozygous MAP4K1 loss-of-function variants were identified in two kindreds presenting with diverse immune dysregulatory symptoms, including recurrent fevers, inflammatory arthritis, EBV-related complications, and nephritis. Functional analysis of primary patient T cells, transcriptomics, and CRISPR-Cas9 editing demonstrated that HPK1 deficiency heightened T cell activation and inflammatory cytokine production. Penetrance was incomplete.

One of the families was multiplex (8 affected individuals) and the other had single individual affected, extensive functional data. Borderline Amber/Green.
Sources: Expert Review
Mendeliome v1.2842 MN1 Zornitza Stark commented on gene: MN1: Recently discussed at Clingen syndromic GCEP. Noted well described C terminal truncating variants to result in GOF and CEBALID syndrome. Defined a milder phenotype with LOF mechanism for NMD predicted variants and whole gene deletions to result in a non specific craniofacial phenotype involving cleft palate.
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Marked gene: ARHGAP36 as ready
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Classified gene: ARHGAP36 as Amber List (moderate evidence)
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2841 ARHGAP36 Zornitza Stark gene: ARHGAP36 was added
gene: ARHGAP36 was added to Mendeliome. Sources: Expert Review
SV/CNV, regulatory region tags were added to gene: ARHGAP36.
Mode of inheritance for gene: ARHGAP36 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ARHGAP36 were set to 35986704; 40015599
Phenotypes for gene: ARHGAP36 were set to Bazex-Dupre-Christol syndrome, MIM# 301845
Mode of pathogenicity for gene: ARHGAP36 was set to Other
Review for gene: ARHGAP36 was set to AMBER
Added comment: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.

At least 9 families reported but AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.
Sources: Expert Review
Mendeliome v1.2840 YWHAZ Zornitza Stark Phenotypes for gene: YWHAZ were changed from Intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related
Mendeliome v1.2839 YWHAZ Zornitza Stark Publications for gene: YWHAZ were set to 36001342
Mendeliome v1.2838 YWHAZ Zornitza Stark Classified gene: YWHAZ as Amber List (moderate evidence)
Mendeliome v1.2838 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2837 YWHAZ Zornitza Stark edited their review of gene: YWHAZ: Added comment: PMID 31024343: 5 individuals with de novo variants in this gene, two had a clinical diagnosis of Rasopathy. 3 missense variants and 2 high impact variants (one is NMD escape). Parentage not confirmed in 3. Two had other possible variants of interest.

Used Xenopus to investigate the effect of one of the missense variants, S230W, and demonstrated activation of the Raf-MEK-Erk pathway and embryonic defects when expressed at high levels. Suggests GoF as mechanism.

Further de novo missense identified in a large cohort of NDDs, PMID 35143101.

PMID 35501409: knockout Zebrafish, altered brain activity and behaviour.

PMID 22124272, 26207352: two mouse models also support role in brain development.

MODERATE by ClinGen, but note this is mostly driven by experimental data points. Also note there is evidence for both GoF and LoF mechanism, potentially two distinct disorders?; Changed rating: AMBER; Changed publications: 36001342, 31024343, 35143101, 35501409, 22124272, 26207352; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related
Mendeliome v1.2837 RUSC2 Zornitza Stark commented on gene: RUSC2: LIMITED by ClinGen but note multiple P/LP ClinVar submissions
Mendeliome v1.2837 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 37768732; 39930170; 36826837; 40319332
Mendeliome v1.2836 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX, MIM#258865; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280 to Orofaciodigital syndrome type IX, MIM#258865; Alsahan-Harris syndrome, MIM#621307; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2835 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 31130284, 36826837 and 32573025: 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by brain abnormalities, including holoprosencephaly and anencephaly, and ocular defects including microphthalmia/anophthalmia and cyclopia. This has been given a separate MIM by OMIM but more likely represents the severe end of the spectrum of a broader ciliopathy phenotype.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170, 36826837, 40319332, 31130284, 36826837; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865, Retinitis pigmentosa 100, MIM# 621280, Alsahan-Harris syndrome, MIM#621307
Mendeliome v1.2835 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280 to Orofaciodigital syndrome type IX, MIM#258865; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2834 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 37768732; 39930170
Mendeliome v1.2833 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 36826837 and 40319332: four more individuals reported with OFD phenotype.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170, 36826837, 40319332; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865, syndromic hypopituitarism, Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2833 SLC9A1 Chirag Patel Classified gene: SLC9A1 as Green List (high evidence)
Mendeliome v1.2833 SLC9A1 Chirag Patel Gene: slc9a1 has been classified as Green List (High Evidence).
Mendeliome v1.2832 SLC9A1 Chirag Patel reviewed gene: SLC9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lichtenstein-Knorr syndrome MONDO:0014572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2832 PSMB10 Chirag Patel commented on gene: PSMB10
Mendeliome v1.2832 PSMB10 Chirag Patel Deleted their review
Mendeliome v1.2832 PSMB10 Chirag Patel reviewed gene: PSMB10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.2832 ESRP1 Chirag Patel Classified gene: ESRP1 as Red List (low evidence)
Mendeliome v1.2832 ESRP1 Chirag Patel Gene: esrp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2831 ESRP1 Chirag Patel reviewed gene: ESRP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.2831 IGKC Bryony Thompson Classified gene: IGKC as Amber List (moderate evidence)
Mendeliome v1.2831 IGKC Bryony Thompson Added comment: Comment on list classification: Gene does not have a NCBI transcript, therefore variants in this gene may not be annotated by some curation tools
Mendeliome v1.2831 IGKC Bryony Thompson Gene: igkc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2830 IGKC Bryony Thompson Tag technically challenging tag was added to gene: IGKC.
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Added comment: Comment on list classification: Gene does not have an NCBI transcript, therefore some curation tools will not annotate variants in this gene.
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2829 TRU-TCA1-1 Bryony Thompson Tag technically challenging tag was added to gene: TRU-TCA1-1.
Mendeliome v1.2829 IGHM Bryony Thompson Classified gene: IGHM as Green List (high evidence)
Mendeliome v1.2829 IGHM Bryony Thompson Added comment: Comment on list classification: Gene does not have an NCBI transcript, so it may have annotation issues in some curation tools
Mendeliome v1.2829 IGHM Bryony Thompson Gene: ighm has been classified as Green List (High Evidence).
Mendeliome v1.2828 IGHM Bryony Thompson Tag technically challenging tag was added to gene: IGHM.
Mendeliome v1.2828 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998 to Haemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v1.2827 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Relapsing HLH; Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998 to Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v1.2826 RC3H1 Zornitza Stark Publications for gene: RC3H1 were set to 31636267
Mendeliome v1.2825 RC3H1 Zornitza Stark edited their review of gene: RC3H1: Added comment: PMID 40769319: 3 individuals (heterozygous c.T674C (p.F225S)) from an extended kindred presenting with a spectrum of infections, lymphoproliferation, and autoimmune manifestations (upper respiratory infections, otitis media, sinusitis, abscess formation, pneumonia, and bacteremia, psoriasis, cytopenias, and liver disease. hyper-inflammation and lymphoproliferation manifesting with exaggerated generalized lymphadenopathy and splenomegaly. Transfected cell model provided functional support.

RED for mono-allelic association, single family.; Changed publications: 31636267, 15917799, 40769319; Changed phenotypes: Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v1.2825 RNU5B-1 Zornitza Stark Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU5B-1 related to Neurodevelopmental disorder with seizures and joint laxity, MIM# 621302
Mendeliome v1.2824 RNU5B-1 Zornitza Stark Publications for gene: RNU5B-1 were set to https://www.medrxiv.org/content/10.1101/2024.10.04.24314692v1.full.pdf; https://www.medrxiv.org/content/10.1101/2024.10.07.24314689v1
Mendeliome v1.2823 RNU5B-1 Zornitza Stark edited their review of gene: RNU5B-1: Changed publications: 40442284; Changed phenotypes: Neurodevelopmental disorder with seizures and joint laxity, MIM# 621302
Mendeliome v1.2823 RNU2-2P Zornitza Stark Phenotypes for gene: RNU2-2P were changed from Neurodevelopmental disorder, MONDO:0700092, RNU2-2-related to Developmental and epileptic encephalopathy 119, MIM# 621304
Mendeliome v1.2822 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679
Mendeliome v1.2821 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed publications: 40210679, 40442284
Mendeliome v1.2821 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed phenotypes: Developmental and epileptic encephalopathy 119, MIM# 621304
Mendeliome v1.2821 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Mendeliome v1.2820 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
Mendeliome v1.2820 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Mendeliome v1.2820 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2820 ST5 Zornitza Stark Tag new gene name tag was added to gene: ST5.
Mendeliome v1.2820 ST5 Zornitza Stark Marked gene: ST5 as ready
Mendeliome v1.2820 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Mendeliome v1.2820 ST5 Zornitza Stark Classified gene: ST5 as Green List (high evidence)
Mendeliome v1.2820 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Mendeliome v1.2819 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Mendeliome v1.2819 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2818 OGFRL1 Zornitza Stark Marked gene: OGFRL1 as ready
Mendeliome v1.2818 OGFRL1 Zornitza Stark Gene: ogfrl1 has been classified as Red List (Low Evidence).
Mendeliome v1.2818 OGFRL1 Zornitza Stark Classified gene: OGFRL1 as Red List (low evidence)
Mendeliome v1.2818 OGFRL1 Zornitza Stark Gene: ogfrl1 has been classified as Red List (Low Evidence).
Mendeliome v1.2817 OGFRL1 Rylee Peters gene: OGFRL1 was added
gene: OGFRL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OGFRL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGFRL1 were set to PMID: 38699440
Phenotypes for gene: OGFRL1 were set to Cherubism (MONDO:0007315), OGFRL1-related
Review for gene: OGFRL1 was set to RED
Added comment: 3x individuals from 2 unrelated families with cherubism and homozygous NMD-predicted variants in OGFRL1.

In one family, the NMD-predicted OGFRL1 variant was identified in 2x affected individuals and was either heterozygous or absent in 7x unaffected family members tested.

OGFRL1 knockout mice and mice carrying a patient frameshift mutation were generated, however, neither mouse model recapitulated human cherubism.

Absence of homozygous LoF variants in gnomAD v4.
Sources: Literature
Mendeliome v1.2817 FRYL Sarah Milton reviewed gene: FRYL: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38479391; Phenotypes: Pan-Chung-Bellen syndrome, MIM# 621049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2817 ST5 Rylee Peters gene: ST5 was added
gene: ST5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ST5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ST5 were set to PMID: 40717498
Phenotypes for gene: ST5 were set to Neurodevelopmental disorder (MONDO:0700092), DENND2B-related
Review for gene: ST5 was set to GREEN
Added comment: HGNC: DENND2B
Cohort of 11 individuals all with a history of motor and/or language developmental delay, intellectual disability in 6/11 (mild to severe), brain structure/function abnormalities were reported in 9/11 patients (7/11 seizures; 5/9 abnormal findings on brain MRI), muscle weakness/hypotonia in 8/9, psychosis in 4/10 patients, symptoms of catatonia in 4/10, other psychiatric/behavioural concerns (anxiety, attention deficit, autism or autistic features) in 10/10.

Total of 10 variants including 2x frameshift/nonsense, 6x missense, 1x splice, 1x single amino acid deletion – all absent from v4 and de novo except 1 inherited from a father with cognitive and psychiatric symptoms and the inframe del which has 2 hets in gnomAD and is inherited an unaffected father (no formal assessment).

In vivo zebrafish modelling measuring cilia length suggests that patient variants tested (9/10 excluding the splice variant) did not induce cilia length shortening, which is consistent with KO models and therefore a loss of function effect.
Sources: Literature
Mendeliome v1.2817 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Mendeliome v1.2817 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Mendeliome v1.2817 BLOC1S1 Rylee Peters reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2817 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Mendeliome v1.2817 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2816 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Phenotypes for gene: TMEM17 were set to Meckel syndrome MONDO:0018921; TMEM17-related
Review for gene: TMEM17 was set to AMBER
Added comment: 4 fetuses (TOP/deceased) from 4 consanguineous unrelated families with a clinical diagnosis of Meckel-Gruber syndrome. Clinical features includes: encephalocele (4/4), enlarged/cystic kidneys (4/4), and postaxial polydactyly (1/4). WES identified 3 homozygous variants (p.(Glu2Serfs*58); p.(Pro123Thrfs*9); and p.(Pro123Arg)).

They also reported a 5th consanguineous family with 3 affected fetuses with clinical diagnosis of Meckel-Gruber syndrome. Both parents were heterozygote carriers of a TMEM17 variant (p.(Glu2Serfs*58)) but biological material from the fetuses was not available.

No functional studies performed. However, TMEM17 is a critical component of a protein complex in the basal body at the base of cilia. Knockdown of Tmem17 via small interfering RNA has been shown to have a modest effect on cilia formation, but significantly reduces the amount of the somatostatin receptor Sstr3 (182453) that localizes to cilia.
Sources: Literature
Mendeliome v1.2815 CHTF18 Zornitza Stark Marked gene: CHTF18 as ready
Mendeliome v1.2815 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Mendeliome v1.2815 CHTF18 Zornitza Stark Phenotypes for gene: CHTF18 were changed from complex neurodevelopmental disorder with or without congenital anomalies (Cohesinopathies) MONDO:0100465 to Neurodevelopmental disorder MONDO#0700092, CHTF18-related
Mendeliome v1.2814 CHTF18 Zornitza Stark Classified gene: CHTF18 as Green List (high evidence)
Mendeliome v1.2814 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Mendeliome v1.2813 CHTF18 Zornitza Stark reviewed gene: CHTF18: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO#0700092, CHTF18-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2813 KDM2B Zornitza Stark Publications for gene: KDM2B were set to 36322151
Mendeliome v1.2812 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Mendeliome v1.2812 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Mendeliome v1.2812 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Mendeliome v1.2812 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Mendeliome v1.2811 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to Neurodevelopmental disorder (MONDO:0700092), SNW1-related
Review for gene: SNW1 was set to GREEN
Added comment: cohort of 9 patients with moderate to profound ID, microcephaly, seizures (7/9), facial dysmorphism, and brain malformations (6/9 - corpus callosum hypoplasia, Dandy-Walker malformation).

3 splice, 1 frameshift, 2 missense, 3 in frame deletions, 1 start loss. all but 1 de novo (the last parents not available).

SNW1 is a core component of the spliceosome and facilitates the conformational changes of the spliceosome. Expression of variants in HEK293 cells showed some decreased SNW1 expression while others increased it (including the frameshift), and only the frameshift variant was mislocalised/in the cytoplasm instead of the nucleus. Several of the variants caused loss of binding to PPIL1 or other proteins which SNW1 usually recruits to the spliceosome. All variants in this study were found to either affect protein expression or localization or influence interactions with other proteins in the spliceosome complex suggesting loss of function.
Sources: Literature
Mendeliome v1.2811 KDM2B Lucy Spencer reviewed gene: KDM2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 40420380; Phenotypes: neurodevelopmental disorder MONDO#0700092, KDM2B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2811 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Mendeliome v1.2811 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Mendeliome v1.2810 CHTF18 Sangavi Sivagnanasundram gene: CHTF18 was added
gene: CHTF18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHTF18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHTF18 were set to 40717333
Phenotypes for gene: CHTF18 were set to complex neurodevelopmental disorder with or without congenital anomalies (Cohesinopathies) MONDO:0100465
Review for gene: CHTF18 was set to GREEN
Added comment: >5 unrelated individuals with a rare missense variant in the gene have been identified by the authors however the clinical details were presented on three.
3 different de novo missense variants were identified

3 individuals - neurodevelopment delay, epilepsy, de novo:
1 - 9M with DD, autism and seizures. De novo variant identified - p.Leu355Val
2 - 23month F with congenital bilateral ventriculomegaly status post ventriculoperitoneal shunt placement, epilepsy, right eye optic nerve hypoplasia, hypotonic cerebral palsy complicated by left hip subluxation, and G-tube dependence. De novo variant identified - p.His645Pro
3 - 3F presenting with global DD, hypotonia, seizure and abnormal brain MRI. De novo variant identified - p.Leu676Arg
Sources: Literature
Mendeliome v1.2810 PDCD6IP Sangavi Sivagnanasundram reviewed gene: PDCD6IP: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1111/cge.70025; Phenotypes: Neurodevelopmental disorder with microcephaly MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2810 SLC44A1 Zornitza Stark Phenotypes for gene: SLC44A1 were changed from progressive ataxia; tremor; cognitive decline; dysphagia; optic atrophy; dysarthria to Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, MIM# 618868
Mendeliome v1.2809 SLC44A1 Zornitza Stark edited their review of gene: SLC44A1: Changed rating: GREEN; Changed phenotypes: Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, MIM# 618868; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2809 ERCC1 Zornitza Stark Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, MIM# 610758; MONDO:0012554 to Cerebrooculofacioskeletal syndrome 4, MIM# 610758; MONDO:0012554; Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Mendeliome v1.2808 ERCC1 Zornitza Stark Publications for gene: ERCC1 were set to 17273966; 23623389; 33315086
Mendeliome v1.2807 SMAD5 Zornitza Stark Marked gene: SMAD5 as ready
Mendeliome v1.2807 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Mendeliome v1.2807 SMAD5 Zornitza Stark Classified gene: SMAD5 as Green List (high evidence)
Mendeliome v1.2807 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Mendeliome v1.2806 SMAD5 Sarah Milton changed review comment from: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature; to: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection of variants into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 SMAD5 Sarah Milton changed review comment from: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenitcal/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature; to: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 SMAD5 Sarah Milton gene: SMAD5 was added
gene: SMAD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD5 were set to PMID: 40619738
Phenotypes for gene: SMAD5 were set to Congenital heart disease, MONDO:0005453, SMAD5-related
Penetrance for gene: SMAD5 were set to Incomplete
Review for gene: SMAD5 was set to GREEN
Added comment: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenitcal/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 TNFRSF11B Bryony Thompson Publications for gene: TNFRSF11B were set to 14672344
Mendeliome v1.2805 TNFRSF11B Bryony Thompson Phenotypes for gene: TNFRSF11B were changed from Paget disease of bone 5, juvenile-onset, MIM# 239000 to juvenile Paget disease MONDO:0009394; chondrocalcinosis 1 MONDO:0010917
Mendeliome v1.2804 TNFRSF11B Bryony Thompson Mode of inheritance for gene: TNFRSF11B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2803 TNFRSF11B Bryony Thompson reviewed gene: TNFRSF11B: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24743232, 40735895, 29578045, 33559312, 33989379, 35412619; Phenotypes: chondrocalcinosis 1 MONDO:0010917; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2803 ATP6V0A4 Krithika Murali reviewed gene: ATP6V0A4: Rating: RED; Mode of pathogenicity: None; Publications: PMID:40299568; Phenotypes: Renal tubular acidosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2803 ATG2A Krithika Murali Marked gene: ATG2A as ready
Mendeliome v1.2803 ATG2A Krithika Murali Gene: atg2a has been classified as Red List (Low Evidence).
Mendeliome v1.2803 ATG2A Krithika Murali gene: ATG2A was added
gene: ATG2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG2A were set to PMID:40631414
Phenotypes for gene: ATG2A were set to complex neurodevelopmental disorder, ATG2A-related - MONDO:0100038
Review for gene: ATG2A was set to RED
Added comment: PMID:40631414 report a 3 yo F with homozygous ATG2A missense variant (c.1372G>C (p.Gly433Ala) with developmental regression, seizures, cerebellar ataxia, and MRI-brain abnormalities (diffuse cerebral and cerebellar atrophy). Provide supportive functional evidence.
Sources: Literature
Mendeliome v1.2802 CFAP43 Zornitza Stark Classified gene: CFAP43 as Amber List (moderate evidence)
Mendeliome v1.2802 CFAP43 Zornitza Stark Gene: cfap43 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2801 CFAP43 Zornitza Stark edited their review of gene: CFAP43: Added comment: DISPUTED by ClinGen for biallelic association with PCD.; Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Marked gene: RNU5A-1 as ready
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Classified gene: RNU5A-1 as Amber List (moderate evidence)
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2800 RNU5A-1 Zornitza Stark gene: RNU5A-1 was added
gene: RNU5A-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder (MONDO:0700092), RNU5A-1 related
Review for gene: RNU5A-1 was set to AMBER
Added comment: PMID: 40379786 (2025) - three unrelated individuals with de novo variants in the RNU5A-1 gene (classified as VUS) and a neurodevelopmental disorder. Six individuals with rare de novo variants were identified in total but clinical details were only available for 3/6. Of these three individuals, two harboured the same variant (n.40_41insA) on the maternal allele, while the third individual harboured a different variant (n.39del) but also on the 5′ loop I domain of RNU5A-1. Clinical data showed neurodevelopmental abnormalities (mild ID (2), severe ID (1), epilepsy (2), brain MRI abnormalities (1)) with variable congenital malformations.
Sources: Literature
Mendeliome v1.2799 AMFR Zornitza Stark Phenotypes for gene: AMFR were changed from Spastic paraplegia 89, autosomal recessive, MIM# 620379 to Spastic paraplegia 89, autosomal recessive, MIM# 620379; Inborn error of immunity, MONDO:0003778, AMFR-related
Mendeliome v1.2798 AMFR Zornitza Stark Publications for gene: AMFR were set to 37119330
Mendeliome v1.2797 AMFR Zornitza Stark edited their review of gene: AMFR: Added comment: PMID 38277122:

Single case report of 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, haemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. HLH was the working diagnosis. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy.

Rare monoallelic variant in autocrine motility factor receptor (AMFR) identified. AMFR encodes a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway.

Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-β reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans.

RED for this association.; Changed publications: 38277122; Changed phenotypes: Spastic paraplegia 89, autosomal recessive, MIM# 620379, Inborn error of immunity, MONDO:0003778, AMFR-related
Mendeliome v1.2797 ASXL1 Zornitza Stark Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome , MIM#605039 to Bohring-Opitz syndrome , MIM#605039; Combined immunodeficiency, MONDO:0015131, ASXL1-related
Mendeliome v1.2796 ASXL1 Zornitza Stark Publications for gene: ASXL1 were set to 29446906; 21706002
Mendeliome v1.2795 ASXL1 Zornitza Stark edited their review of gene: ASXL1: Added comment: PMID 40742536. Single individual with biallelic variants reported. The patient had a history of haematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction.

Note mono allelic variants are associated with Bohring Opitz syndrome and somatic variants are associated with clonal haematopoiesis.

RED for biallelic association.; Changed publications: 29446906, 21706002, 40742536; Changed phenotypes: Bohring-Opitz syndrome , MIM#605039, Combined immunodeficiency, MONDO:0015131, ASXL1-related
Mendeliome v1.2795 RCC1 Zornitza Stark Marked gene: RCC1 as ready
Mendeliome v1.2795 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Mendeliome v1.2795 RCC1 Zornitza Stark Classified gene: RCC1 as Green List (high evidence)
Mendeliome v1.2795 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Mendeliome v1.2794 RCC1 Zornitza Stark gene: RCC1 was added
gene: RCC1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RCC1 were set to 40683276
Phenotypes for gene: RCC1 were set to Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related
Review for gene: RCC1 was set to GREEN
Added comment: 24 individuals from 12 families reported with severe, acute-onset axonal neuropathy following infection (13 female and 11 male patients, with a mean age at diagnosis of 1 year 10 months [SD 2·27]).

Eight biallelic missense variants in RCC1 identified.

Patients had variable phenotypes, ranging from rapidly progressive fatal axonal neuropathy to mild motor neuropathy with impaired walking. Neurological presentation was often secondary to an infection, resulting in initial misdiagnoses of Guillain-Barré syndrome in several patients. 15 children had disease recurrence. The disease was fatal in 15 patients.

The RCC1 variants coded for proteins that alter GDP-to-GTP exchange activity and had reduced thermal stability in vitro. In primary fibroblasts, heat shock or oxidative stress revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model of the disease revealed a fatal intolerance to oxidative stress.
Sources: Expert Review
Mendeliome v1.2793 ERCC1 Sarah Milton reviewed gene: ERCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40684071; Phenotypes: Hepatorenal syndrome, MONDO:0001382, ERCC1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2793 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX; syndromic hypopituitarism to Orofaciodigital syndrome type IX; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2792 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284
Mendeliome v1.2791 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: Association with RP:
PMID 37768732: 4 individuals from three unrelated families with bi-allelic variants as per review by Achchuthan Shamugasundram. Some supportive functional data. PMID 39930170: fourth family reported.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170; Changed phenotypes: Orofaciodigital syndrome type IX, syndromic hypopituitarism, Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2791 BSN Zornitza Stark Phenotypes for gene: BSN were changed from Epilepsy MONDO:0005027 to Neurodevelopmental disorder (MONDO:0700092), BSN-related
Mendeliome v1.2790 BSN Zornitza Stark edited their review of gene: BSN: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder (MONDO:0700092), BSN-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2790 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Craniofacial microsomia MONDO:0015397 to Syndromic disease, MONDO:0002254, NR6A1-related
Mendeliome v1.2789 NR6A1 Zornitza Stark reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, NR6A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2789 BSN Lauren Rogers reviewed gene: BSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 40393460; Phenotypes: Epilepsy (MONDO:0005027), BSN-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2789 ZNF597 Zornitza Stark Marked gene: ZNF597 as ready
Mendeliome v1.2789 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
Mendeliome v1.2789 ZNF597 Zornitza Stark gene: ZNF597 was added
gene: ZNF597 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZNF597 was set to Other
Publications for gene: ZNF597 were set to 19968752; 28157578; 32576657
Phenotypes for gene: ZNF597 were set to Recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: ZNF597 was set to RED
Added comment: ZNF597 is an imprinted gene- maternally expressed and paternally imprinted.
- ZNF597 is highly expressed in the placenta and proposed to have an important role in placental development.
- Knockout ZNF597 mice (homozygous -/-) is embryonic lethal due to failed embryonic organization before cardiogenesis at embryonic day 7.5. This period is equivalent to human Carnegie Stage 9 that occurs during week 3 between 19 to 21 days (5 weeks' gestation).
- Literature associated with ZNF597 including maternal uniparental disomy of chromosome 16 (UPD(16)mat) or loss of paternal imprinting of ZNF59, resulting in an overexpression of ZNF597.
- Unpublished in-house data/observation: A heterozygous deletion with a breakpoint in ZNF597 was observed in the female partner of a couple experiencing x4 early pregnancy loss at 5-8 weeks' gestation.
Sources: Expert list
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Marked gene: ZFP36L2 as ready
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Gene: zfp36l2 has been classified as Green List (High Evidence).
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Classified gene: ZFP36L2 as Green List (high evidence)
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Gene: zfp36l2 has been classified as Green List (High Evidence).
Mendeliome v1.2787 ZFP36L2 Zornitza Stark gene: ZFP36L2 was added
gene: ZFP36L2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZFP36L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFP36L2 were set to 34611029; 38829516; 37211617
Phenotypes for gene: ZFP36L2 were set to Oocyte/zygote/embryo maturation arrest 13, MIM# 620154
Review for gene: ZFP36L2 was set to GREEN
Added comment: i) Literature in OMIM- PMID:34611029- x2 unrelated infertile Chinese women with defective oocyte maturation carrying different biallelic variants and functional analysis suggested that the variants cause maternal mRNA decay defects that result in female infertility.

ii) New papers reporting biallelic variants in conjunction with female infertility due to oocyte maturation defect+/- embryonic development arrest
- PMID: 38829516: Novel compound heterozygous variant (p.His62Gln and p.Pro290Leu) in a patient with oocyte maturation defect. These variants lead to compromised binding capacity of the ZFP36L2-CONT6L complex and impaired mRNA degradation in HeLa cells and mouse oocytes.
- PMID: 37211617: Novel homozygous variant c.853_861del (p.285_287del) in the affected individual with oocyte maturation defect from a consanguineous family. In vitro studies showed that the variant caused decreased protein levels of ZFP36L2 in oocytes due to mRNA instability and might lead to the loss of its function to degrade maternal mRNAs
Sources: Expert list
Mendeliome v1.2786 WNT6 Zornitza Stark Marked gene: WNT6 as ready
Mendeliome v1.2786 WNT6 Zornitza Stark Gene: wnt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2786 WNT6 Zornitza Stark Classified gene: WNT6 as Amber List (moderate evidence)
Mendeliome v1.2786 WNT6 Zornitza Stark Gene: wnt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2785 WNT6 Zornitza Stark gene: WNT6 was added
gene: WNT6 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: WNT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNT6 were set to 36385415; 25750203
Phenotypes for gene: WNT6 were set to recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: WNT6 was set to AMBER
Added comment: i) PMID: 36385415- heterozygous missense variant (p.Arg70Gly) in a female with recurrent pregnancy loss (C21)

ii) PMID: 25750203- four novel heterozygous (checked Sanger traces) variants (i.e, one missense P.Leu148Arg, one synonymous c. 522C>T, one variant in intron 1 c. 297+40G>A, and one variant in the 3′UTR c. 1127G>A ) in 4 women with unexplained recurrent miscarriages (RM), but only the missense variant was shown to affect the functional region of WNT6 that might explain the unexplained RM

In effect, only 2 cases with limited other supporting data, hence Amber.
Sources: Expert list
Mendeliome v1.2784 USP26 Zornitza Stark Marked gene: USP26 as ready
Mendeliome v1.2784 USP26 Zornitza Stark Gene: usp26 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2784 USP26 Zornitza Stark Classified gene: USP26 as Amber List (moderate evidence)
Mendeliome v1.2784 USP26 Zornitza Stark Gene: usp26 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2783 USP26 Zornitza Stark edited their review of gene: USP26: Changed rating: AMBER
Mendeliome v1.2783 USP26 Zornitza Stark gene: USP26 was added
gene: USP26 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: USP26 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: USP26 were set to 34202084; 27089915
Phenotypes for gene: USP26 were set to Spermatogenic failure, X-linked 6, MIM# 301101
Added comment: i) PMID: 34202084- hemizygous missense variants in 2 unrelated affected Chinese men with infertility due to asthenoteratozoospermia (R825G in proband H002, and N799S in proband H042) and functional analysis showed markedly reduced USP26 mRNA and protein levels in patient sperm.

ii) PMID: 27089915- a novel hemizygous missense variant R344W in two affected Chinese men with non-obstructive azoospermia, which has been shown functionally to have reduce binding affinity and deubiquitinating activity of USP26 to androgen receptors.

Rated Amber as missense variants with little other supporting data.
Sources: Expert list
Mendeliome v1.2782 UBE2B Zornitza Stark Marked gene: UBE2B as ready
Mendeliome v1.2782 UBE2B Zornitza Stark Gene: ube2b has been classified as Green List (High Evidence).
Mendeliome v1.2782 UBE2B Zornitza Stark Classified gene: UBE2B as Green List (high evidence)
Mendeliome v1.2782 UBE2B Zornitza Stark Gene: ube2b has been classified as Green List (High Evidence).
Mendeliome v1.2781 UBE2B Zornitza Stark gene: UBE2B was added
gene: UBE2B was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: UBE2B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UBE2B were set to 23378580; 26223869; 12784252
Phenotypes for gene: UBE2B were set to Male infertility, MONDO:0005372
Review for gene: UBE2B was set to GREEN
Added comment: i) PMID: 23378580 (2013)- Identified nine splicing, four missense and two nonsense alterations in unrelated oligospermic patients, majority are heterozygous, only 3 were homozygous. Their findings suggested that two distinct molecular mechanisms, mRNA editing and splicing processing, were disrupted in oligozoospermia.

ii) PMID: 26223869 (2015): Reported four known and novel heterozygous variants in idiopathic azoospermia (IA) patients in the Chinese population, and one of the missense variant was demonstrated to inhibit the transcriptional regulation activity of SP1 transcription factor, suggesting that it confers a high risk for IA.

iii) PMID: 12784252 (2003)- Ube2b(-/-) mice were shown to present male infertility and their sperm head shape anomalies suggested that Ube2b may be involved in the replacement of nuclear proteins during spermatid chromatin condensation.
Sources: Expert list
Mendeliome v1.2780 TIMP2 Zornitza Stark Marked gene: TIMP2 as ready
Mendeliome v1.2780 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2780 TIMP2 Zornitza Stark Classified gene: TIMP2 as Amber List (moderate evidence)
Mendeliome v1.2780 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2779 TIMP2 Zornitza Stark gene: TIMP2 was added
gene: TIMP2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TIMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TIMP2 were set to 20847186; 34756330
Phenotypes for gene: TIMP2 were set to Recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: TIMP2 was set to AMBER
Added comment: i) PMID: 20847186- In family 6, TIMP2 partial duplication (involves Ex1-2) in mother and 4 out of 5 miscarriages. They have not yet been associated with RPL in humans, however, overexpression of TIMP2 was detected in a mouse model of RPL (Dixon et al., 2006). The TIMP2 disruption in miscarriages in Family 6 may have affected the placental development, but the possibility remains that maternal disruption of TIMP2 may contribute to RPL by impairing the remodeling of the endometrium in early pregnancy. Functional study was performed by PMID: 25674159, which showed reduced RNA and protein expression in chorionic villi cultures from miscarriages with the CNV.

ii) PMID: 34756330- de novo damaging heterozygous missense TIMP2 variant, c.[553G>A]; p.[Gly185Arg] in an eight-week euploid embryonic loss. The MMP2/TIMP2 complex is involved in several gestational processes including implantation and placentation.

iii) PMID: 11912288- The disruption of the TIMP2 gene was considered to be relevant for recurrent miscarriage due to its critical role in modulating invasion of the trophoblast into maternal endometrium and in vascular remodeling and angiogenesis of maternal and placenta tissues in the first trimester.
Sources: Expert list
Mendeliome v1.2778 TBPL2 Zornitza Stark Marked gene: TBPL2 as ready
Mendeliome v1.2778 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Mendeliome v1.2778 TBPL2 Zornitza Stark Classified gene: TBPL2 as Green List (high evidence)
Mendeliome v1.2778 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Mendeliome v1.2777 TBPL2 Zornitza Stark gene: TBPL2 was added
gene: TBPL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TBPL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBPL2 were set to 37804378; 33966269; 33893736; 33541821
Phenotypes for gene: TBPL2 were set to Inherited oocyte maturation defect, MONDO:0014769, TBPL2-related
Review for gene: TBPL2 was set to GREEN
Added comment: New papers reporting biallelic variants in infertile women:
i) PMID: 37804378- Compound heterozygous novel p.Arg268Ter and recurrent p.Arg233Ter in a female with impaired ovarian folliculogenesis. Structure prediction by molecular modeling demonstrated that three-dimensional structure of TBPL2 was destabilized in mutant proteins.

ii) PMID: 33966269- Homozygous missense mutation p.C299R in two infertile sisters with oocyte maturation arrest and degeneration from a consanguineous family. Functional assays showed that the transcriptional level of ZP3 was not completely blocked but severely reduced by the regulation of the mutant TBPL2, while the transcriptional level of H2Bc was significantly reduced but to a less severe extent compared with that of ZP3, suggesting that the missense had a damage to the transcription initiation function of TBPL2 and its downstream targeted genes got involved in different degrees. The mutant protein also has less stability, which contributes to the lower activity of transcription initiation in the mutant form.

iii) PMID: 33893736- Homozygous splicing variant (c.788 + 3A>G) in two unrelated families characterized by oocyte maturation defects. Functional assays showed that the variant disrupted the integrity of TBPL2 mRNA and affected oocytes showed that vital genes for oocyte maturation and fertilization were widely and markedly downregulated, suggesting that a mutation in TBPL2, led to global gene alterations in oocytes; the same variant reported before in PMID: 33541821 in three affected females with diminished ovarian reserve from 3 independent families.
Sources: Expert list
Mendeliome v1.2776 TACC3 Zornitza Stark Marked gene: TACC3 as ready
Mendeliome v1.2776 TACC3 Zornitza Stark Gene: tacc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2776 TACC3 Zornitza Stark Classified gene: TACC3 as Amber List (moderate evidence)
Mendeliome v1.2776 TACC3 Zornitza Stark Gene: tacc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2775 TACC3 Zornitza Stark gene: TACC3 was added
gene: TACC3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TACC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TACC3 were set to 36395215
Phenotypes for gene: TACC3 were set to Female infertility due to oocyte meiotic arrest, MONDO:0044626
Review for gene: TACC3 was set to AMBER
Added comment: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility.
Sources: Expert list
Mendeliome v1.2774 RXFP2 Zornitza Stark Phenotypes for gene: RXFP2 were changed from Cryptorchidism to Infertility; cryptorchidism; non-obstructive azoospermia
Mendeliome v1.2773 RXFP2 Zornitza Stark Publications for gene: RXFP2 were set to 31167797; 20963592
Mendeliome v1.2772 RXFP2 Zornitza Stark Classified gene: RXFP2 as Green List (high evidence)
Mendeliome v1.2772 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Green List (High Evidence).
Mendeliome v1.2771 RXFP2 Zornitza Stark edited their review of gene: RXFP2: Added comment: New literature PMID: 39222519- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism.; Changed rating: GREEN; Changed publications: 31167797, 20963592, 39222519
Mendeliome v1.2771 PABPC1L Zornitza Stark Marked gene: PABPC1L as ready
Mendeliome v1.2771 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Mendeliome v1.2771 PABPC1L Zornitza Stark Classified gene: PABPC1L as Green List (high evidence)
Mendeliome v1.2771 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Mendeliome v1.2770 PABPC1L Zornitza Stark gene: PABPC1L was added
gene: PABPC1L was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PABPC1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PABPC1L were set to 37052235; 37723834; 38177974; 32172300
Phenotypes for gene: PABPC1L were set to Oocyte/zygote/embryo maturation arrest 22, #MIM 621093
Review for gene: PABPC1L was set to GREEN
Added comment: i) Literature in OMIM (PMID: 37052235;37723834;38177974)- >3 unrelated infertile women (due to a mixed phenotype including oocyte maturation abnormalities, fertilization failure, and embryonic development arrest) with different biallelic variants

ii) Additional paper (PMID: 32172300)- Homozygous likely deleterious variant in PABPC1L p.(Met26Lys) in a woman whose infertility phenotype resembles that of Pabpc1l−/− mouse. During her IVF cycles, 18 oocytes were retrieved and subjected to IVF and ICSI. Nine oocytes were assigned to ICSI, but eight were at germinal vesicle stage and only one showed polar body and failed to fertilize following ICSI. Similarly, nine oocytes were assigned to IVF, and only two showed polar body on the next day without any sign of fertilization. The remaining oocytes were at germinal vesicle stage.
Sources: Expert list
Mendeliome v1.2769 NLRP14 Zornitza Stark Marked gene: NLRP14 as ready
Mendeliome v1.2769 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2769 NLRP14 Zornitza Stark Classified gene: NLRP14 as Amber List (moderate evidence)
Mendeliome v1.2769 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2768 NLRP14 Zornitza Stark gene: NLRP14 was added
gene: NLRP14 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NLRP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NLRP14 were set to 38060382
Phenotypes for gene: NLRP14 were set to Inherited oocyte maturation defect, MONDO:0014769, NLRP14-related and early embryo arrest
Review for gene: NLRP14 was set to AMBER
Added comment: PMID: 38060382- Compound heterozygous variants (p.Cys428Profs∗28/p.Leu887delinsArgTyr) reported in an infertile woman with oocyte maturation defects and early embryo arrest (EEA).
- Functional analysis showed comparable protein levels compared with the wild-type control, although a truncated band of the expected size (47 kDa) was observed for the p.Cys428Profs∗28 variant.
-The truncated variant, p.Cys428Profs∗28, is lacking the LRR domain and, hence, completely loses the ability to bind with UHRF1. The p.Leu887delinsArgTyr variant results in significant alteration in binding modes with decreased binding area and binding free energy, which introduced regional instability in the NLRP14-UHRF1 interaction. The interaction of both variants and UHRF1 was disrupted and might lead to increased UHRF1 protein degradation in oocytes.
Sources: Expert list
Mendeliome v1.2767 MEI1 Zornitza Stark Marked gene: MEI1 as ready
Mendeliome v1.2767 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Mendeliome v1.2767 MEI1 Zornitza Stark Classified gene: MEI1 as Green List (high evidence)
Mendeliome v1.2767 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Mendeliome v1.2766 MEI1 Zornitza Stark gene: MEI1 was added
gene: MEI1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MEI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MEI1 were set to 30388401; 38416203; 34037756; 36759719; 32741963; 36017582
Phenotypes for gene: MEI1 were set to Recurrent hydatidiform mole 3, MIM# 618431; Non-obstructive azoospermia
Review for gene: MEI1 was set to GREEN
Added comment: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA)

New papers (biallelic variants for OZEMA):
i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles.

ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1.

New papers (biallelic variants for NOA):
i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro.
- others: PMID: 32741963;36017582

Note: Moderate evidence for OZEMA and HM in FeRGI database
Sources: Expert list
Mendeliome v1.2765 MAJIN Zornitza Stark Marked gene: MAJIN as ready
Mendeliome v1.2765 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2765 MAJIN Zornitza Stark Classified gene: MAJIN as Amber List (moderate evidence)
Mendeliome v1.2765 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2764 MAJIN Zornitza Stark gene: MAJIN was added
gene: MAJIN was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MAJIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAJIN were set to 39545410; 33211200
Phenotypes for gene: MAJIN were set to Recurrent hydatidiform mole, non-obstructive azoospermia
Review for gene: MAJIN was set to AMBER
Added comment: New papers (biallelic variant for HM/male infertility):
i) PMID: 39545410- Novel homozygous splice donor site variant c.349+1G>T in patient 1824 (Italian) with 2 HMs followed by secondary infertility and substantially reduced bilateral ovarian volumes. MAJIN codes for a junction protein that forms a complex with TERB1 and TERB2, which together bind to telomeres and anchor them to the inner nuclear membrane components KASH5 and SUN1. This attachment of chromosomes to the nuclear envelope is essential for homologous chromosome movement and synapsis. In mice, both male and female null mutants Majin are infertile (PMID: 26548954). In humans, biallelic mutations in MAJIN have been reported in infertile males.

ii) PMID: 33211200- A homozygous p.Arg53His in NOA-affected male (Individual 4- M1646) with high CADD scores and low gnomad freq. Mice disrupted for either Majin or Terb2 display impaired synapsis, zygotene arrest, a lack of postmeiotic cells and infertility (Shibuya et al. 2015; Zhang et al. 2017).
Sources: Expert list
Mendeliome v1.2763 LHX8 Zornitza Stark Marked gene: LHX8 as ready
Mendeliome v1.2763 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Mendeliome v1.2763 LHX8 Zornitza Stark Classified gene: LHX8 as Green List (high evidence)
Mendeliome v1.2763 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Mendeliome v1.2762 KIAA1683 Zornitza Stark Marked gene: KIAA1683 as ready
Mendeliome v1.2762 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Mendeliome v1.2762 KIAA1683 Zornitza Stark Classified gene: KIAA1683 as Green List (high evidence)
Mendeliome v1.2762 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Mendeliome v1.2761 KIAA1683 Zornitza Stark gene: KIAA1683 was added
gene: KIAA1683 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KIAA1683 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1683 were set to 36321563; 39872118; 37140151; 37184908; 40437858
Phenotypes for gene: KIAA1683 were set to Spermatogenic failure 78, #MIM 620170
Review for gene: KIAA1683 was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 36321563, 39872118, 37140151, 37184908 (>3 unrelated Chinese men with infertility due to spermatogenic failure with hom/com het variants).

New paper: i) PMID: 40437858 (2025)- novel hom p.Trp796Ter in infertile man with fertilization failure and history of two miscarriages with his partner. According to the prediction of protein conformations, it was found that the protein conformations were truncated in the mutated IQCN gene, which probably affected the function of the patient's sperm.
Sources: Expert list
Mendeliome v1.2760 KCNU1 Zornitza Stark Marked gene: KCNU1 as ready
Mendeliome v1.2760 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Mendeliome v1.2760 KCNU1 Zornitza Stark Classified gene: KCNU1 as Green List (high evidence)
Mendeliome v1.2760 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Mendeliome v1.2759 KCNU1 Zornitza Stark gene: KCNU1 was added
gene: KCNU1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNU1 were set to 34980136; 35551387; 20138882; 21427226; 25271166; 35551387
Phenotypes for gene: KCNU1 were set to Spermatogenic failure 79, #MIM 620196
Review for gene: KCNU1 was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 34980136, 35551387- 3 unrelated male with spermatogenic failure with different homozygous variants, supported by functional evidence; PubMed: 20138882, 21427226, 25271166- Slo3 -/- KO mice were infertile, 35551387- mice with homozygous H720R variant, corresponding to the human H715R variant recapitulated human phenotype.
Sources: Expert list
Mendeliome v1.2758 GGN Zornitza Stark Classified gene: GGN as Green List (high evidence)
Mendeliome v1.2758 GGN Zornitza Stark Gene: ggn has been classified as Green List (High Evidence).
Mendeliome v1.2757 GGN Zornitza Stark edited their review of gene: GGN: Changed rating: GREEN
Mendeliome v1.2757 GGN Zornitza Stark edited their review of gene: GGN: Added comment: PMID: 23451117 (2013)- Ggn null mouse line demonstrated that s complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos.; Changed publications: 31985809, 33108537, 23451117; Changed phenotypes: Spermatogenic failure 69, MIM# 619826
Mendeliome v1.2757 FOXD1 Zornitza Stark Marked gene: FOXD1 as ready
Mendeliome v1.2757 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Mendeliome v1.2757 FOXD1 Zornitza Stark Classified gene: FOXD1 as Green List (high evidence)
Mendeliome v1.2757 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Mendeliome v1.2756 FOXD1 Zornitza Stark gene: FOXD1 was added
gene: FOXD1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FOXD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXD1 were set to 27805902; 31395028
Phenotypes for gene: FOXD1 were set to Recurrent pregnancy loss and repeated implantation failure susceptibility, MONDO:0000144, FOXD1-related
Review for gene: FOXD1 was set to GREEN
Added comment: i) PMID: 27805902- 18 heterozygous (only 10 were nonsynonymous) variants were identified only in recurrent spontaneous abortion (RSA) patients (total of 33 patients) not seen in ctrl group, and only 3 variants had functional assays performed- p.Ala356Gly (x1 patient),p.Ile364Met (x2 patients), and p.Ins429AlaAla (x12 patients). In vitro assays revealed they had a functional effect as they led to perturbations in FOXD1 transactivation properties on promoters of the Placental Growth Factor (PGF) and the complement component gene (C3) having key roles during implantation/placentation.

ii) PMID: 31395028- 9 heterozygous non-synonymous variants in patients affected by PE, IUGR, RPL and repeated implantation failure (RIF) , two of which (p.His267Tyr found in one RIF patient and p.Arg57del in one IUGR woman) represented novel and coherent candidates for in vitro testing. Functional experiments revealed that both led to an increased C3 (complement C3) promoter transcriptional activity. Also found increased FOXD1-p.Arg57del variant transactivation capacity on the PlGF (placental growth factor) promoter.The FOXD1 p.Ala356Gly and p.Ile364Met variants (previously found in RPL patients in PMID: 27805902) have also been identified in the present work in women with PE and IUGR and with isolated IUGR, respectively.

Documented in FeRGI database- limited evidence for repeated implantation failure.
Sources: Expert list
Mendeliome v1.2755 FBXO43 Zornitza Stark Marked gene: FBXO43 as ready
Mendeliome v1.2755 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Mendeliome v1.2755 FBXO43 Zornitza Stark Classified gene: FBXO43 as Green List (high evidence)
Mendeliome v1.2755 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Mendeliome v1.2754 FBXO43 Zornitza Stark gene: FBXO43 was added
gene: FBXO43 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FBXO43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO43 were set to 34052850; 30878252; 34595750
Phenotypes for gene: FBXO43 were set to Oocyte/zygote/embryo maturation arrest 12, MIM# 619697; Spermatogenic failure 64, MIM# 619696
Review for gene: FBXO43 was set to GREEN
Added comment: Literature in OMIM: PMID: 34052850 (three different homozygous variants in 3 unrelated women; 30878252, 34595750 (two different families with different homozygous variants)
Sources: Expert list
Mendeliome v1.2753 ELL3 Zornitza Stark Marked gene: ELL3 as ready
Mendeliome v1.2753 ELL3 Zornitza Stark Gene: ell3 has been classified as Green List (High Evidence).
Mendeliome v1.2753 ELL3 Zornitza Stark Classified gene: ELL3 as Green List (high evidence)
Mendeliome v1.2753 ELL3 Zornitza Stark Gene: ell3 has been classified as Green List (High Evidence).
Mendeliome v1.2752 ELL3 Zornitza Stark gene: ELL3 was added
gene: ELL3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ELL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELL3 were set to 39820605
Phenotypes for gene: ELL3 were set to Pregnancy loss, recurrent, susceptibility to, MONDO:0000144, ELL3-related
Review for gene: ELL3 was set to GREEN
Added comment: PMID:39820605- 8 different heterozygous variants (5 missense, 3 splicing) in 8 unrelated couples who experienced consecutive early miscarriages due to embryonic aneuploidy. For the three splice variants, mini-gene splicing assays revealed that all led to abnormal splicing, and consequently premature termination of translation or exon skipping, consistent with LOF effect. Findings from functional analysis on human oocytes and knockout mouse oocytes overall supporting that ELL3 depletion increases the incidence of meiotic spindle abnormality and oocyte aneuploidy.
Sources: Expert list
Mendeliome v1.2751 CHEK1 Zornitza Stark Marked gene: CHEK1 as ready
Mendeliome v1.2751 CHEK1 Zornitza Stark Gene: chek1 has been classified as Green List (High Evidence).
Mendeliome v1.2751 CHEK1 Zornitza Stark Classified gene: CHEK1 as Green List (high evidence)
Mendeliome v1.2751 CHEK1 Zornitza Stark Gene: chek1 has been classified as Green List (High Evidence).
Mendeliome v1.2750 CHEK1 Zornitza Stark gene: CHEK1 was added
gene: CHEK1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CHEK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHEK1 were set to 33953335; 33948904
Phenotypes for gene: CHEK1 were set to Oocyte/zygote/embryo maturation arrest 21, MIM# 620610
Review for gene: CHEK1 was set to GREEN
Added comment: Literature in OMIM- PMID: 33953335; 33948904
- >3 unrelated with infertility due to zygote/embryo cleavage arrest with three different missense variants and 1 1bp deletion. Functional studies using transfection studies showed that all mutant increased cytoplasmic localization significantly greater kinase activity. Injection of all mutant cRNA into mouse zygotes with 2 distinct pronuclei also resulted in significantly decreased cleavage rates compared to wildtype.
Sources: Expert list
Mendeliome v1.2749 CDC25A Zornitza Stark Marked gene: CDC25A as ready
Mendeliome v1.2749 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Mendeliome v1.2749 CDC25A Zornitza Stark Classified gene: CDC25A as Green List (high evidence)
Mendeliome v1.2749 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Mendeliome v1.2748 CDC25A Zornitza Stark gene: CDC25A was added
gene: CDC25A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC25A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDC25A were set to 40342881; 30009144; 16720623
Phenotypes for gene: CDC25A were set to Spermatogenic failure, MONDO:0004983, CDC25A-related
Review for gene: CDC25A was set to GREEN
Added comment: i) PMID: 40342881- Five novel heterozygous variants (Lys500Asn in 8 cases, His459Leu in 12 cases, Ser485Asp, Thr503Ser, c.1434 + 5G>C) and one previously identified SNP (in 7 cases) in azoospermic males from the Bengali-speaking Indian population. qPCR analysis indicated downregulation of CDC25A mRNA expression in azoospermic patients relative to fertile controls. Relative expression levels of CDC25A were about 2.5-fold lower in azoospermic testicular tissue and semen samples, reflecting diminished transcriptional activity in affected patients. This reduction in gene expression may reflect a potential functional deficiency of CDC25A, contributing to spermatogenic arrest. The decreased level of CDC25A mRNA levels corresponds with the findings of pathogenic variants identified in azoospermic patients, thus solidifying the evidence of CDC25A mutations contributing to male infertility.

ii) PMID: 30009144,16720623- decreased expression of CDC25A observed in testicular biopsies from azoospermic men, suggesting association with meiotic arrest as the etiology of spermatogenic failure.
Sources: Literature
Mendeliome v1.2747 CAPS Zornitza Stark Marked gene: CAPS as ready
Mendeliome v1.2747 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2747 CAPS Zornitza Stark Classified gene: CAPS as Amber List (moderate evidence)
Mendeliome v1.2747 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2746 CAPS Zornitza Stark gene: CAPS was added
gene: CAPS was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CAPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPS were set to 30339840
Phenotypes for gene: CAPS were set to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CAPS-related
Review for gene: CAPS was set to AMBER
Added comment: PMID: 30339840- Homozygous p.L127Wfs in a consanguineous family of 3 sisters with unexplained RPL. In vitro study also showed that mRNA expression of CAPS was downregulated in decidual and placental villous tissues of RPL patients, and CAPS expression in CAPS–homo-919–transfected cells showed a significant decrease compared with the other groups. Transwell assay with Matrigel also revealed that CAPS–homo-919 could affect JAR cell invasion compared with NC (P < 0.01), which might impair trophoblast infiltration ability. An enzyme-linked immunosorbent assay showed that CAPS–homo-919 could induce a dramatic increase in PGE2 release from the RL95-2 cells (P < 0.05), compared with NC.
Sources: Expert list
Mendeliome v1.2745 C4BPA Zornitza Stark Marked gene: C4BPA as ready
Mendeliome v1.2745 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2745 C4BPA Zornitza Stark Classified gene: C4BPA as Amber List (moderate evidence)
Mendeliome v1.2745 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2744 C4BPA Zornitza Stark gene: C4BPA was added
gene: C4BPA was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C4BPA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: C4BPA were set to 23508668
Phenotypes for gene: C4BPA were set to recurrent pregnancy loss susceptibility MONDO:0000144, C4BPA-related
Review for gene: C4BPA was set to AMBER
Added comment: PMID: 23508668- Five unrelated female with history of recurrent RPL (<10 weeks) carrying het missnese variants (See table 3- G423E, R120H, I126T, P4Q).
- The I126T mutation in CCP2 of C4BP α-chain is of particular interest as it was found only in one patient but not in healthy controls. This rare mutation affected both expression level of C4BP α-chain as well as its function, i.e., degradation of C4b and C3b in solution.
R120H, found in two patients and no controls, increased the ability of C4BP to act as cofactor in degradation of C4b but decreased its activity in degradation of C3b both in solution and deposited on the cell surface. The other 2 variants have been observed in controls.
- Homozygous C4BP knockout mice often die during second or third pregnancy (unpublished observation). This would imply a pivotal role of this protein in maintenance of successful pregnancy, although the mechanism is not known.
Sources: Expert list
Mendeliome v1.2743 C11orf80 Zornitza Stark Marked gene: C11orf80 as ready
Mendeliome v1.2743 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2743 C11orf80 Zornitza Stark Classified gene: C11orf80 as Amber List (moderate evidence)
Mendeliome v1.2743 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2742 C11orf80 Zornitza Stark Tag new gene name tag was added to gene: C11orf80.
Mendeliome v1.2742 C11orf80 Zornitza Stark gene: C11orf80 was added
gene: C11orf80 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C11orf80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C11orf80 were set to 30388401; 36732965
Phenotypes for gene: C11orf80 were set to Recurrent hydatidiform mole 4, MIM # 618432
Review for gene: C11orf80 was set to AMBER
Added comment: Note: HGNC Approved Gene Symbol- TOP6BL

Literature in OMIM- PubMed: 30388401- Two unrelated females with RHMs carrying a homozygous p.Glu262∗ and p.Ser501Pro, respectively.

New paper (biallelic variants for OZEMA/NOA)
i) PMID: 36732965- A homozygous LOF p.E162* in four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility. Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient.
Sources: Expert list
Mendeliome v1.2741 BCORL1 Zornitza Stark Phenotypes for gene: BCORL1 were changed from Shukla-Vernon syndrome, MIM#301029 to Shukla-Vernon syndrome, MIM#301029; Spermatogenic failure, MONDO:0004983, BCORL1-related
Mendeliome v1.2740 BCORL1 Zornitza Stark Publications for gene: BCORL1 were set to 24123876; 30941876
Mendeliome v1.2739 BCORL1 Zornitza Stark Mode of inheritance for gene: BCORL1 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2738 BCORL1 Zornitza Stark Classified gene: BCORL1 as Green List (high evidence)
Mendeliome v1.2738 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Mendeliome v1.2737 BCORL1 Zornitza Stark edited their review of gene: BCORL1: Added comment: Association with spermatogenic failure:

i) PMID: 38342987- novel hemizygous nonsense variant (c.1564G > T:p.Glu522*) in a male patient with oligoasthenoteratozoospermia (OAT) from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Also identified four hemizygous missense variants (c.2615T > G:p.Val872Gly, c.2669G > A:p.Arg890Gln, c.3164A > G:p.Asp1055Gly and c.3344C > T:p.Pro1115Leu) in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%). They hypothesized that the BCORL1 (c.2615 T > G, c.2669G > A, c.3164A > G, c.3344C > T) missense mutations may have led to an accumulation of dysfunctional toxic proteins that resulted in a more severe male infertility phenotype in the patient (NOA).

ii) PMID: 32376790- Hemizygous missense variant in a male patient with NOA without other diseases, which also found that the knockout of Bcorl1 in mice resulted in OAT with the abnormal brain development. It had not been previously linked to male infertility. This study demonstrates, for the first time, that loss of Bcorl1 causes spermatogenesis failure.

iii) PMID: 39267058- hemizygous missense variant (p.Arg19Gln) in a infertile male with oliogasthenozoospermia, no functional data

iv) PMID: 39189935- novel hemizygous missense variant (p.G1391R) and a recurrent variant (p.V872G) in BCORL1 from four OAT patients. Functional assays showed that the variants disturb the transcription of spermatogenetic genes such as SYCE1 and DAZL, impair the interaction with HDAC7, and cause epigenetic changes such as changes in level of histone modification with different extent, including the enhancement in acetylation of H3K14, and the reduction in acetylation of H4K5 and H4K8.; Changed rating: GREEN; Changed publications: 24123876, 30941876, 38342987, 32376790, 39267058, 39189935; Changed phenotypes: Shukla-Vernon syndrome, MIM#301029, Spermatogenic failure, MONDO:0004983, BCORL1-related
Mendeliome v1.2737 BCORL1 Zornitza Stark changed review comment from: Classified as LIMITED by ClinGen.; to: Classified as LIMITED by ClinGen, Shukla-Vernon syndrome, MIM#301029
Mendeliome v1.2737 ASTL Zornitza Stark Publications for gene: ASTL were set to 34704130
Mendeliome v1.2736 ASTL Zornitza Stark Classified gene: ASTL as Green List (high evidence)
Mendeliome v1.2736 ASTL Zornitza Stark Gene: astl has been classified as Green List (High Evidence).
Mendeliome v1.2735 ASTL Zornitza Stark edited their review of gene: ASTL: Changed rating: GREEN
Mendeliome v1.2735 ASTL Zornitza Stark edited their review of gene: ASTL: Added comment: New papers (biallelic variants)
i) PMID: 37640117 - Novel compound heterozygous missense variants (p.Arg117Cys and p.Arg274Trp) in a Chinese woman with primary infertility and polyspermy in IVF. Moreover, transfection studies using CHO-K1 cells indicated that mutant cells showed abnormal ovastacin zymogen activation or decreased enzyme stability.

ii) PMID: 37133443- Biallelic variants in four independent affected individuals with primary infertility. The frameshift variants significantly decreased the quantity of ASTL protein in vitro. And all missense variants affected the enzymatic activity that cleaves ZP2 in mouse egg in vitro. Three knock-in female mice (corresponding to three missense variants in patients) all show subfertility due to low embryo developmental potential.; Changed publications: 34704130, 37640117, 37133443; Changed phenotypes: Oocyte maturation defect 11, MIM# 619643
Mendeliome v1.2735 ACTL7A Zornitza Stark Marked gene: ACTL7A as ready
Mendeliome v1.2735 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Mendeliome v1.2735 ACTL7A Zornitza Stark Classified gene: ACTL7A as Green List (high evidence)
Mendeliome v1.2735 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Mendeliome v1.2734 ACTL7A Zornitza Stark gene: ACTL7A was added
gene: ACTL7A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ACTL7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL7A were set to 32923619; 34727571; 36593593; 37004249; 37991128; 36574082; 35921706
Phenotypes for gene: ACTL7A were set to Spermatogenic failure 86, #MIM 620499
Review for gene: ACTL7A was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 32923619, 34727571, 36593593, 37004249- different biallelic variants reported in >3 unrelated infertile men

Other papers:
i) PMID: 37991128 (2025)- two infertile males with com het p.R373H/p.G402S and hom p.R373C. All located within actin domain and predicted to be pathogenic.The protein expression of actin-like protein 7A was absent in affected spermatozoa by using immunofluorescence staining and western blotting.

ii)PMID: 36574082 (2023)- Two infertile brothers with hom p.D75A with teratozoospermia and fertilization failure. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. The variant also caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients.

iii) PMID: 35921706 (2022)- Actl7a gene knockout (KO) mice led to malformed formation of sperm acrosomes, male infertility, fertilization failure during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and reduced sperm-zona pellucida (ZP) binding ability. Localization of the zona pellucida binding protein (ZPBP) was altered in the sperm of Actl7a homozygous KO male mice.
Sources: Expert list
Mendeliome v1.2733 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Mendeliome v1.2732 MARK2 Zornitza Stark reviewed gene: MARK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 76, MIM# 621285; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2732 TRIM63 Zornitza Stark Phenotypes for gene: TRIM63 were changed from Hypertrophic cardiomyopathy, MONDO:0005045 to Cardiomyopathy, familial hypertrophic, 31, MIM# 621270
Mendeliome v1.2731 TRIM63 Zornitza Stark edited their review of gene: TRIM63: Changed phenotypes: Cardiomyopathy, familial hypertrophic, 31, MIM# 621270
Mendeliome v1.2731 PDE1B Zornitza Stark Marked gene: PDE1B as ready
Mendeliome v1.2731 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Mendeliome v1.2731 PDE1B Zornitza Stark Phenotypes for gene: PDE1B were changed from movement disorder, MONDO:0005395 to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PDE1B-related
Mendeliome v1.2730 PDE1B Zornitza Stark Classified gene: PDE1B as Green List (high evidence)
Mendeliome v1.2730 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Mendeliome v1.2729 PDE1B Zornitza Stark reviewed gene: PDE1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Complex neurodevelopmental disorder with motor features, MONDO:0100516, PDE1B-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2729 PDE1B Achchuthan Shanmugasundram gene: PDE1B was added
gene: PDE1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE1B were set to 40492975
Phenotypes for gene: PDE1B were set to movement disorder, MONDO:0005395
Review for gene: PDE1B was set to GREEN
Added comment: PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total.

They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability. Functional evidence is also available for these variants.
Sources: Literature
Mendeliome v1.2729 ATG4D Zornitza Stark Phenotypes for gene: ATG4D were changed from Neurodevelopmental disorder, MONDO:0700092, ATG4D-related to Neurodevelopmental disorder, MONDO:0700092, ATG4D-related; Spermatogenic failure 101, MIM# 621269
Mendeliome v1.2728 ATG4D Zornitza Stark Publications for gene: ATG4D were set to PMID: 36765070
Mendeliome v1.2727 ATG4D Zornitza Stark edited their review of gene: ATG4D: Added comment: PMID 33988247: 4 individuals from 3 unrelated families, all variants are missense, limited functional data.; Changed publications: 33988247; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ATG4D-related, Spermatogenic failure 101, MIM# 621269
Mendeliome v1.2727 PMEPA1 Zornitza Stark Classified gene: PMEPA1 as Green List (high evidence)
Mendeliome v1.2727 PMEPA1 Zornitza Stark Gene: pmepa1 has been classified as Green List (High Evidence).
Mendeliome v1.2726 PMEPA1 Zornitza Stark edited their review of gene: PMEPA1: Changed rating: GREEN
Mendeliome v1.2726 LIFR Ava Stevenson reviewed gene: LIFR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, MIM# 601559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2726 ITPR3 Zornitza Stark Phenotypes for gene: ITPR3 were changed from Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111; Combined immunodeficiency, MONDO:0015131, ITPR3-related to Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111; Combined immunodeficiency, MONDO:0015131, ITPR3-related; Immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, MIM# 621254
Mendeliome v1.2725 ITPR3 Zornitza Stark Publications for gene: ITPR3 were set to 32949214; 24627108; 36302985
Mendeliome v1.2724 ITPR3 Zornitza Stark edited their review of gene: ITPR3: Added comment: PMIDs 36302985, 39270020, 39560673: More than 10 individuals reported with heterozygous variant and combined immunodeficiency +/- ectodermal features and neuropathy.; Changed publications: 32949214, 24627108, 36302985, 36302985, 39270020, 39560673; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111, Combined immunodeficiency, MONDO:0015131, ITPR3-related, Immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, MIM# 621254
Mendeliome v1.2724 LRP6 Zornitza Stark Phenotypes for gene: LRP6 were changed from Tooth agenesis, selective, 7, MIM# 616724 to Tooth agenesis, selective, 7, MIM# 616724; Exudative vitreoretinopathy 8, MIM# 621268
Mendeliome v1.2723 LRP6 Zornitza Stark Publications for gene: LRP6 were set to
Mendeliome v1.2722 LRP6 Zornitza Stark reviewed gene: LRP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 34896607; Phenotypes: Exudative vitreoretinopathy 8, MIM# 621268; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2722 FASTKD5 Zornitza Stark Marked gene: FASTKD5 as ready
Mendeliome v1.2722 FASTKD5 Zornitza Stark Gene: fastkd5 has been classified as Green List (High Evidence).
Mendeliome v1.2722 FASTKD5 Zornitza Stark Phenotypes for gene: FASTKD5 were changed from Leigh syndrome MONDO:0009723 to Leigh syndrome MONDO:0009723, FASTKD5-related
Mendeliome v1.2721 DST Zornitza Stark Phenotypes for gene: DST were changed from Neuropathy, hereditary sensory and autonomic, type VI, MIM#614653; Epidermolysis bullosa simplex, autosomal recessive 2, MIM#615425 to Neuropathy, hereditary sensory and autonomic, type VI, MIM#614653; Epidermolysis bullosa simplex, autosomal recessive 2, MIM#615425; congenital myopathy MONDO:0019952, DST-related
Mendeliome v1.2720 DST Zornitza Stark Publications for gene: DST were set to 22522446; 30371979; 28468842
Mendeliome v1.2719 DST Chirag Patel reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40497796; Phenotypes: congenital myopathy MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2719 FASTKD5 Chirag Patel Classified gene: FASTKD5 as Green List (high evidence)
Mendeliome v1.2719 FASTKD5 Chirag Patel Gene: fastkd5 has been classified as Green List (High Evidence).
Mendeliome v1.2718 FASTKD5 Chirag Patel gene: FASTKD5 was added
gene: FASTKD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FASTKD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FASTKD5 were set to PMID: 40499538
Phenotypes for gene: FASTKD5 were set to Leigh syndrome MONDO:0009723
Review for gene: FASTKD5 was set to GREEN
Added comment: 3 unrelated individuals with Leigh syndrome (1 x severe/early-onset/fatal, 1 x milder/childhood-onset, 1 x adult-onset). WES identified compound heterozygous variants in FASTKD5 gene (3 x missense variants, 2 x frameshift variants leading to a premature stop codon). The FASTKD5 gene codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript.

Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense variants, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. 2/3 missense variants resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability.
Sources: Literature
Mendeliome v1.2717 GLIS1 Bryony Thompson Phenotypes for gene: GLIS1 were changed from Increased ocular pressure; Glaucoma to Increased ocular pressure; Glaucoma MONDO:0005041
Mendeliome v1.2716 GINS2 Bryony Thompson Phenotypes for gene: GINS2 were changed from Meier-Gorlin syndrome with craniosynostosis to Meier-Gorlin syndrome with craniosynostosis MONDO:0016817
Mendeliome v1.2715 GATC Bryony Thompson Phenotypes for gene: GATC were changed from Mitochondrial cardiomyopathy to Mitochondrial cardiomyopathy; inborn mitochondrial metabolism disorder MONDO:0004069
Mendeliome v1.2714 FEM1B Zornitza Stark Phenotypes for gene: FEM1B were changed from Syndromic disease MONDO:0002254, FEM1B-related to Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, MIM# 621263
Mendeliome v1.2713 FEM1B Zornitza Stark edited their review of gene: FEM1B: Changed phenotypes: Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, MIM# 621263
Mendeliome v1.2713 DOT1L Zornitza Stark Phenotypes for gene: DOT1L were changed from Neurodevelopmental disorder, MONDO:0700092, DOT1L-related to Nil-Deshwan neurodevelopmental syndrome, MIM# 621265
Mendeliome v1.2712 DOT1L Zornitza Stark edited their review of gene: DOT1L: Changed phenotypes: Nil-Deshwan neurodevelopmental syndrome, MIM# 621265
Mendeliome v1.2712 RPL17 Zornitza Stark Marked gene: RPL17 as ready
Mendeliome v1.2712 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Mendeliome v1.2712 RPL17 Zornitza Stark Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia, MONDO:0015253 to Diamond-Blackfan anaemia 22, MIM# 621262
Mendeliome v1.2711 RPL17 Zornitza Stark Classified gene: RPL17 as Green List (high evidence)
Mendeliome v1.2711 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Mendeliome v1.2710 RPL17 Zornitza Stark reviewed gene: RPL17: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anemia 22, MIM# 621262; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2710 GATB Bryony Thompson Phenotypes for gene: GATB were changed from Mitochondrial cardiomyopathy to inborn mitochondrial metabolism disorder MONDO:0004069
Mendeliome v1.2709 GATB Bryony Thompson Publications for gene: GATB were set to 30283131
Mendeliome v1.2708 GATB Bryony Thompson Classified gene: GATB as Amber List (moderate evidence)
Mendeliome v1.2708 GATB Bryony Thompson Gene: gatb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2707 GATB Bryony Thompson reviewed gene: GATB: Rating: AMBER; Mode of pathogenicity: None; Publications: 30283131, 38703036; Phenotypes: inborn mitochondrial metabolism disorder MONDO:0004069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2707 GAS1 Bryony Thompson Phenotypes for gene: GAS1 were changed from Holoprosencephaly to Holoprosencephaly MONDO:0016296
Mendeliome v1.2706 GALM Bryony Thompson Phenotypes for gene: GALM were changed from galactosaemia; type IV galactosaemia to galactosaemia; type IV galactosaemia MONDO:0030105
Mendeliome v1.2705 FST Bryony Thompson Phenotypes for gene: FST were changed from Cleft lip and palate to Cleft lip and palate MONDO:0016044
Mendeliome v1.2704 FRY Bryony Thompson Phenotypes for gene: FRY were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2703 FOXR1 Bryony Thompson Phenotypes for gene: FOXR1 were changed from Postnatal microcephaly, progressive brain atrophy and global developmental delay to Postnatal microcephaly, progressive brain atrophy and global developmental delay; Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2702 FOXP4 Bryony Thompson Phenotypes for gene: FOXP4 were changed from Neurodevelopmental disorder; multiple congenital abnormalities to Complex neurodevelopmental disorder MONDO:0100038
Mendeliome v1.2701 LONP1 Zornitza Stark Phenotypes for gene: LONP1 were changed from CODAS syndrome, MIM#600373; Mitochondrial cytopathy to CODAS syndrome, MIM#600373; mitochondrial disease (MONDO:0044970), LONP1-related
Mendeliome v1.2700 LONP1 Zornitza Stark Publications for gene: LONP1 were set to 31636596
Mendeliome v1.2699 LONP1 Zornitza Stark Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2698 LONP1 Lauren Rogers Deleted their comment
Mendeliome v1.2698 LONP1 Lauren Rogers changed review comment from: ew reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301.

- PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures.
p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case)

- PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly.
- p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication).
- p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case)

- p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication)

LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded.; to: New reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301.

- PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures.
p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case)

- PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly.
- p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication).
- p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case)

- p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication)

LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded.
Mendeliome v1.2698 LONP1 Lauren Rogers commented on gene: LONP1: ew reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301.

- PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures.
p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case)

- PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly.
- p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication).
- p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case)

- p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication)

LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded.
Mendeliome v1.2698 LONP1 Lauren Rogers reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36353900, 31923470; Phenotypes: mitochondrial disease (MONDO:0044970), LONP1-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2698 BHLHA9 Zornitza Stark Tag SV/CNV tag was added to gene: BHLHA9.
Mendeliome v1.2698 NEXN Zornitza Stark Phenotypes for gene: NEXN were changed from Lethal fetal cardiomyopathy; Hydrops fetalis; Cardiomyopathy, dilated 1CC - MIM#613122 to Cardiomyopathy, dilated, 2M, autosomal recessive, MIM# 621261; Cardiomyopathy, dilated 1CC - MIM#613122
Mendeliome v1.2697 NEXN Zornitza Stark reviewed gene: NEXN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 2M, autosomal recessive, MIM# 621261; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2697 BHLHA9 Sarah Milton changed review comment from: BHLHA9 encodes a transcription factor involved in embryonic limb development, essential for interdigital apoptosis in central limb mesenchyme cells.

Duplications encompassing a 11.8kb critical region involving BHLHA9 have been reported in a number of publications to result in split hand foot malformation with long bone deficiency in at least 50 affected individuals. This has segregated within families of affected individuals on a number of occasions.

However, penetrance of approximately 50% has been noted with significant intrafamilial variability. It should also be noted that in gnomad v4 structural variants there are 15 dups encompassing this same region in het individuals with a DGV gold track demonstrating dups in 3 individuals.

Duan et al 2022 (PMID: 36035248) proposed copy number gains might enhance the regulatory potential as a transcription factor; thus, the apoptosis activity may be overly or ectopically increased in central limb mesenchymal cells during limb development. Authors proposed a gene dosage change with increasing copies of BHLHA9 showing increasing penetrance using examples of individuals with homozygous duplications or heterozygous triplications.; to: BHLHA9 encodes a transcription factor involved in embryonic limb development, essential for interdigital apoptosis in central limb mesenchyme cells.

Duplications encompassing a 11.8kb critical region involving BHLHA9 have been reported in a number of publications to result in split hand foot malformation with long bone deficiency in at least 50 affected individuals. This has segregated within families of affected individuals on a number of occasions.

However, penetrance of approximately 50% has been noted with significant intrafamilial variability. It should also be noted that in gnomad v4 structural variants there are 15 dups encompassing this same region in het individuals with a DGV gold track demonstrating dups in 3 individuals.

Duan et al 2022 (PMID: 36035248) proposed copy number gains might enhance the regulatory potential as a transcription factor; thus, the apoptotic activity may be overly or ectopically increased in central limb mesenchymal cells during limb development. Authors proposed a gene dosage change with increasing copies of BHLHA9 showing increasing penetrance using examples of individuals with homozygous duplications or heterozygous triplications.
Mendeliome v1.2697 BHLHA9 Sarah Milton changed review comment from: BHLHA9 encodes a transcription factor involved in embryonic limb development, essential for interdigital apoptosis in central limb mesenchyme cells.

Duplications encompassing a 11.8kb critical region involving BHLHA9 have been reported in a number of publications to result in split hand foot malformation with long bone deficiency in at least 50 affected individuals. This has segregated in affected families on a number of occasions.

However, penetrance of approximately 50% has been noted with significant intrafamilial variability. It should also be noted that in gnomad v4 structural variants there are 15 dups encompassing this same region in het individuals with a DGV gold track demonstrating dups in 3 individuals.

Duan et al 2022 (PMID: 36035248) proposed copy number gains might enhance the regulatory potential as a transcription factor; thus, the apoptosis activity may be overly or ectopically increased in central limb mesenchymal cells during limb development. Authors proposed a gene dosage change with increasing copies of BHLHA9 showing increasing penetrance using examples of individuals with homozygous duplications or heterozygous triplications.; to: BHLHA9 encodes a transcription factor involved in embryonic limb development, essential for interdigital apoptosis in central limb mesenchyme cells.

Duplications encompassing a 11.8kb critical region involving BHLHA9 have been reported in a number of publications to result in split hand foot malformation with long bone deficiency in at least 50 affected individuals. This has segregated within families of affected individuals on a number of occasions.

However, penetrance of approximately 50% has been noted with significant intrafamilial variability. It should also be noted that in gnomad v4 structural variants there are 15 dups encompassing this same region in het individuals with a DGV gold track demonstrating dups in 3 individuals.

Duan et al 2022 (PMID: 36035248) proposed copy number gains might enhance the regulatory potential as a transcription factor; thus, the apoptosis activity may be overly or ectopically increased in central limb mesenchymal cells during limb development. Authors proposed a gene dosage change with increasing copies of BHLHA9 showing increasing penetrance using examples of individuals with homozygous duplications or heterozygous triplications.
Mendeliome v1.2697 BHLHA9 Sarah Milton reviewed gene: BHLHA9: 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: 22147889, 23790188, 29970136, 31200655, 36035248, 36028842, 36551834; Phenotypes: Split-hand/foot malformation with long bone deficiency 3 MIM#612576; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2697 PIGU Zornitza Stark Classified gene: PIGU as Amber List (moderate evidence)
Mendeliome v1.2697 PIGU Zornitza Stark Gene: pigu has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2696 PIGU Zornitza Stark edited their review of gene: PIGU: Added comment: Downgrade to Amber in light of ClinGen assessment. Only 2 variants reported.; Changed rating: AMBER
Mendeliome v1.2696 POLD3 Zornitza Stark Classified gene: POLD3 as Amber List (moderate evidence)
Mendeliome v1.2696 POLD3 Zornitza Stark Gene: pold3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2695 NFE2 Zornitza Stark Marked gene: NFE2 as ready
Mendeliome v1.2695 NFE2 Zornitza Stark Gene: nfe2 has been classified as Red List (Low Evidence).
Mendeliome v1.2695 NFE2 Zornitza Stark Phenotypes for gene: NFE2 were changed from thrombocytopenia MONDO:0002049 to thrombocytopenia MONDO:0002049, NFE2-related
Mendeliome v1.2694 NFE2 Zornitza Stark Classified gene: NFE2 as Red List (low evidence)
Mendeliome v1.2694 NFE2 Zornitza Stark Gene: nfe2 has been classified as Red List (Low Evidence).
Mendeliome v1.2693 FAAH2 Zornitza Stark Tag disputed tag was added to gene: FAAH2.
Mendeliome v1.2693 FAAH2 Sangavi Sivagnanasundram reviewed gene: FAAH2: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008804; Phenotypes: X-linked complex neurodevelopmental disorder MONDO:0100148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2693 NFE2 Sangavi Sivagnanasundram gene: NFE2 was added
gene: NFE2 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: NFE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFE2 were set to 31951293
Phenotypes for gene: NFE2 were set to thrombocytopenia MONDO:0002049
Review for gene: NFE2 was set to RED
Added comment: Classified as Limited by Hemostasis Thrombosis GCEP on 16/06/2025

Homozygous frameshift variant reported in a single proband (c.952delA, p.T318fsX326 - absent in gnomAD v4.1).
Sources: ClinGen
Mendeliome v1.2693 SLFN14 Sangavi Sivagnanasundram reviewed gene: SLFN14: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006205; Phenotypes: platelet-type bleeding disorder 20 MONDO:0014830; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2693 ERLIN2 Sangavi Sivagnanasundram reviewed gene: ERLIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary spastic paraplegia 18 MONDO:0012639; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2693 POLD3 Sangavi Sivagnanasundram reviewed gene: POLD3: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008872; Phenotypes: immunodeficiency 122 MONDO:0971151; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2693 PIGU Sangavi Sivagnanasundram reviewed gene: PIGU: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005799; Phenotypes: glycosylphosphatidylinositol biosynthesis defect 21 MONDO:0032824; Mode of inheritance: None
Mendeliome v1.2693 FAAP100 Zornitza Stark Phenotypes for gene: FAAP100 were changed from Fanconi anaemia, MONDO:0019391, FAAP100-related to Fanconi anaemia, complementation group X, MIM# 621258
Mendeliome v1.2692 FAAP100 Zornitza Stark edited their review of gene: FAAP100: Changed phenotypes: Fanconi anaemia, complementation group X, MIM# 621258
Mendeliome v1.2692 TMEM63B Zornitza Stark Phenotypes for gene: TMEM63B were changed from developmental and epileptic encephalopathy, MONDO:0100062, TMEM63B-related to Developmental and epileptic encephalopathy 118, MIM#621250
Mendeliome v1.2691 LGI1 Krithika Murali Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1, MIM# 6000512; Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related to Epilepsy, familial temporal lobe, 1, MIM# 6000512; Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related
Mendeliome v1.2690 LGI1 Krithika Murali Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1, MIM# 6000512 to Epilepsy, familial temporal lobe, 1, MIM# 6000512; Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related
Mendeliome v1.2689 LGI1 Krithika Murali Mode of inheritance for gene: LGI1 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 v1.2688 LGI1 Krithika Murali reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40455867; Phenotypes: Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2688 ELFN1 Krithika Murali Classified gene: ELFN1 as Green List (high evidence)
Mendeliome v1.2688 ELFN1 Krithika Murali Gene: elfn1 has been classified as Green List (High Evidence).
Mendeliome v1.2687 ELFN1 Krithika Murali Marked gene: ELFN1 as ready
Mendeliome v1.2687 ELFN1 Krithika Murali Gene: elfn1 has been classified as Red List (Low Evidence).
Mendeliome v1.2687 ELFN1 Krithika Murali gene: ELFN1 was added
gene: ELFN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELFN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ELFN1 were set to PMID: 40576023
Phenotypes for gene: ELFN1 were set to Neurodevelopmental disorder, MONDO:0700092, ELFN1-related
Review for gene: ELFN1 was set to GREEN
Added comment: PMID: 40576023 report 8 individuals from 5 unrelated families and 6 previously reported patients from 2 families. Most patients had homozygous biallelic deletions / PTCs in ELFN1 (including one involving 5'UTR). One family had biallelic missense variants,

All patients had dev delay/ID. Other features included autism/ADHD/behavioural issues, hypotonia/muscle weakness, paediatric-onset ataxia/movement disorder and epilepsy.

Supportive functional modelling in mice and zebrafish. Some emerging evidence for haploinsufficiency.
Sources: Literature
Mendeliome v1.2686 TEX14 Bryony Thompson Marked gene: TEX14 as ready
Mendeliome v1.2686 TEX14 Bryony Thompson Gene: tex14 has been classified as Green List (High Evidence).
Mendeliome v1.2686 TEX14 Bryony Thompson Classified gene: TEX14 as Green List (high evidence)
Mendeliome v1.2686 TEX14 Bryony Thompson Gene: tex14 has been classified as Green List (High Evidence).
Mendeliome v1.2685 TEX14 Bryony Thompson gene: TEX14 was added
gene: TEX14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEX14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEX14 were set to 16549803; 40492599; 28206990; 29790874; 36017582
Phenotypes for gene: TEX14 were set to Spermatogenic failure MONDO:0004983, TEX14-related
Review for gene: TEX14 was set to GREEN
Added comment: Multiple probands reported with biallelic LoF variants and a supporting mouse model.
Sources: Literature
Mendeliome v1.2684 WDR91 Bryony Thompson Phenotypes for gene: WDR91 were changed from Hydrocephalus; cerebellar hypoplasia; hygroma to Complex neurodevelopmental disorder MONDO:0100038
Mendeliome v1.2683 WDR91 Bryony Thompson Publications for gene: WDR91 were set to 34028500; 28860274; 32732226; 28969387
Mendeliome v1.2682 WDR91 Bryony Thompson Classified gene: WDR91 as Green List (high evidence)
Mendeliome v1.2682 WDR91 Bryony Thompson Gene: wdr91 has been classified as Green List (High Evidence).
Mendeliome v1.2681 WDR91 Bryony Thompson reviewed gene: WDR91: Rating: GREEN; Mode of pathogenicity: None; Publications: 32732226, 38041506, 34791078, 40550703, 28860274, 34028500, ClinVar: SCV000965687.1; Phenotypes: Complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2681 MIB1 Zornitza Stark Classified gene: MIB1 as Red List (low evidence)
Mendeliome v1.2681 MIB1 Zornitza Stark Gene: mib1 has been classified as Red List (Low Evidence).
Mendeliome v1.2680 ADD1 Zornitza Stark Classified gene: ADD1 as Amber List (moderate evidence)
Mendeliome v1.2680 ADD1 Zornitza Stark Gene: add1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2679 ADAM23 Zornitza Stark Marked gene: ADAM23 as ready
Mendeliome v1.2679 ADAM23 Zornitza Stark Gene: adam23 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2679 ADAM23 Zornitza Stark Classified gene: ADAM23 as Amber List (moderate evidence)
Mendeliome v1.2679 ADAM23 Zornitza Stark Gene: adam23 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2678 SIDT2 Zornitza Stark Marked gene: SIDT2 as ready
Mendeliome v1.2678 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2678 SIDT2 Zornitza Stark Classified gene: SIDT2 as Amber List (moderate evidence)
Mendeliome v1.2678 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2677 SREK1 Zornitza Stark Marked gene: SREK1 as ready
Mendeliome v1.2677 SREK1 Zornitza Stark Gene: srek1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2677 SREK1 Zornitza Stark Classified gene: SREK1 as Amber List (moderate evidence)
Mendeliome v1.2677 SREK1 Zornitza Stark Gene: srek1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2676 NSUN3 Zornitza Stark Publications for gene: NSUN3 were set to 27356879; 32488845
Mendeliome v1.2675 NSUN3 Zornitza Stark Classified gene: NSUN3 as Green List (high evidence)
Mendeliome v1.2675 NSUN3 Zornitza Stark Gene: nsun3 has been classified as Green List (High Evidence).
Mendeliome v1.2674 POC5 Zornitza Stark Phenotypes for gene: POC5 were changed from Idiopathic scoliosis; retinitis pigmentosa; short stature; microcephaly; recurrent glomerulonephritis to Ciliopathy, MONDO:0005308, POC5-related; Scoliosis, MONDO:0005392, POC5-related
Mendeliome v1.2673 POC5 Zornitza Stark Publications for gene: POC5 were set to 25642776; 29272404
Mendeliome v1.2672 POC5 Zornitza Stark reviewed gene: POC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40590205, 29272404; Phenotypes: Ciliopathy, MONDO:0005308, POC5-related, Scoliosis, MONDO:0005392, POC5-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2672 FGF4 Zornitza Stark Phenotypes for gene: FGF4 were changed from Jeune Syndrome, FGF4-related, MONDO:0018770 to Short-rib thoracic dysplasia 22 without polydactyly, MIM# 621260
Mendeliome v1.2671 FGF4 Zornitza Stark reviewed gene: FGF4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 22 without polydactyly, MIM# 621260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2671 RDH8 Zornitza Stark Marked gene: RDH8 as ready
Mendeliome v1.2671 RDH8 Zornitza Stark Gene: rdh8 has been classified as Red List (Low Evidence).
Mendeliome v1.2671 RDH8 Zornitza Stark gene: RDH8 was added
gene: RDH8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RDH8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH8 were set to 37628710; 18048336; 22621924
Phenotypes for gene: RDH8 were set to Stargardt disease 5, MIM# 621259
Review for gene: RDH8 was set to RED
Added comment: Two siblings reported with homozygous splicing variant and Stargardt disease, some supportive functional data.
Sources: Literature
Mendeliome v1.2670 CFAP221 Zornitza Stark Phenotypes for gene: CFAP221 were changed from Primary ciliary dyskinesia to Ciliary dyskinesia, primary, 55, MIM# 279000
Mendeliome v1.2669 CFAP221 Zornitza Stark Publications for gene: CFAP221 were set to 31636325
Mendeliome v1.2668 CFAP221 Zornitza Stark Classified gene: CFAP221 as Green List (high evidence)
Mendeliome v1.2668 CFAP221 Zornitza Stark Gene: cfap221 has been classified as Green List (High Evidence).
Mendeliome v1.2667 CFAP221 Zornitza Stark edited their review of gene: CFAP221: Added comment: Five additional individuals reported, although two of them are homozygous for the same variant.; Changed rating: GREEN; Changed publications: 31636325, 39362668, 40250778, 38960684, 40272718; Changed phenotypes: Ciliary dyskinesia, primary, 55, MIM# 279000
Mendeliome v1.2667 NSUN3 Sangavi Sivagnanasundram changed review comment from: Four other unrelated families reported with biallelic variants and presented with optic neuropathy of varying severities and oxidative phosphorylation deficiency. All affected individuals presented with a range of other phenotypes including but not limited to ID/DD, cardiac abnormalities, skeletal abnormalities and hearing impairment. Two families (Family 1 and Family 3) show segregation evidence across affected individuals however consanguinity was noted.; to: Four other unrelated families reported with biallelic variants and presented with optic neuropathy of varying severities and oxidative phosphorylation deficiency. All affected individuals presented with a range of other phenotypes including but not limited to ID/DD, cardiac abnormalities, skeletal abnormalities and hearing impairment. Two families (Family 1 and Family 3) show segregation evidence across affected individuals - consanguinity was noted in both families.
Mendeliome v1.2667 NSUN3 Sangavi Sivagnanasundram reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 40465263; Phenotypes: combined oxidative phosphorylation deficiency 48 MONDO:0033566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2667 SREK1 Sangavi Sivagnanasundram gene: SREK1 was added
gene: SREK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SREK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SREK1 were set to 40549565
Phenotypes for gene: SREK1 were set to Prader-Willi-like syndrome, SREK1-related MONDO:0008300
Review for gene: SREK1 was set to AMBER
Added comment: Three Pakistani probands from three consanguineous families identified with biallelic variants in SREK1. Affected individuals presented with hyperphagic obesity and neurodevelopmental delay. They also presented with psychological and behavioural issues and were phenotypically similar to Prader-Willi affected individuals.

Further testing was conducted using human induced pluripotent stem cell (iPSC) -derived neurons followed by RNA sequencing conducted on the neurons.
The results of the assay was suggestive that variants located in the RNA recognition domain (residues 19–96 and 173–256) of SREK1 downregulation of SNORD115 and SNORD116 leading to Prader-Willi-like phenotype however proper validation and controls weren't used.

No relevant mouse models were identified on IMPC (international mouse phenotype consortium) to further support gene-disease association there gene reviewed as Amber.

Variants identified in SREK1 - AF's from gnomADv4.1
P95L - absent in gnomAD v4.1
T194M - EAS PopMax AF - 0.03787% (47 hets)
E601K - SAS PopMax AF - 0.01319% (12 hets)
Sources: Literature
Mendeliome v1.2667 SIDT2 Sarah Milton gene: SIDT2 was added
gene: SIDT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIDT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SIDT2 were set to PMID: 40541391
Phenotypes for gene: SIDT2 were set to Lysosomal storage disease, MONDO:0002561, SIDT2-related
Review for gene: SIDT2 was set to AMBER
Added comment: Encodes a lysosomal membrane protein involved in trafficking of RNA into the lysosome for degradation via RNAutophagy.

1 affected individual described in PMID: 40541391 with two variants in SIDT2 presenting with progressive neurological decline in childhood with poor coordination, dysarthria, ataxia, cerebellar atrophy and cognitive decline. One variant confirmed to be maternally inherited, the other inheritance was unknown due to lack of availability of family members (as such phase not confirmed). Variants were c.1586G>A (?listed as p.Arg529Trp however protein consequence should be p.Arg529Gln) and c.2032C>T|p.Arg678Trp.

Functional studies of patient fibroblasts showed markers of autophagy impairment and mouse models with reduced expression of SIDT2 had signs of progressive incoordination.
LOF proposed mechanism.
Sources: Literature
Mendeliome v1.2667 ADAM23 Sarah Milton changed review comment from: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature; to: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 form a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature
Mendeliome v1.2667 ADAM23 Sarah Milton changed review comment from: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature; to: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature
Mendeliome v1.2667 ADAM23 Sarah Milton gene: ADAM23 was added
gene: ADAM23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAM23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAM23 were set to (PMID: 40455867)
Phenotypes for gene: ADAM23 were set to Neonatal-onset developmental and epileptic encephalopathy, MONDO:0100455, ADAM23-related
Review for gene: ADAM23 was set to AMBER
Added comment: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature
Mendeliome v1.2667 ADD1 Ava Stevenson reviewed gene: ADD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34906466; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2667 MIB1 Ava Stevenson reviewed gene: MIB1: Rating: RED; 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: 23033978, 23314057, 33057194, 30322850, 37405741, 39057643; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2667 C10orf71 Zornitza Stark reviewed gene: C10orf71: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1QQ, MIM# 621251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2667 CD274 Zornitza Stark Phenotypes for gene: CD274 were changed from Immune dysregulation, autoimmunity and auto inflammation, MONDO:0957790 to Autoimmune disease, multisystem, infantile-onset, 5, MIM# 621235
Mendeliome v1.2666 CD274 Zornitza Stark edited their review of gene: CD274: Changed phenotypes: Autoimmune disease, multisystem, infantile-onset, 5, MIM# 621235
Mendeliome v1.2666 PDCD2 Zornitza Stark Marked gene: PDCD2 as ready
Mendeliome v1.2666 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2666 PDCD2 Zornitza Stark Classified gene: PDCD2 as Amber List (moderate evidence)
Mendeliome v1.2666 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2665 PDCD2 Zornitza Stark gene: PDCD2 was added
gene: PDCD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD2 were set to 40208938
Phenotypes for gene: PDCD2 were set to Non-immune hydrops fetalis, MONDO:0009369, PDCD2-related
Review for gene: PDCD2 was set to AMBER
Added comment: PMID: 40208938- Novel biallelic PDCD2 variants associated with hydrops fetalis and early pregnancy loss in two affected families. Family 1 with RPL had three fetuses with NIHF who were all homozygous for p.(Pro28Ser) in PDCD2, while Family 2 had p.(Pro28Ser) in trans with p.(Arg34Pro) in two fetuses with NIHF. Family 2 was additionally notable for having a healthy child who was homozygous for the reference allele, consistent with appropriate disease segregation with the PDCD2 variants. Functional studies using primary fetal fibroblasts and human cell lines for both variants showed reduced PDCD2 mRNA level in affected patients' fibroblasts, reduced cellular accumulation of mutant proteins with impaired ability to associate with the 40S subunit ribosomal protein uS5, and further depletion of PDCD2 in fibroblast cells severely impacted ribosome biogenesis. It is notable that formation of the PDCD2-uS5 complex was not completely abolished by the patient variants and that rRNA processing was only partially impaired, as indicated by levels of 40S pre-rRNAs. We thus suspect that the PDCD2 pathogenic variants p.(Pro28Ser) and p.(Arg34Pro) are hypomorphic alleles, with a low level of residual function allowing for cellular differentiation and growth to a certain extent.
Sources: Literature
Mendeliome v1.2664 SOX17 Zornitza Stark Phenotypes for gene: SOX17 were changed from Vesicoureteral reflux 3 MIM#613674; Pulmonary arterial hypertension, MONDO:0015924 to Vesicoureteral reflux 3 MIM#613674; Pulmonary hypertension, primary, 7, MIM# 621248
Mendeliome v1.2663 SOX17 Zornitza Stark edited their review of gene: SOX17: Changed phenotypes: Vesicoureteral reflux 3 MIM#613674, Pulmonary hypertension, primary, 7, MIM# 621248
Mendeliome v1.2663 TBC1D32 Achchuthan Shanmugasundram reviewed gene: TBC1D32: Rating: GREEN; Mode of pathogenicity: None; Publications: 37768732; Phenotypes: retinitis pigmentosa, MONDO:0019200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2663 RPL17 Achchuthan Shanmugasundram gene: RPL17 was added
gene: RPL17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPL17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL17 were set to 39088281
Phenotypes for gene: RPL17 were set to Diamond-Blackfan anemia, MONDO:0015253
Review for gene: RPL17 was set to GREEN
Added comment: PMID:39088281 reported two different pedigrees identified with monoallelic variants in RPL17 gene (3C>G & c.452delC/ p.(Thr151Argfs*25). Affected individuals from both pedigrees exhibited clinical features and erythroid proliferation defects consistent with Diamond-Blackfan anaemia. Individuals from first family also presented with skeletal abnormalities, which were not reported in family 2. Modelling of rpl17 deficiency in zebrafish recapitulated the major clinical features of the disorder including anaemia and micrognathia. There is also functional evidence available from lymphoblastoid cell lines (LCLs) derived from patients, which displayed a ribosomal RNA maturation defect reflecting haploinsufficiency of RPL17.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.2663 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related to Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233; Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, MIM# 621234; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related
Mendeliome v1.2662 IKZF2 Zornitza Stark Publications for gene: IKZF2 were set to 34920454; 34826259; 39406892
Mendeliome v1.2661 IKZF2 Zornitza Stark edited their review of gene: IKZF2: Added comment: PMID 37316189: two individuals with de novo variants and syndromic immunodysregulation, including craniofacial anomalies, hearing impairment, athelia, and developmental delay.; Changed publications: 34920454, 34826259, 37316189; Changed phenotypes: Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233, Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, MIM# 621234
Mendeliome v1.2661 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immunodeficiency, MONDO:0021094, IKZF2-related; Immune dysregulation; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related to Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related
Mendeliome v1.2660 IKZF2 Zornitza Stark edited their review of gene: IKZF2: Changed phenotypes: Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233
Mendeliome v1.2660 BMP6 Bryony Thompson Classified gene: BMP6 as Amber List (moderate evidence)
Mendeliome v1.2660 BMP6 Bryony Thompson Gene: bmp6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2659 LDB3 Zornitza Stark Phenotypes for gene: LDB3 were changed from Cardiomyopathy, dilated, 1C, with or without LVNC MIM#601493; Cardiomyopathy, hypertrophic, 24 MIM#601493; Left ventricular noncompaction 3 MIM#601493; Myopathy, myofibrillar, 4 MIM#609452 to Cardiomyopathy, dilated, 2L, MIM# 621237; Cardiomyopathy, dilated, 1C, with or without LVNC MIM#601493; Cardiomyopathy, hypertrophic, 24 MIM#601493; Left ventricular noncompaction 3 MIM#601493; Myopathy, myofibrillar, 4 MIM#609452
Mendeliome v1.2658 LDB3 Zornitza Stark Publications for gene: LDB3 were set to 26419279; 16427346; 14660611; 14662268; 27546599; 25911362
Mendeliome v1.2657 LDB3 Zornitza Stark reviewed gene: LDB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36253531; Phenotypes: Cardiomyopathy, dilated, 2L, MIM# 621237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2657 THPO Elena Savva Mode of inheritance for gene: THPO was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2656 ATP2A2 Zornitza Stark Phenotypes for gene: ATP2A2 were changed from Acrokeratosis verruciformis MIM#101900; Darier disease MIM#124200; Congenital myopathy, MONDO:0019952, ATP2A2-related; rhabdomyolysis to Acrokeratosis verruciformis MIM#101900; Darier disease MIM#124200; Congenital myopathy, MONDO:0019952, ATP2A2-related; {Rhabdomyolysis, susceptibility to, 2}, MIM# 621236
Mendeliome v1.2655 ATP2A2 Zornitza Stark edited their review of gene: ATP2A2: Changed phenotypes: Congenital myopathy, MONDO:0019952, ATP2A2-related, {Rhabdomyolysis, susceptibility to, 2}, MIM# 621236
Mendeliome v1.2655 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited (fathers listed as affected). Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2655 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from fathers listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2655 CCM2 Sangavi Sivagnanasundram reviewed gene: CCM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19088123, 31446422; Phenotypes: cerebral cavernous malformation 2 MONDO:0011304; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2655 ANKS1B Zornitza Stark Phenotypes for gene: ANKS1B were changed from Neurodevelopmental syndrome; developmental delay; speech delay; motor delay; autism; intellectual disability to Neurodevelopmental disorder (MONDO:0700092), ANKS1B-related
Mendeliome v1.2654 ANKS1B Zornitza Stark Classified gene: ANKS1B as Green List (high evidence)
Mendeliome v1.2654 ANKS1B Zornitza Stark Gene: anks1b has been classified as Green List (High Evidence).
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from parents said to be affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from fathers listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from parents said to be affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2653 ANKS1B Lilian Downie Marked gene: ANKS1B as ready
Mendeliome v1.2653 ANKS1B Lilian Downie Added comment: Comment when marking as ready: Intragenic deletions >3indepedant families with developmental delay (speech and motor apraxia and dysmorphism) borderline IQ's, behavioural/ASD, reduced penetrance, most inherited from mildly or not affected parents. Mouse model.
Mendeliome v1.2653 ANKS1B Lilian Downie Gene: anks1b has been removed from the panel.
Mendeliome v1.2653 ANKS1B Lilian Downie Tag SV/CNV tag was added to gene: ANKS1B.
Mendeliome v1.2653 PMP2 Sangavi Sivagnanasundram reviewed gene: PMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37238449; Phenotypes: Charcot-Marie-Tooth disease MONDO:0015626; Mode of inheritance: None
Mendeliome v1.2653 BMP6 Sangavi Sivagnanasundram reviewed gene: BMP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 28335084, 29695288, 27590690, 34037557, 38719717; Phenotypes: iron overload, susceptibility to MONDO:0859316; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2653 NADK2 Sangavi Sivagnanasundram reviewed gene: NADK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: progressive encephalopathy with leukodystrophy due to DECR deficiency MONDO:0014464; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2653 A4GALT Sangavi Sivagnanasundram reviewed gene: A4GALT: Rating: GREEN; Mode of pathogenicity: None; Publications: 12823750, 15142124, 10747952, 10993874, 11896312, 27612185; Phenotypes: A4GALT-congenital disorder of glycosylation MONDO:0100587; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE (long isoform) and the two short isoforms.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE long isoform and the two short isoforms.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE (long isoform) and the two short isoforms.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE long isoform and the two short isoforms.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.
Mendeliome v1.2653 Bryony Thompson removed gene:NOTCH2NL from the panel
Mendeliome v1.2652 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Mendeliome v1.2651 TUBA1C Zornitza Stark Marked gene: TUBA1C as ready
Mendeliome v1.2651 TUBA1C Zornitza Stark Gene: tuba1c has been classified as Green List (High Evidence).
Mendeliome v1.2651 TUBA1C Zornitza Stark Classified gene: TUBA1C as Green List (high evidence)
Mendeliome v1.2651 TUBA1C Zornitza Stark Gene: tuba1c has been classified as Green List (High Evidence).
Mendeliome v1.2650 TUBA1C Zornitza Stark gene: TUBA1C was added
gene: TUBA1C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TUBA1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBA1C were set to 39209701
Phenotypes for gene: TUBA1C were set to Oocyte/zygote/embryo maturation arrest 24, MIM# 621232
Review for gene: TUBA1C was set to GREEN
Added comment: New paper (biallelic variants for OZEMA)- i) PMID: 39209701- patients 1 and 2 from unrelated families with primary infertility experiencing recurrent preimplantation embryo development arrest (RPEA) carrying homozygous nonsense variant (p.Gln358Ter) and frameshift deletion variant (p.Tyr444Metfs*42), respectively. Transfection studies showed that both variants caused a significant decrease in the abundance of encoded proteins and abnormal cytoplasmic localisation manifested as localised protein aggregation.
Sources: Literature
Mendeliome v1.2649 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from Congenital myopathy 26, MIM# 621225; Hereditary ataxia MONDO:0100309, TUBA4A-related to Congenital myopathy 26, MIM# 621225; Hereditary ataxia MONDO:0100309, TUBA4A-related; Oocyte/zygote/embryo maturation arrest 23, MIM# 621231
Mendeliome v1.2648 TUBA4A Zornitza Stark reviewed gene: TUBA4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte/zygote/embryo maturation arrest 23, MIM# 621231; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2648 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from Congenital myopathy MONDO:0019952 to Congenital myopathy 26, MIM# 621225; Hereditary ataxia MONDO:0100309, TUBA4A-related
Mendeliome v1.2647 NAA60 Sangavi Sivagnanasundram reviewed gene: NAA60: Rating: ; Mode of pathogenicity: None; Publications: 38480682; Phenotypes: basal ganglia calcification, idiopathic, 9, autosomal recessive MONDO:0968977; Mode of inheritance: None
Mendeliome v1.2647 MYPN Sangavi Sivagnanasundram edited their review of gene: MYPN: Changed publications: 28017374, 28220527, 31133047, 18006477
Mendeliome v1.2647 MYPN Sangavi Sivagnanasundram changed review comment from: Comment for gene-disease association
AR myopathy - Definitive classification by ClinGen: https://search.clinicalgenome.org/CCID:005552
AD HCM - DISPUTED classification by ClinGen: https://search.clinicalgenome.org/CCID:005553
AD DCM - Limited classification by ClinGen: https://search.clinicalgenome.org/CCID:005554; to: Comment for gene-disease association (addition of publications)
AR myopathy - Definitive classification by ClinGen: https://search.clinicalgenome.org/CCID:005552
(PMID for myopathy: 28017374, 28220527, 31133047)

AD DCM - Limited classification by ClinGen: https://search.clinicalgenome.org/CCID:005554
(PMID for DCM: 18006477)

AD HCM - DISPUTED classification by ClinGen: https://search.clinicalgenome.org/CCID:005553
Mendeliome v1.2647 MYPN Sangavi Sivagnanasundram changed review comment from: Comment for gene-disease association
AR myopathy - Definitive classification by ClinGen: https://search.clinicalgenome.org/CCID:005552
AD HCM - DISPUTED classification by ClinGen: https://search.clinicalgenome.org/CCID:005553
AD DCM - Limited classification by ClinGen: https://search.clinicalgenome.org/CCID:005554; to: Comment for gene-disease association
AR myopathy - Definitive classification by ClinGen: https://search.clinicalgenome.org/CCID:005552
AD HCM - DISPUTED classification by ClinGen: https://search.clinicalgenome.org/CCID:005553
AD DCM - Limited classification by ClinGen: https://search.clinicalgenome.org/CCID:005554
Mendeliome v1.2647 MYPN Sangavi Sivagnanasundram reviewed gene: MYPN: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: MYPN-related myopathy MONDO:0015023, dilated cardiomyopathy MONDO:0005021, hypertrophic cardiomyopathy MONDO:0005045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2647 HRURF Zornitza Stark Marked gene: HRURF as ready
Mendeliome v1.2647 HRURF Zornitza Stark Gene: hrurf has been classified as Green List (High Evidence).
Mendeliome v1.2647 HRURF Zornitza Stark Classified gene: HRURF as Green List (high evidence)
Mendeliome v1.2647 HRURF Zornitza Stark Gene: hrurf has been classified as Green List (High Evidence).
Mendeliome v1.2646 HRURF Zornitza Stark gene: HRURF was added
gene: HRURF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HRURF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HRURF were set to 39872230; 40433810; 37012647; 28406533; 26269244; 24961381
Phenotypes for gene: HRURF were set to Hypotrichosis 4, MIM# 146550
Review for gene: HRURF was set to GREEN
Added comment: More than 10 unrelated individuals reported.
Sources: Literature
Mendeliome v1.2645 KCNA6 Zornitza Stark Marked gene: KCNA6 as ready
Mendeliome v1.2645 KCNA6 Zornitza Stark Gene: kcna6 has been classified as Green List (High Evidence).
Mendeliome v1.2645 KCNA6 Zornitza Stark Classified gene: KCNA6 as Green List (high evidence)
Mendeliome v1.2645 KCNA6 Zornitza Stark Gene: kcna6 has been classified as Green List (High Evidence).
Mendeliome v1.2644 KCNA6 Zornitza Stark gene: KCNA6 was added
gene: KCNA6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNA6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA6 were set to 36318112; 40472070
Phenotypes for gene: KCNA6 were set to Developmental and epileptic encephalopathy, MONDO:0100620, KCNA6-related
Review for gene: KCNA6 was set to GREEN
Added comment: PMID 36318112: four individuals with de novo variants in this gene and NDD/epilepsy phenotype. Supportive functional data. Additional individual in PMID 40472070 with de novo variant and epilepsy.
Sources: Literature
Mendeliome v1.2643 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.
Mendeliome v1.2643 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature
Mendeliome v1.2643 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature
Mendeliome v1.2643 ANKS1B Monica Petica gene: ANKS1B was added
gene: ANKS1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANKS1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKS1B were set to PMID: 31388001; 38129387
Phenotypes for gene: ANKS1B were set to Neurodevelopmental syndrome; developmental delay; speech delay; motor delay; autism; intellectual disability
Penetrance for gene: ANKS1B were set to unknown
Review for gene: ANKS1B was set to GREEN
Added comment: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature
Mendeliome v1.2643 ZBTB7B Zornitza Stark Marked gene: ZBTB7B as ready
Mendeliome v1.2643 ZBTB7B Zornitza Stark Gene: zbtb7b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2643 ZBTB7B Zornitza Stark Classified gene: ZBTB7B as Amber List (moderate evidence)
Mendeliome v1.2643 ZBTB7B Zornitza Stark Gene: zbtb7b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2642 ZBTB7B Zornitza Stark gene: ZBTB7B was added
gene: ZBTB7B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB7B were set to 40392549
Phenotypes for gene: ZBTB7B were set to Inborn error of immunity, MONDO:0003778, ZBTB7B-related
Review for gene: ZBTB7B was set to AMBER
Added comment: Single patient presented with a complex syndromic phenotype including CID, severe atopy, severe fibroinflammatory interstitial lung disease, corneal vascularization and scarring, sensorineural hearing loss, global developmental delay, and growth failure.

K360N variant is not found in unaffected individuals; functional investigations indicate that K360N exhibits damaging multimorphic effects; and the causal relationship between K360N and the clinical phenotype was confirmed through gene transfer experiments in both T cells and pulmonary fibroblasts.
Sources: Literature
Mendeliome v1.2641 TOP2B Zornitza Stark Publications for gene: TOP2B were set to 28343847; 31198993; 31409799; 12773624
Mendeliome v1.2640 TOP2B Zornitza Stark edited their review of gene: TOP2B: Added comment: PMID 33459963: patient with intermediate phenotype and a de novo inframe deletion at p.Glu587. This variant is absent in gnomad and located in the Toprim domain (DECIPHER, PMID: 33459963). Clinical presentation included moderate intellectual disability, focal epilepsy and failure to thrive. This individual also presented with dysmorphic features, distal limb abnormalities and B-cell immunodeficiency characteristic of the current OMIM associated phenotype (MIM#609296) which ClinGen has assessed as moderate.
Phenotype may be related to variant location but more cases needed to see whether phenotypes are distinct, representing multiple disease entities or a continuum.; Changed publications: 28343847, 31198993, 31409799, 12773624, 33459963
Mendeliome v1.2640 PTPN2 Zornitza Stark Phenotypes for gene: PTPN2 were changed from Lupus; arthritis; common variable immunodeficiency to Autoinflammatory syndrome of childhood, MONDO:0957018, PTPN2-related
Mendeliome v1.2639 PTPN2 Zornitza Stark Publications for gene: PTPN2 were set to 32499645; 27658548
Mendeliome v1.2638 PTPN2 Zornitza Stark Classified gene: PTPN2 as Green List (high evidence)
Mendeliome v1.2638 PTPN2 Zornitza Stark Gene: ptpn2 has been classified as Green List (High Evidence).
Mendeliome v1.2637 PTPN2 Zornitza Stark reviewed gene: PTPN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39028869; Phenotypes: Autoinflammatory syndrome of childhood, MONDO:0957018, PTPN2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2637 ARF1 Zornitza Stark Phenotypes for gene: ARF1 were changed from Periventricular nodular heterotopia 8, MIM# 618185 to Periventricular nodular heterotopia 8, MIM# 618185; Type 1 interferrinopathy of childhood, MONDO:0957408, ARF1 related
Mendeliome v1.2636 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862; 36345169
Mendeliome v1.2635 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862; 36345169
Mendeliome v1.2634 ARF1 Zornitza Stark changed review comment from: Three unrelated individuals reported with de novo missense in this gene.
Sources: Expert list; to: Three unrelated individuals reported with de novo missense in this gene and PVNH.
Sources: Expert list
Mendeliome v1.2634 ARF1 Zornitza Stark edited their review of gene: ARF1: Added comment: PMID 37914730: Three individuals presenting with skin lesions resembling chilblains reported with missense changes at the same amino acid position, R99. Two demonstrated to be de novo. Extensive functional data.; Changed publications: 28868155, 37914730; Changed phenotypes: Periventricular nodular heterotopia 8, MIM# 618185, Type 1 interferrinopathy of childhood, MONDO:0957408, ARF1 related
Mendeliome v1.2634 PTPN1 Zornitza Stark Marked gene: PTPN1 as ready
Mendeliome v1.2634 PTPN1 Zornitza Stark Gene: ptpn1 has been classified as Green List (High Evidence).
Mendeliome v1.2634 PTPN1 Zornitza Stark Classified gene: PTPN1 as Green List (high evidence)
Mendeliome v1.2634 PTPN1 Zornitza Stark Gene: ptpn1 has been classified as Green List (High Evidence).
Mendeliome v1.2633 PTPN1 Zornitza Stark gene: PTPN1 was added
gene: PTPN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 39986310
Phenotypes for gene: PTPN1 were set to Type 1 interferonopathy of childhood, MONDO:0957408, PTPN1-related
Review for gene: PTPN1 was set to GREEN
Added comment: 12 patients from 11 families with phenotype characterised by subacute loss of skills following initially normal development, spastic dystonia, bulbar involvement, preserved head circumference, and an absence of seizures. The observation of enhanced type 1 IFN signalling in patient blood and CSF, and of increased levels of CSF neopterin suggests that PTPN1 haploinsufficiency can be classified as a novel type 1 interferonopathy. Features apparently distinguishing PTP1B-related encephalopathy from Aicardi-Goutières syndrome are a later age at onset (nine of 12 cases in cohort presenting beyond 18 months of age), notable bulbar involvement manifesting as difficulties with swallowing and expressive speech, and cerebral atrophy as the predominant neuroradiological sign.
Sources: Literature
Mendeliome v1.2632 WSB2 Krithika Murali Marked gene: WSB2 as ready
Mendeliome v1.2632 WSB2 Krithika Murali Gene: wsb2 has been classified as Green List (High Evidence).
Mendeliome v1.2632 WSB2 Krithika Murali Classified gene: WSB2 as Green List (high evidence)
Mendeliome v1.2632 WSB2 Krithika Murali Gene: wsb2 has been classified as Green List (High Evidence).
Mendeliome v1.2631 WSB2 Krithika Murali gene: WSB2 was added
gene: WSB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to PMID:40374945
Phenotypes for gene: WSB2 were set to Complex neurodevelopmental disorder, MONDO:0100038, WSB2-related
Review for gene: WSB2 was set to GREEN
Added comment: PMID: 40374945 describe 5 individuals from 4 unrelated families with biallelic WSB2 variants and a complex neurodevelopmental disorder. Phenotypic features include:
- Dev delay (all)
- Brain anomalies (4/5 including callosal anomalies and cerebellar hypoplasia)
- Dysmorphic feature
- IUGR/oligohydramnios (3/5)
- Hypotonia (all)
- Microcephaly (3/5)
- Seizures (3/5)

Includes two siblings with biallelic missense variants and shared phenotype. 3 unaffected siblings were heterozygous for the variant or hmz wt. Phenotypic features associated with hmz nonsense/fs variants were more severe than missense.

Supportive mouse model.
Sources: Literature
Mendeliome v1.2630 NKAP Zornitza Stark Mode of inheritance for gene: NKAP was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2629 PTPRB Bryony Thompson Marked gene: PTPRB as ready
Mendeliome v1.2629 PTPRB Bryony Thompson Gene: ptprb has been classified as Red List (Low Evidence).
Mendeliome v1.2629 PTPRB Bryony Thompson gene: PTPRB was added
gene: PTPRB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPRB was set to Unknown
Publications for gene: PTPRB were set to 40319023
Phenotypes for gene: PTPRB were set to central serous chorioretinopathy; varicose veins; glaucoma
Review for gene: PTPRB was set to RED
Added comment: A single risk allele (rs113791087 - missense) associated with the risk of central serous chorioretinopathy, varicose veins and glaucoma (reduced risk). Not associated with Mendelian disease.
Sources: Literature
Mendeliome v1.2628 OSM Bryony Thompson Marked gene: OSM as ready
Mendeliome v1.2628 OSM Bryony Thompson Gene: osm has been classified as Green List (High Evidence).
Mendeliome v1.2628 OSM Bryony Thompson Classified gene: OSM as Green List (high evidence)
Mendeliome v1.2628 OSM Bryony Thompson Gene: osm has been classified as Green List (High Evidence).
Mendeliome v1.2627 OSM Bryony Thompson gene: OSM was added
gene: OSM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OSM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSM were set to 39847438; 40309776; 17118758
Phenotypes for gene: OSM were set to bone marrow failure syndrome MONDO:0000159
Review for gene: OSM was set to GREEN
Added comment: 6 individuals with with OSM deficiency and an inherited severe bone marrow failure syndrome from 3 consanguineous families with 2 different homozygous LoF variants. Supporting zebrafish and mouse models.
Sources: Literature
Mendeliome v1.2626 RREB1 Zornitza Stark Publications for gene: RREB1 were set to 32938917; 38332451
Mendeliome v1.2625 TAF1C Zornitza Stark Classified gene: TAF1C as Green List (high evidence)
Mendeliome v1.2625 TAF1C Zornitza Stark Gene: taf1c has been classified as Green List (High Evidence).
Mendeliome v1.2624 GALNT14 Zornitza Stark Marked gene: GALNT14 as ready
Mendeliome v1.2624 GALNT14 Zornitza Stark Gene: galnt14 has been classified as Red List (Low Evidence).
Mendeliome v1.2624 GALNT14 Zornitza Stark gene: GALNT14 was added
gene: GALNT14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GALNT14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GALNT14 were set to 40153534
Phenotypes for gene: GALNT14 were set to IgA Nephropathy, susceptibility to, MONDO:0100555, GALNT14-related
Review for gene: GALNT14 was set to RED
Added comment: LoF variant identified in large pedigree, including 6 affected individuals. Also found in 3 unaffected relatives. Supportive mouse model.
Sources: Literature
Mendeliome v1.2623 FAAP100 Zornitza Stark Marked gene: FAAP100 as ready
Mendeliome v1.2623 FAAP100 Zornitza Stark Gene: faap100 has been classified as Green List (High Evidence).
Mendeliome v1.2623 FAAP100 Zornitza Stark Classified gene: FAAP100 as Green List (high evidence)
Mendeliome v1.2623 FAAP100 Zornitza Stark Gene: faap100 has been classified as Green List (High Evidence).
Mendeliome v1.2622 FAAP100 Zornitza Stark gene: FAAP100 was added
gene: FAAP100 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAAP100 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAAP100 were set to 40244696; 40232843
Phenotypes for gene: FAAP100 were set to Fanconi anaemia, MONDO:0019391, FAAP100-related
Review for gene: FAAP100 was set to GREEN
Added comment: PMID 40244696: reports two families with homozygous LoF variants. First family had 6 pregnancy losses and two infants with a severe phenotype characterised by multiple congenital anomalies. Second family had one liveborn child with multiple anomalies and a termination of pregnancy for multiple congenital anomalies. Supportive functional data. Third family reported in PMID 40232843, homozygous missense variant in a fetus with multiple congenital anomalies suggestive of FA. Functional data.
Sources: Literature
Mendeliome v1.2621 TM2D3 Zornitza Stark Marked gene: TM2D3 as ready
Mendeliome v1.2621 TM2D3 Zornitza Stark Gene: tm2d3 has been classified as Green List (High Evidence).
Mendeliome v1.2621 TM2D3 Zornitza Stark Classified gene: TM2D3 as Green List (high evidence)
Mendeliome v1.2621 TM2D3 Zornitza Stark Gene: tm2d3 has been classified as Green List (High Evidence).
Mendeliome v1.2620 TM2D3 Zornitza Stark gene: TM2D3 was added
gene: TM2D3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TM2D3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TM2D3 were set to 40449487
Phenotypes for gene: TM2D3 were set to Neurodevelopmental disorder, MONDO:0700092, TM2D3-related
Review for gene: TM2D3 was set to GREEN
Added comment: Four individuals from 4 unrelated families identified with biallelic variants in this gene. Supportive functional data.
Sources: Literature
Mendeliome v1.2619 SLK Zornitza Stark Marked gene: SLK as ready
Mendeliome v1.2619 SLK Zornitza Stark Gene: slk has been classified as Green List (High Evidence).
Mendeliome v1.2619 SLK Zornitza Stark Classified gene: SLK as Green List (high evidence)
Mendeliome v1.2619 SLK Zornitza Stark Gene: slk has been classified as Green List (High Evidence).
Mendeliome v1.2618 SLK Zornitza Stark gene: SLK was added
gene: SLK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLK were set to 40347834
Phenotypes for gene: SLK were set to Neurodevelopmental disorder, MONDO:0700092, SLK-related
Review for gene: SLK was set to GREEN
Added comment: Three affected individuals from three unrelated families reported. Two of the families were consanguineous and homozygous LoF variants were present in the probands. Third individual had compound het missense variants. Functional data from a Drosophila model and transdifferentiated neurons.
Sources: Literature
Mendeliome v1.2617 ERBB2 Bryony Thompson Mode of inheritance for gene: ERBB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2616 ERBB2 Bryony Thompson Publications for gene: ERBB2 were set to
Mendeliome v1.2615 ERBB2 Bryony Thompson Phenotypes for gene: ERBB2 were changed from Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465 to Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465; Congenital heart disease - left ventricular outflow tract obstruction defects; MONDO:0005453
Mendeliome v1.2614 ERBB2 Bryony Thompson Mode of inheritance for gene: ERBB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2613 ERBB2 Bryony Thompson Classified gene: ERBB2 as Amber List (moderate evidence)
Mendeliome v1.2613 ERBB2 Bryony Thompson Gene: erbb2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2612 ERBB2 Eleanor Ludington reviewed gene: ERBB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 40329538; Phenotypes: Congenital heart disease - left ventricular outflow tract obstruction defects, MONDO:0005453; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2612 TAF1C Sangavi Sivagnanasundram edited their review of gene: TAF1C: Changed phenotypes: complex neurodevelopmental disorder, TAF1C-related, MONDO:0100038
Mendeliome v1.2612 TAF1C Sangavi Sivagnanasundram reviewed gene: TAF1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 40371665; Phenotypes: complex neurodevelopmental disorder, TAF1C-realted, MONDO:0100038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2612 RREB1 Chirag Patel Classified gene: RREB1 as Green List (high evidence)
Mendeliome v1.2612 RREB1 Chirag Patel Gene: rreb1 has been classified as Green List (High Evidence).
Mendeliome v1.2611 RREB1 Chirag Patel reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40418122; Phenotypes: Rasopathy, MONDO:0021060, RREB1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2611 LEF1 Zornitza Stark Phenotypes for gene: LEF1 were changed from Syndromic disease, MONDO:0002254, LEF1-related to Ectodermal dysplasia 17 with or without limb malformations, MIM# 621224
Mendeliome v1.2610 LEF1 Zornitza Stark edited their review of gene: LEF1: Changed phenotypes: Ectodermal dysplasia 17 with or without limb malformations, MIM# 621224
Mendeliome v1.2610 GON4L Zornitza Stark reviewed gene: GON4L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Li-Takada-Miyake syndrome, MIM# 621212; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2610 GON4L Zornitza Stark Phenotypes for gene: GON4L were changed from complex neurodevelopmental disorder MONDO:0100038 to Li-Takada-Miyake syndrome, MIM# 621212
Mendeliome v1.2609 NKAP Elena Savva Mode of inheritance for gene: NKAP was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.2608 NKAP Elena Savva Phenotypes for gene: NKAP were changed from Intellectual disability to intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, MONDO:0026733, MIM#301039
Mendeliome v1.2607 NKAP Elena Savva Mode of inheritance for gene: NKAP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2606 FBXL7 Bryony Thompson Phenotypes for gene: FBXL7 were changed from Hennekam lymphangiectasia-lymphedema syndrome to Hennekam lymphangiectasia-lymphedema syndrome MONDO:0016256
Mendeliome v1.2605 FAAH2 Bryony Thompson Phenotypes for gene: FAAH2 were changed from to autism spectrum disorder MONDO:0005258
Mendeliome v1.2604 ESRP2 Bryony Thompson Phenotypes for gene: ESRP2 were changed from Cleft lip to Orofacial cleft MONDO:0000358
Mendeliome v1.2603 ERGIC3 Bryony Thompson Phenotypes for gene: ERGIC3 were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2602 ADAM10 Bryony Thompson Marked gene: ADAM10 as ready
Mendeliome v1.2602 ADAM10 Bryony Thompson Gene: adam10 has been classified as Green List (High Evidence).
Mendeliome v1.2602 ADAM10 Bryony Thompson Classified gene: ADAM10 as Green List (high evidence)
Mendeliome v1.2602 ADAM10 Bryony Thompson Gene: adam10 has been classified as Green List (High Evidence).
Mendeliome v1.2601 ADAM10 Bryony Thompson gene: ADAM10 was added
gene: ADAM10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAM10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAM10 were set to 23666529; 30488468
Phenotypes for gene: ADAM10 were set to reticulate acropigmentation of Kitamura MONDO:0014234
Review for gene: ADAM10 was set to GREEN
Added comment: Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation. >5 families have been reported. Loss of function is the reported mechanism of disease.
Sources: Literature
Mendeliome v1.2600 IKBKG Bryony Thompson Tag technically challenging tag was added to gene: IKBKG.
Mendeliome v1.2600 MYCBP2 Zornitza Stark Classified gene: MYCBP2 as Red List (low evidence)
Mendeliome v1.2600 MYCBP2 Zornitza Stark Gene: mycbp2 has been classified as Red List (Low Evidence).
Mendeliome v1.2599 MYCBP2 Zornitza Stark reviewed gene: MYCBP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, MYCBP2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2599 DNAH12 Zornitza Stark Marked gene: DNAH12 as ready
Mendeliome v1.2599 DNAH12 Zornitza Stark Gene: dnah12 has been classified as Green List (High Evidence).
Mendeliome v1.2599 DNAH12 Zornitza Stark Classified gene: DNAH12 as Green List (high evidence)
Mendeliome v1.2599 DNAH12 Zornitza Stark Gene: dnah12 has been classified as Green List (High Evidence).
Mendeliome v1.2598 DNAH12 Zornitza Stark gene: DNAH12 was added
gene: DNAH12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH12 were set to 39071892; 40146200
Phenotypes for gene: DNAH12 were set to Spermatogenic failure 100, MIM# 621209
Review for gene: DNAH12 was set to GREEN
Added comment: Twelve individuals from 7 families and two mouse models support this association
Sources: Literature
Mendeliome v1.2597 BBIP1 Zornitza Stark Classified gene: BBIP1 as Green List (high evidence)
Mendeliome v1.2597 BBIP1 Zornitza Stark Gene: bbip1 has been classified as Green List (High Evidence).
Mendeliome v1.2596 BBIP1 Zornitza Stark edited their review of gene: BBIP1: Added comment: Third family with homozygous LoF variant reported; Changed rating: GREEN; Changed publications: 24026985, 32055034, 37239474
Mendeliome v1.2596 FAM177A1 Zornitza Stark Phenotypes for gene: FAM177A1 were changed from Neurodevelopmental disorder, MONDO_0100500, FAM177A1-related to Neurodevelopmental disorder with white matter abnormalities and gait disturbance, MIM# 621152
Mendeliome v1.2595 FAM177A1 Zornitza Stark reviewed gene: FAM177A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with white matter abnormalities and gait disturbance, MIM# 621152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2595 GTF3C3 Zornitza Stark Phenotypes for gene: GTF3C3 were changed from Neurodevelopmental disorder MONDO:0700092, GTF3C3-related to Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, MIM# 621201
Mendeliome v1.2594 GTF3C3 Zornitza Stark edited their review of gene: GTF3C3: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, MIM# 621201
Mendeliome v1.2594 PTPMT1 Zornitza Stark Phenotypes for gene: PTPMT1 were changed from inborn mitochondrial metabolism disorder MONDO:0004069 to Neurodevelopmental disorder with ataxia and brain abnormalities, MIM# 621199
Mendeliome v1.2593 PTPMT1 Zornitza Stark reviewed gene: PTPMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with ataxia and brain abnormalities, MIM# 621199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2593 WNT3 Zornitza Stark commented on gene: WNT3: LIMITED by ClinGen.
Mendeliome v1.2593 PPP2R5C Zornitza Stark Phenotypes for gene: PPP2R5C were changed from Neurodevelopmental disorder, PPP2R5C-related (MONDO:070092); macrocephaly; intellectual disability to Houge-Janssens syndrome 4, MIM# 621185
Mendeliome v1.2592 PPP2R5C Zornitza Stark reviewed gene: PPP2R5C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Houge-Janssens syndrome 4, MIM# 621185; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2592 SCO2 Zornitza Stark Mode of inheritance for gene: SCO2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2591 MMAB Sangavi Sivagnanasundram reviewed gene: MMAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 24813872; Phenotypes: methylmalonic aciduria, cblB type MONDO:0009614; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2591 SEPT4 Zornitza Stark reviewed gene: SEPT4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 99, MIM# 621194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2591 ABCC8 Zornitza Stark Phenotypes for gene: ABCC8 were changed from 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
Mendeliome v1.2590 MRPL49 Zornitza Stark Phenotypes for gene: MRPL49 were changed from Mitochondrial disease, MONDO:0044970, MRPL49-related to Combined oxidative phosphorylation deficiency 60, MIM# 621195
Mendeliome v1.2589 MRPL49 Zornitza Stark edited their review of gene: MRPL49: Changed phenotypes: Combined oxidative phosphorylation deficiency 60, MIM# 621195
Mendeliome v1.2589 IDH3G Zornitza Stark Phenotypes for gene: IDH3G were changed from X-linked retinitis pigmentosa, MONDO:0019200 to Retinitis pigmentosa 99, MIM# 301148
Mendeliome v1.2588 IDH3G Zornitza Stark reviewed gene: IDH3G: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 99, MIM# 301148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2588 MAN2B1 Sangavi Sivagnanasundram reviewed gene: MAN2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18651971, 9158146, 9758606, 9915946, 22161967; Phenotypes: alpha-mannosidosis MONDO:0009561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2588 LYST Sangavi Sivagnanasundram edited their review of gene: LYST: Changed publications: 8896560, 9215680, 31906877, 9215679, 26499269, 24112114, 28145517
Mendeliome v1.2588 LYST Sangavi Sivagnanasundram reviewed gene: LYST: Rating: GREEN; Mode of pathogenicity: None; Publications: 8896560, 9215680, 31906877, 9215679, 26499269, 24112114, 28145517); Phenotypes: Chediak-Higashi syndrome MONDO:0008963; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2588 LYRM7 Sangavi Sivagnanasundram reviewed gene: LYRM7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24014394, 26912632; Phenotypes: mitochondrial disease, LYRM7-related MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2588 LPAR6 Sangavi Sivagnanasundram reviewed gene: LPAR6: Rating: GREEN; Mode of pathogenicity: None; Publications: 18297072, 18297070, 18461368; Phenotypes: LPAR6-related hypotrichosis/woolly hair with or without hypotrichosis, MONDO:MONDO:0800312; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2588 LSM1 Zornitza Stark Phenotypes for gene: LSM1 were changed from Neurodevelopmental disorder, MONDO:0700092, LSM1-related to FICUS syndrome, MIM# 621193
Mendeliome v1.2587 LSM1 Zornitza Stark edited their review of gene: LSM1: Changed phenotypes: FICUS syndrome, MIM# 621193
Mendeliome v1.2587 CERS1 Zornitza Stark Marked gene: CERS1 as ready
Mendeliome v1.2587 CERS1 Zornitza Stark Gene: cers1 has been classified as Green List (High Evidence).
Mendeliome v1.2587 CERS1 Zornitza Stark Classified gene: CERS1 as Green List (high evidence)
Mendeliome v1.2587 CERS1 Zornitza Stark Gene: cers1 has been classified as Green List (High Evidence).
Mendeliome v1.2586 DBF4 Zornitza Stark Marked gene: DBF4 as ready
Mendeliome v1.2586 DBF4 Zornitza Stark Gene: dbf4 has been classified as Red List (Low Evidence).
Mendeliome v1.2586 DBF4 Zornitza Stark Classified gene: DBF4 as Red List (low evidence)
Mendeliome v1.2586 DBF4 Zornitza Stark Gene: dbf4 has been classified as Red List (Low Evidence).
Mendeliome v1.2585 GINS4 Zornitza Stark Marked gene: GINS4 as ready
Mendeliome v1.2585 GINS4 Zornitza Stark Gene: gins4 has been classified as Red List (Low Evidence).
Mendeliome v1.2585 GINS4 Zornitza Stark Classified gene: GINS4 as Red List (low evidence)
Mendeliome v1.2585 GINS4 Zornitza Stark Gene: gins4 has been classified as Red List (Low Evidence).
Mendeliome v1.2584 ARSI Zornitza Stark Marked gene: ARSI as ready
Mendeliome v1.2584 ARSI Zornitza Stark Gene: arsi has been classified as Red List (Low Evidence).
Mendeliome v1.2584 ARSI Zornitza Stark Classified gene: ARSI as Red List (low evidence)
Mendeliome v1.2584 ARSI Zornitza Stark Gene: arsi has been classified as Red List (Low Evidence).
Mendeliome v1.2583 ADGRB3 Zornitza Stark Marked gene: ADGRB3 as ready
Mendeliome v1.2583 ADGRB3 Zornitza Stark Gene: adgrb3 has been classified as Red List (Low Evidence).
Mendeliome v1.2583 ADGRB3 Zornitza Stark Classified gene: ADGRB3 as Red List (low evidence)
Mendeliome v1.2583 ADGRB3 Zornitza Stark Gene: adgrb3 has been classified as Red List (Low Evidence).
Mendeliome v1.2582 BRCC3 Zornitza Stark Marked gene: BRCC3 as ready
Mendeliome v1.2582 BRCC3 Zornitza Stark Gene: brcc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2582 BRCC3 Zornitza Stark Classified gene: BRCC3 as Amber List (moderate evidence)
Mendeliome v1.2582 BRCC3 Zornitza Stark Gene: brcc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2581 BRCC3 Zornitza Stark Tag SV/CNV tag was added to gene: BRCC3.
Mendeliome v1.2581 SH3BP4 Zornitza Stark Marked gene: SH3BP4 as ready
Mendeliome v1.2581 SH3BP4 Zornitza Stark Gene: sh3bp4 has been classified as Red List (Low Evidence).
Mendeliome v1.2581 SH3BP4 Zornitza Stark Classified gene: SH3BP4 as Red List (low evidence)
Mendeliome v1.2581 SH3BP4 Zornitza Stark Gene: sh3bp4 has been classified as Red List (Low Evidence).
Mendeliome v1.2580 WDR48 Zornitza Stark Marked gene: WDR48 as ready
Mendeliome v1.2580 WDR48 Zornitza Stark Gene: wdr48 has been classified as Red List (Low Evidence).
Mendeliome v1.2580 WDR48 Zornitza Stark Classified gene: WDR48 as Red List (low evidence)
Mendeliome v1.2580 WDR48 Zornitza Stark Gene: wdr48 has been classified as Red List (Low Evidence).
Mendeliome v1.2579 SNRPA Zornitza Stark Marked gene: SNRPA as ready
Mendeliome v1.2579 SNRPA Zornitza Stark Gene: snrpa has been classified as Red List (Low Evidence).
Mendeliome v1.2579 SNRPA Zornitza Stark Classified gene: SNRPA as Red List (low evidence)
Mendeliome v1.2579 SNRPA Zornitza Stark Gene: snrpa has been classified as Red List (Low Evidence).
Mendeliome v1.2578 ZFR Zornitza Stark Marked gene: ZFR as ready
Mendeliome v1.2578 ZFR Zornitza Stark Gene: zfr has been classified as Red List (Low Evidence).
Mendeliome v1.2578 ZFR Zornitza Stark Classified gene: ZFR as Red List (low evidence)
Mendeliome v1.2578 ZFR Zornitza Stark Gene: zfr has been classified as Red List (Low Evidence).
Mendeliome v1.2577 ZNF674 Zornitza Stark Marked gene: ZNF674 as ready
Mendeliome v1.2577 ZNF674 Zornitza Stark Gene: znf674 has been classified as Red List (Low Evidence).
Mendeliome v1.2577 ZNF674 Zornitza Stark Classified gene: ZNF674 as Red List (low evidence)
Mendeliome v1.2577 ZNF674 Zornitza Stark Gene: znf674 has been classified as Red List (Low Evidence).
Mendeliome v1.2576 ZNF674 Zornitza Stark Tag disputed tag was added to gene: ZNF674.
Mendeliome v1.2576 FAAHP1 Zornitza Stark Marked gene: FAAHP1 as ready
Mendeliome v1.2576 FAAHP1 Zornitza Stark Gene: faahp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2576 FAAHP1 Zornitza Stark Classified gene: FAAHP1 as Red List (low evidence)
Mendeliome v1.2576 FAAHP1 Zornitza Stark Gene: faahp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2575 ERN1 Zornitza Stark Marked gene: ERN1 as ready
Mendeliome v1.2575 ERN1 Zornitza Stark Gene: ern1 has been classified as Red List (Low Evidence).
Mendeliome v1.2575 ERN1 Zornitza Stark Classified gene: ERN1 as Red List (low evidence)
Mendeliome v1.2575 ERN1 Zornitza Stark Gene: ern1 has been classified as Red List (Low Evidence).
Mendeliome v1.2574 AGXT2 Zornitza Stark Marked gene: AGXT2 as ready
Mendeliome v1.2574 AGXT2 Zornitza Stark Gene: agxt2 has been classified as Red List (Low Evidence).
Mendeliome v1.2574 AGXT2 Zornitza Stark Classified gene: AGXT2 as Red List (low evidence)
Mendeliome v1.2574 AGXT2 Zornitza Stark Gene: agxt2 has been classified as Red List (Low Evidence).
Mendeliome v1.2573 SLC29A1 Zornitza Stark Marked gene: SLC29A1 as ready
Mendeliome v1.2573 SLC29A1 Zornitza Stark Gene: slc29a1 has been classified as Red List (Low Evidence).
Mendeliome v1.2573 SLC29A1 Zornitza Stark Classified gene: SLC29A1 as Red List (low evidence)
Mendeliome v1.2573 SLC29A1 Zornitza Stark Gene: slc29a1 has been classified as Red List (Low Evidence).
Mendeliome v1.2572 PLK1 Zornitza Stark Phenotypes for gene: PLK1 were changed from Epilepsy; microcephaly; intellectual disability to Neurodevelopmental disorder, PLK1-related, MONDO:0700092
Mendeliome v1.2571 PLOD3 Zornitza Stark Phenotypes for gene: PLOD3 were changed from to Lysyl hydroxylase 3 deficiency, MIM#612394; Bone fragility with contractures, arterial rupture, and deafness (BCARD syndrome) MONDO:0012892
Mendeliome v1.2570 PLOD3 Zornitza Stark Publications for gene: PLOD3 were set to
Mendeliome v1.2569 PLXNA2 Zornitza Stark Phenotypes for gene: PLXNA2 were changed from Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology to Complex neurodevelopmental disorder, PLXNA2-related, MONDO:0100038
Mendeliome v1.2568 RECQL Zornitza Stark Phenotypes for gene: RECQL were changed from Photosensitivity; facial dysmorphism; xeropthalmia; skeletal abnormalities to RECON progeroid syndrome MONDO:0957266
Mendeliome v1.2567 RFX3 Zornitza Stark Phenotypes for gene: RFX3 were changed from ID, ASD, ADHD to RFX3-related neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2566 RFX4 Zornitza Stark Phenotypes for gene: RFX4 were changed from ID, ASD, ADHD to RFX4-related neurodevelopmental disorder, MONDO:0700092
Mendeliome v1.2565 ROBO4 Zornitza Stark Publications for gene: ROBO4 were set to 30455415; 32748548
Mendeliome v1.2564 ROBO4 Rylee Peters reviewed gene: ROBO4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36855159; Phenotypes: Aortic valve disease 8 MIM#618496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2564 AMOTL1 Zornitza Stark Phenotypes for gene: AMOTL1 were changed from Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related to Craniofaciocardiohepatic syndrome, MIM# 621192
Mendeliome v1.2563 AMOTL1 Zornitza Stark edited their review of gene: AMOTL1: Changed phenotypes: Craniofaciocardiohepatic syndrome, MIM# 621192
Mendeliome v1.2563 LSM7 Zornitza Stark Phenotypes for gene: LSM7 were changed from leukodystrophy MONDO:0019046, LRM7-related to Leukodystrophy and cerebellar atrophy, MIM# 621191
Mendeliome v1.2562 LSM7 Zornitza Stark reviewed gene: LSM7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy and cerebellar atrophy, MIM# 621191; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2562 RFX4 Sangavi Sivagnanasundram reviewed gene: RFX4: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RFX4-related neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: None
Mendeliome v1.2562 RFX3 Sangavi Sivagnanasundram reviewed gene: RFX3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RFX3-related neurodevelopmental disorder MONDO:0700092; Mode of inheritance: None
Mendeliome v1.2562 RECQL Sangavi Sivagnanasundram reviewed gene: RECQL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RECON progeroid syndrome MONDO:0957266; Mode of inheritance: None
Mendeliome v1.2562 PYCR1 Sangavi Sivagnanasundram reviewed gene: PYCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive cutis laxa type 2B MONDO:0013051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2562 PLXNA2 Sangavi Sivagnanasundram reviewed gene: PLXNA2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Complex neurodevelopmental disorder, PLXNA2-related, MONDO:0100038; Mode of inheritance: None
Mendeliome v1.2562 PLOD3 Sangavi Sivagnanasundram reviewed gene: PLOD3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Bone fragility with contractures, arterial rupture, and deafness (BCARD syndrome) MONDO:0012892; Mode of inheritance: None
Mendeliome v1.2562 PLK1 Sangavi Sivagnanasundram reviewed gene: PLK1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, PLK1-related, MONDO:0700092; Mode of inheritance: None
Mendeliome v1.2562 SLC29A1 Sangavi Sivagnanasundram edited their review of gene: SLC29A1: Changed rating: RED
Mendeliome v1.2562 SLC29A1 Sangavi Sivagnanasundram gene: SLC29A1 was added
gene: SLC29A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC29A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC29A1 were set to 35955904; 25896650
Phenotypes for gene: SLC29A1 were set to Disorders of ectonucleotide and nucleic acid metabolism; Equilibrative nucleoside transporter 1 deficiency MONDO:0019052
Review for gene: SLC29A1 was set to AMBER
Added comment: This gene-disease association is an inborn error of metabolism known as disorders of ectonucleotide and nucleic acid metabolism. More evidence is required to support the gene-disease association. - https://iembase.com/disorder/783

PMID: 35955904
Homozygous Glu391Lys responsible for the A-negative blood time in people of African ancestry however is not shown to alter the protein function. Affected individuals will likely not have any phenotypes except the A- blood type. Missense variant is present in gnomAD v4.1 (GrpMax FAF - 1.159% in African/African American Population)

PMID: 25896650
3 sibs of European ancestry identified with homozygous c.589+1G>C (rare on gnomAD v4.1 for AR gene)
No severe phenotype was observed however periarticular and ectopic mineralization was observed which important regarding bone homeostasis.
Sources: Literature
Mendeliome v1.2562 AGXT2 Sangavi Sivagnanasundram gene: AGXT2 was added
gene: AGXT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AGXT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGXT2 were set to 21572414
Phenotypes for gene: AGXT2 were set to beta-aminoisobutyric acid, urinary excretion of MONDO:0008860
Review for gene: AGXT2 was set to RED
Added comment: This gene-disease association needs further evidence to support pathogenicity.

PMID: 21572414
GWAS study identified common SNP (V140I - https://gnomad.broadinstitute.org/variant/5-35037010-C-T?dataset=gnomad_r4) showing the strongest association with BAIB in the present study.
Sources: Literature
Mendeliome v1.2562 ERN1 Sangavi Sivagnanasundram gene: ERN1 was added
gene: ERN1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ERN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ERN1 were set to Immune Dysregulation, MONDO:0005046
Review for gene: ERN1 was set to RED
Added comment: No new evidence to support gene-disease association. Review copied from Disorders of immune dysregulation Panel:
"On the IUIS 2024 update for IEIs as a gene associated with an AD disease of immune dysregulation, I cannot find any evidence of Mendelian disease."
Sources: Expert Review
Mendeliome v1.2562 FAAHP1 Sangavi Sivagnanasundram gene: FAAHP1 was added
gene: FAAHP1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FAAHP1 was set to Unknown
Publications for gene: FAAHP1 were set to 30929760
Phenotypes for gene: FAAHP1 were set to Pain insensitivity
Review for gene: FAAHP1 was set to RED
Added comment: Review from Pain Syndromes Panel:
"This is a pseudogene. A single case with pain insensitivity has been reported with co-inheritance of a microdeletion in dorsal root ganglia and brain-expressed pseudogene and a common functional SNP in FAAH (rs324420 ) conferring reduced expression and activity."
Sources: Expert Review
Mendeliome v1.2562 ZNF674 Sangavi Sivagnanasundram gene: ZNF674 was added
gene: ZNF674 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZNF674 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZNF674 were set to https://search.clinicalgenome.org/CCID:006588
Phenotypes for gene: ZNF674 were set to X-linked intellectual disability MONDO:0100284
Review for gene: ZNF674 was set to RED
Added comment: Classified DISPUTED by ClinGen ID and Autism GCEP on 04/05/2021 - https://search.clinicalgenome.org/CCID:006588
Sources: Expert Review
Mendeliome v1.2562 ZFR Sangavi Sivagnanasundram gene: ZFR was added
gene: ZFR was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFR were set to 24482476
Phenotypes for gene: ZFR were set to hereditary spastic paraplegia, MONDO:0019064
Review for gene: ZFR was set to RED
Added comment: No new proband/evidence supporting gene-disease association.

Review copied from HSP paediatric panel:
"A single family reported with a homozygous variant."
Sources: Expert Review
Mendeliome v1.2562 SNRPA Sangavi Sivagnanasundram gene: SNRPA was added
gene: SNRPA was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SNRPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNRPA were set to 29437235
Phenotypes for gene: SNRPA were set to complex neurodevelopmental disorder, SNRPA-related MONDO:0100038
Review for gene: SNRPA was set to RED
Added comment: No new reported probands supporting the gene-disease association.

Review copied from ID panel:
"1 report of concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in 2 female siblings with 3 homozygous missense variants in SNRPA. Combined, c.97A>G, c.98T>C, and c.100T>A, in exon 2 of SNRPA lead to p.Ile33Ala and p.Phe34Ile exchanges, which were predicted in silico to be deleterious. No functional studies."
Sources: Expert Review
Mendeliome v1.2562 WDR48 Sangavi Sivagnanasundram gene: WDR48 was added
gene: WDR48 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: WDR48 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR48 were set to 24482476
Phenotypes for gene: WDR48 were set to Hereditary spastic paraplegia MONDO:0015150
Review for gene: WDR48 was set to RED
Added comment: Gene Reviews - https://www.ncbi.nlm.nih.gov/books/NBK1509/
SPG60 - paediatric onset of complex HSP.
Polyneuropathy and DD are the typical onset of symptoms

No new reported probands - review copied from HSP paediatric panel:
"A single family reported with a homozygous in-frame deletion."
Sources: Expert Review
Mendeliome v1.2562 SH3BP4 Sangavi Sivagnanasundram gene: SH3BP4 was added
gene: SH3BP4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SH3BP4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SH3BP4 were set to 24627108
Phenotypes for gene: SH3BP4 were set to Peripheral neuropathy, MONDO:0005244
Review for gene: SH3BP4 was set to RED
Added comment: No new information supportive of gene-disease association.

Review copied from Hereditary Neuropathy_CMT - isolated Panel:
"A single family reported with inherited peripheral neuropathy, with no functional analyses."
Sources: Expert Review
Mendeliome v1.2562 BRCC3 Sangavi Sivagnanasundram gene: BRCC3 was added
gene: BRCC3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: BRCC3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: BRCC3 were set to 21596366; 33868155; 35815106; 39552268
Phenotypes for gene: BRCC3 were set to MoyaMoya Disease, syndromic, MONDO:0016820
Review for gene: BRCC3 was set to AMBER
Added comment: The same common ~26kb Xq28 deletion was identified in all affected individuals below. No other evidence of any SNVs.

Additional probands with MoyaMoya:
PMID: 35815106 & 39552268
Two unrelated individuals with MoyaMoya and other neurodevelopmental features.
A hemizygous ~26kb Xq28 deletion was identified in both individuals

------------------------------
Review from CVM panel:
“PMID 21596366: three unrelated families with multiple affected males segregating a deletion involving MTCP1 and BRCC3. Positional approach used. Supportive zebrafish model, knockdown of BRCC3; angiogenesis affected.

PMID 33868155, additional report of affected male, with similar deletion.

No reports of SNVs identified, including in ClinVar.”
Sources: Expert Review
Mendeliome v1.2562 ADGRB3 Sangavi Sivagnanasundram gene: ADGRB3 was added
gene: ADGRB3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ADGRB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADGRB3 were set to 30659260; 18628273
Phenotypes for gene: ADGRB3 were set to Intellectual disability MONDO:0001071
Review for gene: ADGRB3 was set to RED
Added comment: No new information supportive of gene-disease association. Review copied from ID panel:

"Single family with intragenic bi-allelic duplications and ID reported; association studies with schizophrenia."
Sources: Expert Review
Mendeliome v1.2562 ARSI Sangavi Sivagnanasundram gene: ARSI was added
gene: ARSI was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ARSI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARSI were set to 24482476
Phenotypes for gene: ARSI were set to Complex spastic paraplegia, MONDO:0015150
Review for gene: ARSI was set to RED
Added comment: No new information supporting gene-disease association.

Review from HSP paediatric panel - "Single family reported"
Sources: Expert Review
Mendeliome v1.2562 GINS4 Sangavi Sivagnanasundram gene: GINS4 was added
gene: GINS4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: GINS4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS4 were set to 36345943
Phenotypes for gene: GINS4 were set to combined immunodeficiency MONDO:0015131
Review for gene: GINS4 was set to RED
Added comment: No further information has been published to support the gene-disease association.

Review copied from Combined Immunodeficiency panel:
"2 affected siblings with compound het variants are reported in a single family."
Sources: Expert Review
Mendeliome v1.2562 DBF4 Sangavi Sivagnanasundram changed review comment from: Review taken from Phagocyte Defects panel:

"A single case with a homozygous variant & some supporting in vitro functional assay."
Sources: Literature; to: No new information supporting gene-disease association. Review taken from Phagocyte Defects panel:

"A single case with a homozygous variant & some supporting in vitro functional assay."
Sources: Literature
Mendeliome v1.2562 DBF4 Sangavi Sivagnanasundram gene: DBF4 was added
gene: DBF4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DBF4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DBF4 were set to 36841265
Phenotypes for gene: DBF4 were set to severe congenital neutropenia MONDO:0018542
Review for gene: DBF4 was set to RED
Added comment: Review taken from Phagocyte Defects panel:

"A single case with a homozygous variant & some supporting in vitro functional assay."
Sources: Literature
Mendeliome v1.2562 CERS1 Sangavi Sivagnanasundram gene: CERS1 was added
gene: CERS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CERS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CERS1 were set to 24782409; 21625621; 30800706
Phenotypes for gene: CERS1 were set to Epilepsy, progressive myoclonic, 8, MONDO:0020074
Review for gene: CERS1 was set to GREEN
Added comment: Addition of this gene to the Mendeliome - review taken from Genetic Epilepsy Panel

"Two unrelated families with PME identified, and functional assays in vitro and in patient cells demonstrating impaired ceramide biosynthesis. Mouse model shows neurodegeneration and lipofuscin accumulation"

Classified as MODERATE by ClinGen Epilepsy GCEP on 16/07/2024 - https://search.clinicalgenome.org/CCID:008331
Sources: Literature
Mendeliome v1.2562 NAV3 Zornitza Stark Phenotypes for gene: NAV3 were changed from Neurodevelopmental disorder, MONDO:0700092, NAV3-related to Neurodevelopmental disorder with poor or absent speech, dysmorphic facies, and behavioral abnormalities, MIM# 621182
Mendeliome v1.2561 NAV3 Zornitza Stark edited their review of gene: NAV3: Changed phenotypes: Neurodevelopmental disorder with poor or absent speech, dysmorphic facies, and behavioral abnormalities, MIM# 621182
Mendeliome v1.2561 GPKOW Zornitza Stark Phenotypes for gene: GPKOW were changed from male-lethal microcephaly with intrauterine growth restriction to syndromic disease, MONDO:0002254, GPKOW-related
Mendeliome v1.2560 GPKOW Zornitza Stark Publications for gene: GPKOW were set to 28612833
Mendeliome v1.2559 FBXO22 Zornitza Stark Marked gene: FBXO22 as ready
Mendeliome v1.2559 FBXO22 Zornitza Stark Gene: fbxo22 has been classified as Green List (High Evidence).
Mendeliome v1.2559 FBXO22 Zornitza Stark Classified gene: FBXO22 as Green List (high evidence)
Mendeliome v1.2559 FBXO22 Zornitza Stark Gene: fbxo22 has been classified as Green List (High Evidence).
Mendeliome v1.2558 FBXO22 Sarah Milton gene: FBXO22 was added
gene: FBXO22 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXO22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO22 were set to PMID: 40215970
Phenotypes for gene: FBXO22 were set to Neurodevelopmental disorder, MONDO:0700092, FBXO22-related
Review for gene: FBXO22 was set to GREEN
Added comment: Encodes substrate recognition component of SCF E3 ubiquitin ligase complex. Has role in post translational ubiquitination and degradation of certain substrates e.g. histone demethylases.

14 cases from 12 families published with affected individuals noted to have homozygous frameshift variants (FBXO22:c.159_162del,c.8_36del,c.719_722del - all rare/absent gnomad v4).

Phenotype included prenatal growth restriction/short stature, neurodevelopmental delay, microcephaly, hypotonia, seizures, craniofacial dysmorphisms (high forehead, depressed nasal bridge, hypertelorism), variable additional findings including cardiovascular and gastrointestinal anomalies.

Supportive functional studies - FBXO22 is involved of degradation of KDM4B, KDM4B protein levels in one affected individual were found to be higher than control. Unique genome wide episignature identified for FBXO22 in 3 individuals with the disorder (given loss of this protein results in increased levels of various histone demethylases).
Sources: Literature
Mendeliome v1.2558 RNU2-2P Sarah Milton changed review comment from: Note current HGNC accepted gene name RNU2-2
Previously referred to as RNU2-2P
Upstream of WDR74, as such variants may be incorrectly annotated as 5' WDR74
Encodes part of minor spliceosome (RNA) - non protein coding gene.

Total of 25 affected individuals with 16 described in PMID: 40210679 to have a neurodevelopmental disorder including intellectual disability (mod to severe), dysmorphism, global developmental delay, autistic behaviour, early onset drug resistant epilepsy, microcephaly, hyperventilation. Variants were de novo.

Recurrent variants included n.4G>A and n.35A>G
(should note another variant n.35A>T relatively common in population and said to be mosaic somatic by authors); to: Note current HGNC accepted gene name RNU2-2
Previously referred to as RNU2-2P
Upstream of WDR74, as such variants may be incorrectly annotated as 5' WDR74
Encodes part of minor spliceosome (RNA) - non protein coding gene.

Total of 25 affected individuals with 16 described in PMID: 40210679 to have a neurodevelopmental disorder including intellectual disability (mod to severe), dysmorphism, global developmental delay, autistic behaviour, early onset drug resistant epilepsy, microcephaly, hyperventilation. Variants were de novo.

Recurrent variants included n.4G>A and n.35A>G
(both absent from gnomad v4, should note another variant n.35A>T relatively common in population and said to be mosaic somatic by authors)
Mendeliome v1.2558 RNU2-2P Sarah Milton reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40210679; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNU2-2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2558 GPKOW Chirag Patel Classified gene: GPKOW as Green List (high evidence)
Mendeliome v1.2558 GPKOW Chirag Patel Gene: gpkow has been classified as Green List (High Evidence).
Mendeliome v1.2557 GPKOW Chirag Patel reviewed gene: GPKOW: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40221893, 28612833; Phenotypes: microcephaly MONDO:0001149, fetal growth restriction MONDO:0005030; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.2557 CFB Bryony Thompson reviewed gene: CFB: Rating: AMBER; Mode of pathogenicity: None; Publications: 33165708, 24152280; Phenotypes: complement factor b deficiency MONDO:0014255; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2557 SIRT1 Zornitza Stark Phenotypes for gene: SIRT1 were changed from autoimmune disease, MONDO:0007179 to autoimmune disease, MONDO:0007179; monogenic diabetes MONDO:0015967
Mendeliome v1.2556 SIRT1 Zornitza Stark Deleted their review
Mendeliome v1.2556 SIRT1 Zornitza Stark reviewed gene: SIRT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: monogenic diabetes MONDO:0015967; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2556 NARS Zornitza Stark Phenotypes for gene: NARS were changed from Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092; Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092; Hereditary peripheral neuropathy, MONDO:0020127, NARS-related
Mendeliome v1.2555 NARS Zornitza Stark Publications for gene: NARS were set to 32738225
Mendeliome v1.2554 NARS Zornitza Stark edited their review of gene: NARS: Added comment: Three families with isolated neuropathy and missense variants in this gene. Segregation and functional evidence. Likely phone expansion into the milder end of the spectrum for NARS-related disorders.; Changed publications: 32738225, 38495304, 38769024; Changed phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092, Hereditary peripheral neuropathy, MONDO:0020127, NARS-related, Abnormal muscle tone, Microcephaly, Global developmental delay, Intellectual disability, Seizures, Ataxia, Abnormality of the face, Demyelinating peripheral neuropathy
Mendeliome v1.2554 NOS3 Zornitza Stark Phenotypes for gene: NOS3 were changed from {Hypertension, susceptibility to}, MIM#145500; {Ischemic stroke, susceptibility to}, MIM# 601367; {Hypertension, pregnancy-induced}, MIM# 189800 to Moyamoya disease, MONDO:0016820
Mendeliome v1.2553 NOS3 Zornitza Stark Publications for gene: NOS3 were set to 24986538; 28084234; 33652340
Mendeliome v1.2552 NOS3 Zornitza Stark Mode of inheritance for gene: NOS3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2551 NOS3 Zornitza Stark Classified gene: NOS3 as Amber List (moderate evidence)
Mendeliome v1.2551 NOS3 Zornitza Stark Gene: nos3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2550 KEL Zornitza Stark Phenotypes for gene: KEL were changed from [Blood group, Kell] 110900 to vein of Galen aneurysm, MONDO:0015196
Mendeliome v1.2549 KEL Zornitza Stark Publications for gene: KEL were set to
Mendeliome v1.2548 KEL Zornitza Stark Mode of inheritance for gene: KEL was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2547 KEL Zornitza Stark reviewed gene: KEL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: vein of Galen aneurysm, MONDO:0015196; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2547 SIRT6 Zornitza Stark Phenotypes for gene: SIRT6 were changed from perinatal disease MONDO:0100086 to syndromic disease, MONDO:0002254, SIRT6-related
Mendeliome v1.2546 SIRT6 Zornitza Stark reviewed gene: SIRT6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: syndromic disease, MONDO:0002254, SIRT6-related; Mode of inheritance: None
Mendeliome v1.2546 LSM1 Zornitza Stark Phenotypes for gene: LSM1 were changed from neurodevelopmental disorder MONDO:0700092, LSM1-related to Neurodevelopmental disorder, MONDO:0700092, LSM1-related
Mendeliome v1.2545 LSM1 Zornitza Stark Publications for gene: LSM1 were set to 31010896
Mendeliome v1.2544 LSM1 Zornitza Stark Classified gene: LSM1 as Green List (high evidence)
Mendeliome v1.2544 LSM1 Zornitza Stark Gene: lsm1 has been classified as Green List (High Evidence).
Mendeliome v1.2543 LSM1 Zornitza Stark edited their review of gene: LSM1: Added comment: LSM1 encodes a subunit of a complex composed of proteins LSM1-7 which is involved in mRNA stabilisation as well as degradation. Other proteins within the complex are yet to have a definitive disease association however LSM7 has been reported a candidate gene.

3 papers detail 10 affected individuals from 6 families with either a homozygous recurrent splice variant (LSM1:c.231+4A>C) or a homozygous missense variant (LSM1:p.Asn40Tyr in only 1 family). Both very rare in gnomad v4 with 0 homozygotes.

The phenotype of the individuals encompassed severe intellectual disability/developmental delay, shared dysmorphic features (broad forehead, pointed chin, medially thickened arched eyebrows, hypertelorism, bulbous nasal tip), skeletal anomalies, cardiovascular (ASD/VSD/aortic valve) and genitourinary abnormalities (CAKUT/hypospadias), gastrointestinal manifestations, hypotonia and visual impairments.

RT PCR of the splice variant demonstrated exon 3 skipping with a resultant truncated protein with presumed loss of function mechanism. It was noted by authors there are no biallelic loss of function variant in the gnomad v4, as such it was suggested complete loss of function is non viable. Variants outside of exon 3 have not yet been reported in affected individuals.; Changed rating: GREEN; Changed publications: 31010896, 36100156, 40204357; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, LSM1-related
Mendeliome v1.2543 RNU2-2P Zornitza Stark Phenotypes for gene: RNU2-2P were changed from Neurodevelopmental disorder, MONDO:0700092, RNU2-2P-related to Neurodevelopmental disorder, MONDO:0700092, RNU2-2-related
Mendeliome v1.2542 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to https://www.medrxiv.org/content/10.1101/2024.09.03.24312863v1
Mendeliome v1.2541 RNU2-2P Zornitza Stark Tag new gene name tag was added to gene: RNU2-2P.
Mendeliome v1.2541 BRF2 Zornitza Stark Marked gene: BRF2 as ready
Mendeliome v1.2541 BRF2 Zornitza Stark Gene: brf2 has been classified as Green List (High Evidence).
Mendeliome v1.2541 BRF2 Zornitza Stark Classified gene: BRF2 as Green List (high evidence)
Mendeliome v1.2541 BRF2 Zornitza Stark Gene: brf2 has been classified as Green List (High Evidence).
Mendeliome v1.2540 BRF2 Zornitza Stark gene: BRF2 was added
gene: BRF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BRF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRF2 were set to 40229899
Phenotypes for gene: BRF2 were set to Syndromic disease, MONDO:0002254, BRF2-related
Review for gene: BRF2 was set to GREEN
Added comment: 7 individuals from 3 unrelated families reported. In addition, 3 Icelanding families with same recurrent splicing variant and recurrent perinatal deaths; however, affected individuals unable to be genotyped and this seems to be a founder variant. Craniofacial malformations, microcephaly and perinatal death in several individuals. Survivors had ID. Supportive functional data, including animal model.
Sources: Literature
Mendeliome v1.2539 ATP2A2 Zornitza Stark Phenotypes for gene: ATP2A2 were changed from Acrokeratosis verruciformis MIM#101900; Darier disease MIM#124200 to Acrokeratosis verruciformis MIM#101900; Darier disease MIM#124200; Congenital myopathy, MONDO:0019952, ATP2A2-related; rhabdomyolysis
Mendeliome v1.2538 ATP2A2 Zornitza Stark Publications for gene: ATP2A2 were set to PMID: 24336169
Mendeliome v1.2537 ATP2A2 Zornitza Stark reviewed gene: ATP2A2: Rating: AMBER; Mode of pathogenicity: None; Publications: 39970126; Phenotypes: Congenital myopathy, MONDO:0019952, ATP2A2-related, rhabdomyolysis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2537 MYO1A Bryony Thompson Mode of inheritance for gene: MYO1A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2536 MYO1A Bryony Thompson Classified gene: MYO1A as Amber List (moderate evidence)
Mendeliome v1.2536 MYO1A Bryony Thompson Gene: myo1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2535 FGF4 Bryony Thompson Marked gene: FGF4 as ready
Mendeliome v1.2535 FGF4 Bryony Thompson Gene: fgf4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2535 FGF4 Bryony Thompson Classified gene: FGF4 as Amber List (moderate evidence)
Mendeliome v1.2535 FGF4 Bryony Thompson Gene: fgf4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2534 EIF3K Bryony Thompson Marked gene: EIF3K as ready
Mendeliome v1.2534 EIF3K Bryony Thompson Gene: eif3k has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2534 EIF3K Bryony Thompson Classified gene: EIF3K as Amber List (moderate evidence)
Mendeliome v1.2534 EIF3K Bryony Thompson Gene: eif3k has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2533 PCNA Bryony Thompson Marked gene: PCNA as ready
Mendeliome v1.2533 PCNA Bryony Thompson Gene: pcna has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2533 PCNA Bryony Thompson Classified gene: PCNA as Amber List (moderate evidence)
Mendeliome v1.2533 PCNA Bryony Thompson Gene: pcna has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2532 RAB3A Bryony Thompson Marked gene: RAB3A as ready
Mendeliome v1.2532 RAB3A Bryony Thompson Gene: rab3a has been classified as Green List (High Evidence).
Mendeliome v1.2532 RAB3A Bryony Thompson Classified gene: RAB3A as Green List (high evidence)
Mendeliome v1.2532 RAB3A Bryony Thompson Gene: rab3a has been classified as Green List (High Evidence).
Mendeliome v1.2531 RAB3A Bryony Thompson gene: RAB3A was added
gene: RAB3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB3A were set to 40166812
Phenotypes for gene: RAB3A were set to autosomal dominant cerebellar ataxia MONDO:0020380; neurodevelopmental disorder MONDO:0700092
Review for gene: RAB3A was set to GREEN
Added comment: 18 individuals from 10 unrelated cerebellar ataxia families were heterozygous for a RAB3A missense variant. 9/10 families had a recurrent variant - p.Arg83Trp. The age of onset of the ataxia was adult, except for 3 paediatric/adolescent onset cases. Additionally, 4 individuals from 3 families (F11, F12, F13) with 2 de novo missense and a stopgain had similar phenotypes consisting of a neurodevelopmental syndrome with progressive cognitive deficits and spasticity. F14 was a singleton with a missense variant and HMSN & optic atrophy. Initially included in the cohort for gait ataxia, was found to be a sensory ataxia. There were supporting in vitro functional assays and Drosophila rescue models that suggest partial loss of function as the disease mechanism, but were unable to differentiate the genotype-phenotype correlation for the cerebellar ataxia phenotype vs the neurodevelopmental syndrome.
Sources: Literature
Mendeliome v1.2530 MYRF Zornitza Stark Phenotypes for gene: MYRF were changed from Nanophthalmos and high hyperopia; Cardiac-urogenital syndrome, MIM# 618280; Encephalitis/encephalopathy, mild, with reversible myelin vacuolization, MIM# 618113 to Nanophthalmos 1, MIM# 600165; Cardiac-urogenital syndrome, MIM# 618280; Encephalitis/encephalopathy, mild, with reversible myelin vacuolization, MIM# 618113
Mendeliome v1.2529 SIRT6 Bryony Thompson Marked gene: SIRT6 as ready
Mendeliome v1.2529 SIRT6 Bryony Thompson Gene: sirt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2529 SIRT6 Bryony Thompson Phenotypes for gene: SIRT6 were changed from to perinatal disease MONDO:0100086
Mendeliome v1.2528 SIRT6 Bryony Thompson Classified gene: SIRT6 as Amber List (moderate evidence)
Mendeliome v1.2528 SIRT6 Bryony Thompson Added comment: Comment on list classification: Single family and animal model
Mendeliome v1.2528 SIRT6 Bryony Thompson Gene: sirt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2527 MYO1A Sangavi Sivagnanasundram edited their review of gene: MYO1A: Added comment: A male infant presenting with congenital diarrhea from the age of 2.
Compound heterozygous variants in MYO1A detected in trans were identified (I678F (FAF 0.5%); D240N (FAF - 0.004%)
Supportive functional assay in patient fibroblasts was conducted along with a knockout mice model recapitulating human phenotype and findings consistent with the findings from the probands biopsy.; Changed rating: AMBER; Changed publications: 40174224; Changed phenotypes: Congenital diarrhea, MONDO:0000824; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2527 MYO1A Sangavi Sivagnanasundram reviewed gene: MYO1A: Rating: RED; Mode of pathogenicity: None; Publications: 24616153; Phenotypes: nonsyndromic genetic hearing loss MONDO:0019497; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2527 FGF4 Sangavi Sivagnanasundram gene: FGF4 was added
gene: FGF4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FGF4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGF4 were set to 40259859
Phenotypes for gene: FGF4 were set to Jeune Syndrome, FGF4-related, MONDO:0018770
Review for gene: FGF4 was set to AMBER
Added comment: Two families with three affected individuals reported with homozygous variants in FGF4.

Family 1 - Consanguineous parents with five children. Three are unaffected and two are affected with Jeune syndrome - like phenotypes. One of the affected siblings is deceased.
Proband was diagnosed with pulmonary hypoplasia at 6 months and later identified to have Jeune Syndrome due to other findings.
Homozygous p.Leu86Phe missense variant was identified (variant absent from gnomAD v4.1)

Family 2 - Non-consanguineous parents with affected son with Jeune syndrome like phenotype (pulmonary hypoplasia and thoracic dystrophy)
Homozygous p.Pro204His missense variant was identified (variant absent from gnomAD v4.1)
Sources: Literature
Mendeliome v1.2527 EIF3K Sangavi Sivagnanasundram edited their review of gene: EIF3K: Changed rating: AMBER
Mendeliome v1.2527 UNC50 Bryony Thompson Phenotypes for gene: UNC50 were changed from Arthrogryposis multiplex congenita to arthrogryposis multiplex congenita MONDO:0015168; congenital myasthenic syndrome MONDO:0018940
Mendeliome v1.2526 UNC50 Bryony Thompson Publications for gene: UNC50 were set to 29016857; 33820833
Mendeliome v1.2525 UNC50 Bryony Thompson reviewed gene: UNC50: Rating: AMBER; Mode of pathogenicity: None; Publications: 33820833, 29016857, 40219868; Phenotypes: arthrogryposis multiplex congenita MONDO:0015168, congenital myasthenic syndrome MONDO:0018940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2525 EIF3K Sangavi Sivagnanasundram changed review comment from: More evidence will be needed to determine whether variants in EIF3K result in a neurodevelopmental disorder.

Four individuals with global DD, microcephaly, and short stature. Three out of the four individuals had the recurrent homozygous EIF3K (Asp43Gly - gnomAD v4.1 GrpMax FAF - 0.06044%) variant whilst another individual has homozygous intronic EIF3K variant, c.355-13A>G (gnomADv4.1 GrpMax FAF = 0.002551%).
The 3 individuals of Puerto Rican ancestry with the recurrent missense variant also had homozygous SYNE4 variant (Arg119Trp) identified which the author related to the probands' hearing loss phenotype.
The Asp43Gly missense variant could potentially be a founder variant however only three families with affected probands have been reported with the variant.
Sources: Literature; to: More evidence will be needed to determine whether variants in EIF3K result in a neurodevelopmental disorder. Only two variants have been reported.

Four individuals with global DD, microcephaly, and short stature. Three out of the four individuals had the recurrent homozygous EIF3K (Asp43Gly - gnomAD v4.1 GrpMax FAF - 0.06044%) variant whilst another individual has homozygous intronic EIF3K variant, c.355-13A>G (gnomADv4.1 GrpMax FAF = 0.002551%).
The 3 individuals of Puerto Rican ancestry with the recurrent missense variant also had homozygous SYNE4 variant (Arg119Trp) identified which the author related to the probands' hearing loss phenotype.
The Asp43Gly missense variant could potentially be a founder variant however only three families with affected probands have been reported with the variant.
Sources: Literature
Mendeliome v1.2525 EIF3K Sangavi Sivagnanasundram gene: EIF3K was added
gene: EIF3K was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF3K were set to 40219605
Phenotypes for gene: EIF3K were set to EIF3K-related neurodevelopmental disorder, MONDO:0700092
Review for gene: EIF3K was set to RED
Added comment: More evidence will be needed to determine whether variants in EIF3K result in a neurodevelopmental disorder.

Four individuals with global DD, microcephaly, and short stature. Three out of the four individuals had the recurrent homozygous EIF3K (Asp43Gly - gnomAD v4.1 GrpMax FAF - 0.06044%) variant whilst another individual has homozygous intronic EIF3K variant, c.355-13A>G (gnomADv4.1 GrpMax FAF = 0.002551%).
The 3 individuals of Puerto Rican ancestry with the recurrent missense variant also had homozygous SYNE4 variant (Arg119Trp) identified which the author related to the probands' hearing loss phenotype.
The Asp43Gly missense variant could potentially be a founder variant however only three families with affected probands have been reported with the variant.
Sources: Literature
Mendeliome v1.2525 MON1A Bryony Thompson Marked gene: MON1A as ready
Mendeliome v1.2525 MON1A Bryony Thompson Gene: mon1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2525 MON1A Bryony Thompson Classified gene: MON1A as Amber List (moderate evidence)
Mendeliome v1.2525 MON1A Bryony Thompson Gene: mon1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2524 MON1A Bryony Thompson gene: MON1A was added
gene: MON1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MON1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MON1A were set to 40174224
Phenotypes for gene: MON1A were set to Congenital diarrhea MONDO:0000824
Review for gene: MON1A was set to AMBER
Added comment: Sources: Literature
Mendeliome v1.2523 GAP43 Bryony Thompson Marked gene: GAP43 as ready
Mendeliome v1.2523 GAP43 Bryony Thompson Gene: gap43 has been classified as Red List (Low Evidence).
Mendeliome v1.2523 GAP43 Bryony Thompson Classified gene: GAP43 as Red List (low evidence)
Mendeliome v1.2523 GAP43 Bryony Thompson Gene: gap43 has been classified as Red List (Low Evidence).
Mendeliome v1.2522 FOXM1 Bryony Thompson Marked gene: FOXM1 as ready
Mendeliome v1.2522 FOXM1 Bryony Thompson Gene: foxm1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2522 FOXM1 Bryony Thompson Classified gene: FOXM1 as Amber List (moderate evidence)
Mendeliome v1.2522 FOXM1 Bryony Thompson Gene: foxm1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2521 GRWD1 Bryony Thompson Marked gene: GRWD1 as ready
Mendeliome v1.2521 GRWD1 Bryony Thompson Gene: grwd1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2521 GRWD1 Bryony Thompson Classified gene: GRWD1 as Amber List (moderate evidence)
Mendeliome v1.2521 GRWD1 Bryony Thompson Gene: grwd1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2520 GRWD1 Bryony Thompson gene: GRWD1 was added
gene: GRWD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GRWD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRWD1 were set to 40174224
Phenotypes for gene: GRWD1 were set to Congenital diarrhoea MONDO:0000824
Review for gene: GRWD1 was set to AMBER
Added comment: Single family (sib pair) with biallelic missense variants. Supporting zebrafish model and in vitro functional assays. Deficiency is the expected mechanism of disease.
Sources: Literature
Mendeliome v1.2519 IFT57 Krithika Murali Phenotypes for gene: IFT57 were changed from Orofaciodigital syndrome XVIII, MIM# 617927; Bardet-Bield syndrome; ciliopathy - MONDO:0005308 to Orofaciodigital syndrome XVIII, MIM# 617927; Bardet-Bield syndrome; ciliopathy - MONDO:0005308
Mendeliome v1.2518 IFT57 Krithika Murali Phenotypes for gene: IFT57 were changed from Orofaciodigital syndrome XVIII, MIM# 617927 to Orofaciodigital syndrome XVIII, MIM# 617927; Bardet-Bield syndrome; ciliopathy - MONDO:0005308
Mendeliome v1.2517 IFT57 Krithika Murali Classified gene: IFT57 as Amber List (moderate evidence)
Mendeliome v1.2517 IFT57 Krithika Murali Gene: ift57 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2516 UGGT1 Krithika Murali Marked gene: UGGT1 as ready
Mendeliome v1.2516 UGGT1 Krithika Murali Gene: uggt1 has been classified as Green List (High Evidence).
Mendeliome v1.2516 UGGT1 Krithika Murali Phenotypes for gene: UGGT1 were changed from to Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG
Mendeliome v1.2515 UGGT1 Krithika Murali Publications for gene: UGGT1 were set to
Mendeliome v1.2514 UGGT1 Krithika Murali Mode of inheritance for gene: UGGT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2513 UGGT1 Krithika Murali Classified gene: UGGT1 as Green List (high evidence)
Mendeliome v1.2513 UGGT1 Krithika Murali Gene: uggt1 has been classified as Green List (High Evidence).
Mendeliome v1.2512 UGGT1 Krithika Murali reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40267907; Phenotypes: Congenital disorder of glycosylation - MONDO:0015286, UGGT1-CDG; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2512 IFT57 Krithika Murali reviewed gene: IFT57: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:40273360; Phenotypes: Bardet-Bield syndrome, ciliopathy - MONDO:0005308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2512 DLG3 Lilian Downie Phenotypes for gene: DLG3 were changed from Mental retardation, X-linked 90, MIM#300850 to Intellectual developmental disorder, X-linked 90 MIM#300850
Mendeliome v1.2511 NUDT2 Sangavi Sivagnanasundram reviewed gene: NUDT2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: intellectual developmental disorder with or without peripheral neuropathy, MONDO:0859240; Mode of inheritance: None
Mendeliome v1.2511 NLRP2 Sangavi Sivagnanasundram reviewed gene: NLRP2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte/zygote/embryo maturation arrest 18, MONDO:0957230; Mode of inheritance: None
Mendeliome v1.2511 NKAP Sangavi Sivagnanasundram reviewed gene: NKAP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, MONDO:0026733, MIM#301039; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2511 NDUFAF8 Sangavi Sivagnanasundram reviewed gene: NDUFAF8: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Leigh Syndrome MONDO:0009723; Mode of inheritance: None
Mendeliome v1.2511 NDUFAF7 Sangavi Sivagnanasundram reviewed gene: NDUFAF7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Pathological Myopia MONDO:0001383; Mode of inheritance: None
Mendeliome v1.2511 DIP2B_FRA12A_CGG Bryony Thompson FRA12A was changed to DIP2B_FRA12A_CGG
Mendeliome v1.2510 ZFHX3_SCA4_GGC Bryony Thompson SCA4_ZFHX3_GGC was changed to ZFHX3_SCA4_GGC
Mendeliome v1.2509 TBP_SCA17_CAG Bryony Thompson SCA17 was changed to TBP_SCA17_CAG
Mendeliome v1.2508 STARD7_FAME2_ATTTC Bryony Thompson FAME2 was changed to STARD7_FAME2_ATTTC
Mendeliome v1.2507 SAMD12_FAME1_TTTCA Bryony Thompson FAME1 was changed to SAMD12_FAME1_TTTCA
Mendeliome v1.2506 RILPL1_OPDM4_CGG Bryony Thompson OPDM4 was changed to RILPL1_OPDM4_CGG
Mendeliome v1.2505 PPP2R2B_SCA12_CAG Bryony Thompson SCA12 was changed to PPP2R2B_SCA12_CAG
Mendeliome v1.2504 PLIN4_MRUPAV_33-mer Bryony Thompson MRUPAV_PLIN4 was changed to PLIN4_MRUPAV_33-mer
Mendeliome v1.2503 NOTCH2NLC_NIID_GGC Bryony Thompson NIID was changed to NOTCH2NLC_NIID_GGC
Mendeliome v1.2502 NOP56_SCA36_GGCCTG Bryony Thompson SCA36 was changed to NOP56_SCA36_GGCCTG
Mendeliome v1.2501 JPH3_HDL2_CTG Bryony Thompson HDL2 was changed to JPH3_HDL2_CTG
Mendeliome v1.2500 GIPC1_OPDM2_CGG Bryony Thompson OPDM2 was changed to GIPC1_OPDM2_CGG
Mendeliome v1.2499 KEL Achchuthan Shanmugasundram reviewed gene: KEL: Rating: AMBER; Mode of pathogenicity: None; Publications: 30578106, 37978175; Phenotypes: vein of Galen aneurysm, MONDO:0015196; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2499 NOS3 Achchuthan Shanmugasundram reviewed gene: NOS3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36941667, 37383439; Phenotypes: Moyamoya disease, MONDO:0016820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2499 DMPK_DM1_CTG Bryony Thompson DM1 was changed to DMPK_DM1_CTG
Mendeliome v1.2498 DAB1_SCA37_ATTTC Bryony Thompson SCA37 was changed to DAB1_SCA37_ATTTC
Mendeliome v1.2497 CNBP_DM2_CCTG Bryony Thompson DM2 was changed to CNBP_DM2_CCTG
Mendeliome v1.2496 BEAN1_SCA31_TGGAA Bryony Thompson SCA31 was changed to BEAN1_SCA31_TGGAA
Mendeliome v1.2495 ATXN7_SCA7_CAG Bryony Thompson SCA7 was changed to ATXN7_SCA7_CAG
Mendeliome v1.2494 ATXN3_SCA3_CAG Bryony Thompson SCA3 was changed to ATXN3_SCA3_CAG
Mendeliome v1.2493 ATXN2_SCA2_CAG Bryony Thompson SCA2 was changed to ATXN2_SCA2_CAG
Mendeliome v1.2492 ATXN1_SCA1_CAG Bryony Thompson SCA1 was changed to ATXN1_SCA1_CAG
Mendeliome v1.2491 ATXN10_SCA10_ATTCT Bryony Thompson SCA10 was changed to ATXN10_SCA10_ATTCT
Mendeliome v1.2490 AFF2_FRAXE_GCC Bryony Thompson Marked STR: AFF2_FRAXE_GCC as ready
Mendeliome v1.2490 AFF2_FRAXE_GCC Bryony Thompson Str: aff2_fraxe_gcc has been classified as Green List (High Evidence).
Mendeliome v1.2490 AFF2_FRAXE_GCC Bryony Thompson Classified STR: AFF2_FRAXE_GCC as Green List (high evidence)
Mendeliome v1.2490 AFF2_FRAXE_GCC Bryony Thompson Str: aff2_fraxe_gcc has been classified as Green List (High Evidence).
Mendeliome v1.2489 AFF2_FRAXE_GCC Bryony Thompson STR: AFF2_FRAXE_GCC was added
STR: AFF2_FRAXE_GCC was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: AFF2_FRAXE_GCC was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for STR: AFF2_FRAXE_GCC were set to 8334699; 8673085; 11388762
Phenotypes for STR: AFF2_FRAXE_GCC were set to Intellectual developmental disorder, X-linked 109 MIM#309548
Review for STR: AFF2_FRAXE_GCC was set to GREEN
STR: AFF2_FRAXE_GCC was marked as clinically relevant
STR: AFF2_FRAXE_GCC was marked as current diagnostic
Added comment: NM_001169122.1(AFF2):c.-460_-458GCC(6_25)
Loss of function through methylation silencing is the mechanism of disease
Normal - 5-44 repeats
Inconclusive - 45-54 repeats
Premutation - 55-200 repeats
Abnormal - >200 or >230 repeats
Sources: Expert list
Mendeliome v1.2488 ABCD3_OPDM_GCC Bryony Thompson OPDM_ABCD3_GCC was changed to ABCD3_OPDM_GCC
Mendeliome v1.2487 Bryony Thompson removed STR:CANVAS_ACAGG from the panel
Mendeliome v1.2486 CANVAS_ACAGG Bryony Thompson Classified STR: CANVAS_ACAGG as No list
Mendeliome v1.2486 CANVAS_ACAGG Bryony Thompson Str: canvas_acagg has been removed from the panel.
Mendeliome v1.2485 RFC1_CANVAS_ANNGN Bryony Thompson RFC1_CANVAS_ANNGG was changed to RFC1_CANVAS_ANNGN
Repeated Sequence for RFC1_CANVAS_ANNGN was changed from ANNGG to ANNGN.
Publications for STR: RFC1_CANVAS_ANNGN were changed from 33237689; 32694621; 33103729; 35355059 to 33237689; 32694621; 33103729; 35355059; 37450567
Mendeliome v1.2484 RFC1_CANVAS_ANNGG Bryony Thompson RFC1_CANVAS_AMRGG was changed to RFC1_CANVAS_ANNGG
Mendeliome v1.2483 RFC1_CANVAS_AMRGG Bryony Thompson CANVAS was changed to RFC1_CANVAS_AMRGG
Repeated Sequence for RFC1_CANVAS_AMRGG was changed from AAGGG to ANNGG.
Publications for STR: RFC1_CANVAS_AMRGG were changed from 30926972; 32851396 to 33237689; 32694621; 33103729; 35355059
Mendeliome v1.2482 USP25 Zornitza Stark Classified gene: USP25 as Amber List (moderate evidence)
Mendeliome v1.2482 USP25 Zornitza Stark Gene: usp25 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2481 IFT140 Zornitza Stark Phenotypes for gene: IFT140 were changed from Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; Retinitis pigmentosa 80, MIM# 617781; {Polycystic kidney disease 9, susceptibility to} MIM#621164 to Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; Retinitis pigmentosa 80, MIM# 617781; {Polycystic kidney disease 9, susceptibility to} MIM#621164; Cranioectodermal dysplasia 5, MIM# 621180
Mendeliome v1.2480 IFT140 Zornitza Stark Publications for gene: IFT140 were set to 34890546; 22503633; 23418020; 28288023; 28724397; 26216056; 26968735
Mendeliome v1.2479 IFT140 Zornitza Stark edited their review of gene: IFT140: Added comment: Four unrelated families reported with biallelic variants and a cranioectrodermal dysplasia phenotype, part of the ciliopathy spectrum.; Changed publications: 22503633, 23418020, 28288023, 28724397, 26216056, 26968735, 32007091, 35873489, 37628605; Changed phenotypes: Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920, Retinitis pigmentosa 80, MIM# 617781, {Polycystic kidney disease 9, susceptibility to} MIM#621164, Cranioectodermal dysplasia 5, MIM# 621180
Mendeliome v1.2479 USP25 Sangavi Sivagnanasundram edited their review of gene: USP25: Added comment: This gene-disease association has been DISPUTED by ClinGen Epilepsy GCEP on 01/04/2025 - https://search.clinicalgenome.org/CCID:008786

ClinGen's reason for disuputed classification - "Case-level data was not considered strong enough to score. Functional data was not consistent among the variants and was difficult to interpret in relationship to a seizure phenotype. The knock-out mouse model did not exhibit spontaneous seizures so was not scored."

Downgrade to Amber due to the uncertainty was agreed within the user group.; Changed rating: AMBER; Changed phenotypes: USP25-related epilepsy (epilepsy MONDO:0005027)
Mendeliome v1.2479 FOXM1 Achchuthan Shanmugasundram gene: FOXM1 was added
gene: FOXM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXM1 were set to 38969938
Phenotypes for gene: FOXM1 were set to Moyamoya disease, MONDO:0016820
Review for gene: FOXM1 was set to AMBER
Added comment: PMID:38969938 reported a 60-year-old father and 31-year-old daughter with unilateral Moyamoya Disease and with c.1205 C > A variant in FOXM1 gene (p.(Ala402Glu). There is also functional evidence available for the identified variant from the publication. This gene should be rated amber with current evidence.
Sources: Literature
Mendeliome v1.2479 B3GALT6 Sangavi Sivagnanasundram reviewed gene: B3GALT6: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008674; Phenotypes: B3GALT6-congenital disorder of glycosylation MONDO:0100586; Mode of inheritance: None
Mendeliome v1.2479 PIK3R5 Sangavi Sivagnanasundram reviewed gene: PIK3R5: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008779; Phenotypes: ataxia with oculomotor apraxia type 3 MONDO:0014084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2479 PCNA Sangavi Sivagnanasundram gene: PCNA was added
gene: PCNA was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: PCNA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCNA were set to 24911150, 33426167, 36990216
Phenotypes for gene: PCNA were set to hereditary ataxia MONDO:0100309
Review for gene: PCNA was set to AMBER
Added comment: Classified as Limited by Cerebellar Ataxia GCEP on 09/04/2025 - https://search.clinicalgenome.org/CCID:008778

Two missense variants have been reported across 5 families. Both the missense variants are present in gnomAD (rare enough for AR gene). Method of pathogenicity is still unknown.
Affected individuals reported with ataxia, photosensitivity, telangiectasias, and some degree of intellectual disability.
Sources: ClinGen
Mendeliome v1.2479 ANKZF1 Sangavi Sivagnanasundram reviewed gene: ANKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008790; Phenotypes: inflammatory bowel disease MONDO:0005265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2479 SIRT1 Sangavi Sivagnanasundram reviewed gene: SIRT1: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008794; Phenotypes: monogenic diabetes MONDO:0015967; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2479 FGFR3 Bryony Thompson Mode of inheritance for gene: FGFR3 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 v1.2478 FGFR1 Bryony Thompson Publications for gene: FGFR1 were set to 18034870; 23812909; 26942290; 16470795; 15625620; 29147600; 20339250
Mendeliome v1.2477 FGFR1 Bryony Thompson Publications for gene: FGFR1 were set to 18034870; 23812909; 26942290
Mendeliome v1.2476 FGF8 Bryony Thompson Publications for gene: FGF8 were set to 34433009; 32664970; 7768185; 32664970; 10603341; 19509466; 9462741; 10603341; 12223415
Mendeliome v1.2475 FGF8 Bryony Thompson Publications for gene: FGF8 were set to 34433009
Mendeliome v1.2474 FGA Bryony Thompson Publications for gene: FGA were set to 31064749; 17295221; 19073821; 11739173
Mendeliome v1.2473 FGA Bryony Thompson Mode of inheritance for gene: FGA 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
Mendeliome v1.2472 FGB Bryony Thompson Publications for gene: FGB were set to 12393540; 16195396
Mendeliome v1.2471 FGB Bryony Thompson Mode of inheritance for gene: FGB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2470 FGB Bryony Thompson reviewed gene: FGB: Rating: GREEN; Mode of pathogenicity: None; Publications: 24560896; Phenotypes: Congenital fibrinogen deficiency MONDO:0018060; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2470 FGA Bryony Thompson reviewed gene: FGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 10602365, 11460510; Phenotypes: Congenital fibrinogen deficiency MONDO:0018060; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.2470 FAR1 Bryony Thompson reviewed gene: FAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33586168, 25439727; Phenotypes: Fatty acyl-CoA reductase 1 deficiency MONDO:0014510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.2470 FANCM Bryony Thompson edited their review of gene: FANCM: Added comment: Now 4 families with biallelic variants reported with spermatogenic failure; Changed publications: 29231814, 28837162, 33036707, 25010009, 38927643, 35413094, 30075111, 29895858; Changed phenotypes: Premature ovarian failure 15 MIM#618096, spermatogenic failure 28 MONDO:0054732; Set current diagnostic: yes
Mendeliome v1.2470 FANCI Bryony Thompson Publications for gene: FANCI were set to 17452773
Mendeliome v1.2469 F9 Bryony Thompson reviewed gene: F9: Rating: GREEN; Mode of pathogenicity: Other; Publications: 19846852, 32079698, 38886735, 38358900, 37414287, 33656538; Phenotypes: thrombophilia, X-linked, due to factor 9 defect MONDO:0010432; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2469 F9 Bryony Thompson Publications for gene: F9 were set to 19846852; 34015304; 33656538; 3001143; 9016521; 19815722
Mendeliome v1.2468 F9 Bryony Thompson Publications for gene: F9 were set to 19846852; 34015304; 33656538
Mendeliome v1.2467 F5 Bryony Thompson Publications for gene: F5 were set to
Mendeliome v1.2466 F2 Bryony Thompson Classified gene: F2 as Green List (high evidence)
Mendeliome v1.2466 F2 Bryony Thompson Added comment: Comment on list classification: Gain of function is the mechanism of disease for dominant thrombophilia, and biallelic loss of function is the mechanism for congenital prothrombin deficiency.
Mendeliome v1.2466 F2 Bryony Thompson Gene: f2 has been classified as Green List (High Evidence).
Mendeliome v1.2465 F2 Bryony Thompson Tag 5'UTR was removed from gene: F2.
Tag UTR tag was added to gene: F2.
Mendeliome v1.2465 F2 Bryony Thompson Publications for gene: F2 were set to 30297698
Mendeliome v1.2464 IFT140 Zornitza Stark Phenotypes for gene: IFT140 were changed from Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; MONDO:0009964; Retinitis pigmentosa 80, MIM# 617781; Cystic Kidney Disease, MONDO: 0002473 to Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; Retinitis pigmentosa 80, MIM# 617781; {Polycystic kidney disease 9, susceptibility to} MIM#621164
Mendeliome v1.2463 IFT140 Zornitza Stark edited their review of gene: IFT140: Changed phenotypes: Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920, Retinitis pigmentosa 80, MIM# 617781, {Polycystic kidney disease 9, susceptibility to} MIM#621164
Mendeliome v1.2463 EYA4 Bryony Thompson reviewed gene: EYA4: Rating: AMBER; Mode of pathogenicity: None; Publications: 10769282, 30155266, 33745059; Phenotypes: dilated cardiomyopathy 1J MONDO:0011541; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2463 ERLIN2 Bryony Thompson Mode of inheritance for gene: ERLIN2 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2462 ERLIN2 Bryony Thompson edited their review of gene: ERLIN2: Added comment: AR and AD variants appear to have a different mechanism of disease. AR is presumably loss of function. The mechanism of disease for AD HSP is expected to be dominant negative but has not been confirmed; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2462 SIRT6 Achchuthan Shanmugasundram gene: SIRT6 was added
gene: SIRT6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIRT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SIRT6 were set to 29555651; 30135584
Review for gene: SIRT6 was set to GREEN
Added comment: PMID:29555651 reported a family with four consecutive cases of late foetal loss with gestational ages between 17 and 35 weeks. The foetuses showed prenatal abnormalities including intrauterine growth restriction (IUGR), microcephaly, craniofacial anomalies, sex reversal in male foetuses, and congenital heart defects. A homozygous inactivating variant in SIRT6 gene (c.187G > C; p.(Asp63His)) was identified by WES in the four foetuses. There is also functional data available from in vitro studies, SIRT6 D63H mouse embryonic stem cells and human induced pluripotent stem cells (iPSCs) derived from D63H homozygous foetuses.

There is also functional evidence available from several other studies including PMID:30135584, where CRISPR-Cas9-based approach was used to generate a SIRT6-null cynomolgus monkey (Macaca fascicularis) model. SIRT6-deficient monkeys died hours after birth and exhibited severe prenatal developmental retardation.

This gene has not been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.2462 RNU2-2P Achchuthan Shanmugasundram reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: None; Publications: 40210679; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2462 ENAM Bryony Thompson Added comment: Comment on mode of inheritance: Same mechanism of disease for monoallelic vs biallelic. Biallelic phenotype is more severe
Mendeliome v1.2462 ENAM Bryony Thompson Mode of inheritance for gene: ENAM 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
Mendeliome v1.2461 ELOVL4 Bryony Thompson changed review comment from: Well-established gene-disease associations. Monoallelic loss-of-function variants are associated with macular dystrophy/Stargardt disease. Biallelic loss-of-function variants cause congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome. Monoallelic missense variants cause spinocerebellar ataxia.; to: Well-established gene-disease associations. Monoallelic truncating variants in the last exon with an expected dominant effect are associated with macular dystrophy/Stargardt disease. Biallelic loss-of-function variants cause congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome. Monoallelic missense variants cause spinocerebellar ataxia.
Mendeliome v1.2461 ELOVL1 Bryony Thompson Publications for gene: ELOVL1 were set to
Mendeliome v1.2460 ELOVL1 Bryony Thompson Mode of inheritance for gene: ELOVL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2459 ELOVL1 Bryony Thompson reviewed gene: ELOVL1: Rating: RED; Mode of pathogenicity: None; Publications: 35379526; Phenotypes: ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features MONDO:0032798; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2459 ELOVL1 Bryony Thompson Deleted their review
Mendeliome v1.2459 EIF2AK4 Bryony Thompson Publications for gene: EIF2AK4 were set to
Mendeliome v1.2458 EIF2AK2 Bryony Thompson Phenotypes for gene: EIF2AK2 were changed from Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness; Dystonia to Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness; Dystonia; complex neurodevelopmental disorder MONDO:0100038
Mendeliome v1.2457 EIF2A Bryony Thompson Phenotypes for gene: EIF2A were changed from Intellectual disability, epilepsy to Intellectual disability, epilepsy; MONDO:0700092
Mendeliome v1.2456 EIF2AK1 Bryony Thompson Phenotypes for gene: EIF2AK1 were changed from Intellectual disability; white matter abnormalities to Intellectual disability; white matter abnormalities; MONDO:0100038
Mendeliome v1.2455 EGR2 Bryony Thompson Mode of inheritance for gene: EGR2 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2454 EGR2 Bryony Thompson Mode of inheritance for gene: EGR2 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
Mendeliome v1.2453 EFNA4 Bryony Thompson Classified gene: EFNA4 as Red List (low evidence)
Mendeliome v1.2453 EFNA4 Bryony Thompson Gene: efna4 has been classified as Red List (Low Evidence).
Mendeliome v1.2452 EFNA4 Bryony Thompson changed review comment from: Supporting animal models, but no compelling evidence in human cases. There’s no supporting segregation evidence and most of the variants reports to date are more common than expected for a dominant disease.

PMID: 34586326 - 3 missense variants identified in a cohort of 101 children with non-syndromic craniosynostosis (EFNA4, c.178C>T: p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1, c.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr - 337 hets in gnomAD v2.1). All 3 variants were present in at least one non-affected family member

PMID: 23983218, 33065355 - Efna4 KO mouse line demonstrates skeletal variance. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls

PMID: 29215649 - 1 missense variant (c.211G>A, p.(Glu71Lys) - 7 hets in gnomAD v2.1) identified in a unicoronal craniosynostosis case in a cohort of 309 craniosynostosis cases

PMID: 29168297 - 1 missense variant (c.550C>T; p.(Leu184Phe) - 1 het in gnomAD v2.1) in a metopic craniosynostosis case from a cohort of 391 single suture craniosynostosis cases. The variant was inherited from an unaffected parent.

PMID: 19772933 - a de novo 1.4 Mb microdeletion of chromosome 1q21.3, including EFNA1, EFNA3 and EFNA4, was identified in a child with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly.

PMID: 19201948 - EphA4 -/- mutant mice exhibit defects in the coronal suture and neural crest-mesoderm boundary that phenocopy those of Twist1+/- mice. The EphA4 +/- mice were similar to the wild-type controls.

PMID: 16540516 - 3 variants (178C>T p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1; c.349C>A p.Pro117Thr - 337 hets in gnomAD v2.1; frameshift 471_472delCCinsA) in cohort of 81 non-syndromic coronal synostosis cases. 2 of the variants were inherited from unaffected parents and Pro117Thr was de novo (confirmed). In vitro functional assays demonstrated partial or complete loss of function for the missense variants. Fibroblasts from the patient with the frameshift expressed in an alternatively spliced minor isoform of EFNA4.; to: Supporting animal models, but no compelling evidence in human cases has been reported since 2006. There’s no supporting segregation evidence and most of the variants reports to date are more common than expected for a dominant disease.

PMID: 34586326 - 3 missense variants identified in a cohort of 101 children with non-syndromic craniosynostosis (EFNA4, c.178C>T: p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1, c.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr - 337 hets in gnomAD v2.1). All 3 variants were present in at least one non-affected family member

PMID: 23983218, 33065355 - Efna4 KO mouse line demonstrates skeletal variance. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls

PMID: 29215649 - 1 missense variant (c.211G>A, p.(Glu71Lys) - 7 hets in gnomAD v2.1) identified in a unicoronal craniosynostosis case in a cohort of 309 craniosynostosis cases

PMID: 29168297 - 1 missense variant (c.550C>T; p.(Leu184Phe) - 1 het in gnomAD v2.1) in a metopic craniosynostosis case from a cohort of 391 single suture craniosynostosis cases. The variant was inherited from an unaffected parent.

PMID: 19772933 - a de novo 1.4 Mb microdeletion of chromosome 1q21.3, including EFNA1, EFNA3 and EFNA4, was identified in a child with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly.

PMID: 19201948 - EphA4 -/- mutant mice exhibit defects in the coronal suture and neural crest-mesoderm boundary that phenocopy those of Twist1+/- mice. The EphA4 +/- mice were similar to the wild-type controls.

PMID: 16540516 - 3 variants (178C>T p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1; c.349C>A p.Pro117Thr - 337 hets in gnomAD v2.1; frameshift 471_472delCCinsA) in cohort of 81 non-syndromic coronal synostosis cases. 2 of the variants were inherited from unaffected parents and Pro117Thr was de novo (confirmed). In vitro functional assays demonstrated partial or complete loss of function for the missense variants. Fibroblasts from the patient with the frameshift expressed in an alternatively spliced minor isoform of EFNA4.
Mendeliome v1.2452 EFNA4 Bryony Thompson edited their review of gene: EFNA4: Changed rating: RED; Changed publications: 16540516, 19201948, 19772933, 23983218, 29168297, 29215649, 33065355, 34586326, 36140816
Mendeliome v1.2452 EFEMP1 Bryony Thompson Publications for gene: EFEMP1 were set to 32006683; 31792352; 33807164
Mendeliome v1.2451 EEF1D Bryony Thompson Publications for gene: EEF1D were set to 30787422; 28097321
Mendeliome v1.2450 EEF1D Bryony Thompson Classified gene: EEF1D as Green List (high evidence)
Mendeliome v1.2450 EEF1D Bryony Thompson Gene: eef1d has been classified as Green List (High Evidence).
Mendeliome v1.2449 EEF1D Bryony Thompson reviewed gene: EEF1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 38083972, 36576126, 30787422, 28097321; Phenotypes: Neurodevelopmental disorder MONDO:0700092, EEF1D-related; Mode of inheritance: None
Mendeliome v1.2449 EDARADD Bryony Thompson Publications for gene: EDARADD were set to
Mendeliome v1.2448 BLK Bryony Thompson Classified gene: BLK as Red List (low evidence)
Mendeliome v1.2448 BLK Bryony Thompson Added comment: Comment on list classification: Two individuals in a single family heterozygous for a missense variant p.L3P (46 hets in gnomAD v4) reported with CVID. There have been no other reports in the last 10 years.
Mendeliome v1.2448 BLK Bryony Thompson Gene: blk has been classified as Red List (Low Evidence).
Mendeliome v1.2447 SPOUT1 Zornitza Stark reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, MIM# 621154; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2447 SPOUT1 Zornitza Stark Phenotypes for gene: SPOUT1 were changed from complex neurodevelopmental disorder MONDO:0100038, SPOUT1-related to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, MIM# 621154
Mendeliome v1.2446 DISP1 Zornitza Stark Phenotypes for gene: DISP1 were changed from Holoprosencephaly, MONDO:0016296 to Holoprosencephaly 10, MIM# 621143
Mendeliome v1.2445 KRT83 Zornitza Stark Phenotypes for gene: KRT83 were changed from Erythrokeratodermia variabilis et progressiva 5, MIM# 617756; Monilethrix , MIM#158000 to Erythrokeratodermia variabilis et progressiva 5, MIM# 617756; Monilethrix , MIM#621170
Mendeliome v1.2444 KRT83 Zornitza Stark edited their review of gene: KRT83: Changed phenotypes: Erythrokeratodermia variabilis et progressiva 5, MIM# 617756, Monilethrix , MIM#621170
Mendeliome v1.2444 KRT81 Zornitza Stark Phenotypes for gene: KRT81 were changed from Monilethrix, MIM# 158000 to Monilethrix, MIM# 621169
Mendeliome v1.2443 KRT81 Zornitza Stark edited their review of gene: KRT81: Changed phenotypes: Monilethrix, MIM# 621169
Mendeliome v1.2443 ATP11A Sangavi Sivagnanasundram changed review comment from: PMID: 39432785 (upgraded to GREEN on leukodystrophy panel)
3 unrelated probands with variable neurological features presenting in childhood however only two presented with leukodystrophy like symptoms
Patient 1 (canadian) and 3 (USA) showed bilateral hypomyelination on brain MRI

PMID: 40185629 - refractory focal epilepsy (AMBER for epilepsy)
chinese probands - childhood cases
De novo missense variants were identified in the two unrelated probands of chinese descent
Case 1 - female patient experiencing epileptic seizures from the age of 4 - Lys812Ile
Case 2 - male patient experienceing epileptic seizures from the age of 7 - Trp1036Cys; to: PMID: 39432785 (upgraded to GREEN on leukodystrophy panel)
3 unrelated probands with variable neurological features presenting in childhood however only two presented with leukodystrophy like symptoms
Patient 1 (canadian) and 3 (USA) showed bilateral hypomyelination on brain MRI

PMID: 40185629 - Two chinese individuals reported with refractory focal epilepsy (AMBER for epilepsy)

De novo missense variants were identified in the two unrelated probands of chinese descent
Case 1 - female patient experiencing epileptic seizures from the age of 4 - Lys812Ile
Case 2 - male patient experienceing epileptic seizures from the age of 7 - Trp1036Cys
Mendeliome v1.2443 ATP11A Sangavi Sivagnanasundram reviewed gene: ATP11A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39432785, 40185629; Phenotypes: leukodystrophy, hypomyelinating, 24, MONDO:0859242, Focal epilepsy MONDO:0005384; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2443 AP5B1 Bryony Thompson Marked gene: AP5B1 as ready
Mendeliome v1.2443 AP5B1 Bryony Thompson Gene: ap5b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2443 AP5B1 Bryony Thompson Classified gene: AP5B1 as Amber List (moderate evidence)
Mendeliome v1.2443 AP5B1 Bryony Thompson Gene: ap5b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2442 AP5B1 Bryony Thompson gene: AP5B1 was added
gene: AP5B1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AP5B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP5B1 were set to 40081374
Phenotypes for gene: AP5B1 were set to Hereditary macular dystrophy MONDO:0020242, AP-5 complex-related
Review for gene: AP5B1 was set to AMBER
Added comment: Currently only 2 unrelated cases with macular dystrophy (1 hom & 1 chet). The study also presents sufficient evidence for an association of another AP-5 complex gene (AP5Z1) with macular dystrophy. AP-5 complex proteins (AP5Z1, AP5M1, and AP5B1) display punctate localization in human RPE explants.
Sources: Literature
Mendeliome v1.2441 AP5M1 Bryony Thompson Marked gene: AP5M1 as ready
Mendeliome v1.2441 AP5M1 Bryony Thompson Gene: ap5m1 has been classified as Green List (High Evidence).
Mendeliome v1.2441 AP5M1 Bryony Thompson Classified gene: AP5M1 as Green List (high evidence)
Mendeliome v1.2441 AP5M1 Bryony Thompson Gene: ap5m1 has been classified as Green List (High Evidence).
Mendeliome v1.2440 AP5M1 Bryony Thompson gene: AP5M1 was added
gene: AP5M1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AP5M1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP5M1 were set to 40081374
Phenotypes for gene: AP5M1 were set to Hereditary macular dystrophy MONDO:0020242, AP-5 complex-related
Review for gene: AP5M1 was set to GREEN
Added comment: 3 unrelated cases with macular dystrophy and homozygous variants (2x nonsense & a missense). The study also presents sufficient evidence for an association of another AP-5 complex gene (AP5Z1) with macular dystrophy. AP-5 complex proteins (AP5Z1, AP5M1, and AP5B1) display punctate localization in human RPE explants.
Sources: Literature
Mendeliome v1.2439 AP5Z1 Bryony Thompson reviewed gene: AP5Z1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40081374, 33543803; Phenotypes: Spastic paraplegia 48, autosomal recessive, MIM# 613647, MONDO:0013342, Hereditary macular dystrophy MONDO:0020242; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2439 KCTD10 Bryony Thompson Marked gene: KCTD10 as ready
Mendeliome v1.2439 KCTD10 Bryony Thompson Gene: kctd10 has been classified as Green List (High Evidence).
Mendeliome v1.2439 KCTD10 Bryony Thompson Classified gene: KCTD10 as Green List (high evidence)
Mendeliome v1.2439 KCTD10 Bryony Thompson Gene: kctd10 has been classified as Green List (High Evidence).
Mendeliome v1.2438 KCTD10 Bryony Thompson gene: KCTD10 was added
gene: KCTD10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCTD10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCTD10 were set to 24705121; 24430697; 38489388; 40121532
Phenotypes for gene: KCTD10 were set to multiple congenital anomalies/dysmorphic syndrome MONDO:0019042, KCTD10-related
Review for gene: KCTD10 was set to GREEN
Added comment: Two unrelated probands with multiple congenital anomalies, both with abnormalities of the cardiovascular system and confirmed de novo novel missense variants (p.R248Q and p.N169S). There were also additional individuals (<5) in the GeneDx in-house database who didn’t consent to case-level publication with confirmed de novo missesne variants in KCTD10 and overlapping phenotypes (100% with abnormalities of the cardiovascular system). Other congenital anomalies of different organs systems were present in 33-67% of the individuals. Further elucidation of the phenotypes associated with this gene are required. Additionally, null mouse and zebrafish models suggest Kctd10 is critical for cardiovascular development and is involved in the regulation of brain development.
Sources: Literature
Mendeliome v1.2437 ATP6V1B1 Sarah Leigh reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39837581, 9916796, 12566520, 18798332; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM#267300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2437 CDKL2 Zornitza Stark Marked gene: CDKL2 as ready
Mendeliome v1.2437 CDKL2 Zornitza Stark Gene: cdkl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2437 CDKL2 Zornitza Stark Classified gene: CDKL2 as Amber List (moderate evidence)
Mendeliome v1.2437 CDKL2 Zornitza Stark Gene: cdkl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2436 CDKL2 Zornitza Stark reviewed gene: CDKL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CDKL2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2436 CDKL1 Zornitza Stark Marked gene: CDKL1 as ready
Mendeliome v1.2436 CDKL1 Zornitza Stark Gene: cdkl1 has been classified as Red List (Low Evidence).
Mendeliome v1.2436 CDKL1 Zornitza Stark Classified gene: CDKL1 as Red List (low evidence)
Mendeliome v1.2436 CDKL1 Zornitza Stark Gene: cdkl1 has been classified as Red List (Low Evidence).
Mendeliome v1.2435 CDKL1 Zornitza Stark reviewed gene: CDKL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CDKL1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2435 EIF4ENIF1 Zornitza Stark Publications for gene: EIF4ENIF1 were set to 31810472; 23902945; 33095795
Mendeliome v1.2434 EIF4ENIF1 Zornitza Stark Classified gene: EIF4ENIF1 as Green List (high evidence)
Mendeliome v1.2434 EIF4ENIF1 Zornitza Stark Gene: eif4enif1 has been classified as Green List (High Evidence).
Mendeliome v1.2433 EIF4ENIF1 Zornitza Stark reviewed gene: EIF4ENIF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23902945, 39827467, 36030004, 38604507, 31810472, 33095795; Phenotypes: Primary ovarian insufficiency, MONDO:0005387, EIF4ENIF1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2433 CDC20 Zornitza Stark Marked gene: CDC20 as ready
Mendeliome v1.2433 CDC20 Zornitza Stark Gene: cdc20 has been classified as Green List (High Evidence).
Mendeliome v1.2433 CDC20 Zornitza Stark Classified gene: CDC20 as Green List (high evidence)
Mendeliome v1.2433 CDC20 Zornitza Stark Gene: cdc20 has been classified as Green List (High Evidence).
Mendeliome v1.2432 CDC20 Zornitza Stark gene: CDC20 was added
gene: CDC20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC20 were set to 32666501; 33683667; 33898437; 34218387
Phenotypes for gene: CDC20 were set to Oocyte/zygote/embryo maturation arrest 14, MIM# 620276
Review for gene: CDC20 was set to GREEN
Added comment: i) PMID: 32666501- Biallelic (homozygous/compound heterozygous) variants in 5 unrelated Chinese women with infertility due to oocyte maturation arrest. Knocked down mouse oocytes showed an metaphase I (MI) arrest phenotype that could be rescued by injection of wildtype human CDC20 cRNA; all of the variants significantly reduced the ability of CDC20 to rescue the phenotype.

ii) PMID: 33683667- a compound heterozygous (missense and nonsense) variant in a Chinese woman with infertility due to oocyte maturation abnormalities and early embryonic arrest.

iii) PMID: 33898437- 4 patients from 3 Chinese families with homozygous or compound heterozygous variants with infertility due to oocyte maturation arrest, fertilization failure, and early embryonic arrest. Functional analysis in mouse oocytes with knockdown of Cdc20 showed that the homozygous and compound heterozygous variants significantly reduced the ability of CDC20 to rescue the lack of PB1 extrusion (MI arrest).

iv) PMID: 34218387- homozygous missense variant in a Chinese woman with infertility due to oocyte maturation arrest at MI and fertilization failure of MII oocytes.
Sources: Literature
Mendeliome v1.2431 CCNB3 Zornitza Stark Marked gene: CCNB3 as ready
Mendeliome v1.2431 CCNB3 Zornitza Stark Gene: ccnb3 has been classified as Green List (High Evidence).
Mendeliome v1.2431 CCNB3 Zornitza Stark Classified gene: CCNB3 as Green List (high evidence)
Mendeliome v1.2431 CCNB3 Zornitza Stark Gene: ccnb3 has been classified as Green List (High Evidence).
Mendeliome v1.2430 CCNB3 Zornitza Stark gene: CCNB3 was added
gene: CCNB3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CCNB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCNB3 were set to 35722368; 32938693; 34021051; 30770433; 34850816
Phenotypes for gene: CCNB3 were set to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CCNB3-related
Review for gene: CCNB3 was set to GREEN
Added comment: i) PMID: 35722368- homozygous missense variant (p.P119Q) in the female of unexplained recurrent pregnancy loss (RPL) couple (couple 29)
ii) PMID: 32938693- homozygous missense variant (p.V1251D) in two sisters with RPL and two of their POCs were characterised and found to be triploid digynic due to the failure of meiosis II.
iii) PMID: 34021051- novel homozygous frameshift variant (p.Val1321Glyfs*4, due to splicing causing exon skipping) in a patient with 16 RPL and one of her miscarriages is triploid digynic resulted from the failure of meiosis I.

Supporting mouse evidence:
iv) PMID: 30770433- Ccnb3 knockout also causes female infertility due to the failure of metaphase to anaphase transition in meiosis I and the extrusion of the first polar body. The infertility in these mice appeared to be due to embryonic lethality before embryonic day 7.5 and some of their oocytes fertilised by intracytoplasmic sperm injection led to triploid embryos.
v) PMID: 34850816- Ccnb3-deficient mouse model is similar to a human infertility condition—recurrent pregnancy loss (RPL). Their findings demonstrate that the triploidy of embryos derived from Ccnb3-deficient oocytes is the primary cause of embryo death (i.e., such embryos can be rescued with euploid nuclei, whereas cytoplasmic Ccnb3 transcript is dispensable for zygotic genome activation and embryo development).
Sources: Expert Review
Mendeliome v1.2429 CDKL1 Sarah Milton gene: CDKL1 was added
gene: CDKL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDKL1 were set to PMID: 40088891
Phenotypes for gene: CDKL1 were set to Neurodevelopmental disorder, MONDO:0700092, CDKL1-related
Mode of pathogenicity for gene: CDKL1 was set to Other
Review for gene: CDKL1 was set to AMBER
Added comment: CDKL1 encodes a cyclin dependent kinase of which there are CDKL1-5 in humans.
(CDKL5 has been associated with a neurodevelopmental disorder previously.)

Bereshneh et al describe 2 individuals with a neurodevelopmental disorder with de novo variants in CDKL1 sourced from databases containing individuals with neurodevelopmental disorders, no additional phenotypic information was provided. Both variants were missense and present in the population (c.505C>T - 13 heterozygotes in gnomad 4, c.344T>C - 2 heterozygotes gnomad 4).

Both missense variants were located in the kinase domain and dominant negative mechanism was postulated based on drosophilia studies.

Functional studies in drosphilia showed variants seen in probands partially rescued a loss of function model however overexpression of transcripts containing the variants resulted in a more severe phenotype suggesting dominant negative.
Authors also noted the larger than expected number of LOF variants in gnomad for the disease to be caused by this mechanism.
Sources: Literature
Mendeliome v1.2429 CDKL2 Sarah Milton gene: CDKL2 was added
gene: CDKL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDKL2 were set to PMID: 40088891
Phenotypes for gene: CDKL2 were set to Neurodevelopmental disorder, MONDO:0700092, CDKL2-related
Mode of pathogenicity for gene: CDKL2 was set to Other
Review for gene: CDKL2 was set to AMBER
Added comment: CDKL2 encodes a cyclin dependent kinase of which there are CDKL1-5 in humans.
(CDKL5 has been associated with a neurodevelopmental disorder previously.)

Bereshneh et al describe 5 individuals with a neurodevelopmental disorder with de novo variants in CDKL2. 3 variants were missense, 1 was an in frame single amino acid deletion.
2 of the individuals described were monozygotic twins who were born at 30/40 and also had PVL on neuroimaging.

Phenotype included GDD (5/5) - severity not described, speech impairment (5/5), motor impairment (4/5), epilepsy (3/5), ID (3/5), IUGR (3/5), poor growth postnatally (3/5), GI/feeding issues (3/5), tone abnormality (3/5)

Missense variants were located in the kinase domain and dominant negative mechanism was postulated based on drosophilia studies.

Functional studies in drosphilia showed variants seen in probands did not completely rescue a loss of function model, as well as this, overexpression of transcripts containing the variants resulted in a more severe phenotype suggesting dominant negative.
Authors also noted the larger than expected number of LOF variants in gnomad for the disease to be caused by this mechanism.
Sources: Literature
Sources: Literature
Mendeliome v1.2429 TEX11 Zornitza Stark Marked gene: TEX11 as ready
Mendeliome v1.2429 TEX11 Zornitza Stark Gene: tex11 has been classified as Green List (High Evidence).
Mendeliome v1.2429 TEX11 Zornitza Stark Classified gene: TEX11 as Green List (high evidence)
Mendeliome v1.2429 TEX11 Zornitza Stark Gene: tex11 has been classified as Green List (High Evidence).
Mendeliome v1.2428 TEX11 Zornitza Stark gene: TEX11 was added
gene: TEX11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: TEX11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TEX11 were set to 25970010; 29661171; 34621296; 37124723
Phenotypes for gene: TEX11 were set to Spermatogenic failure, X-linked 2, MIM# 309120
Review for gene: TEX11 was set to GREEN
Added comment: i) PMID:25970010- hemizygous variants in 7 out of of 289 azoospermic men, including a 90kb exonic deletion (Ex10-12) in 2 European men, 2 missense variants in 2 European/German men, and 3 splice variants in two white and one Arabic men.
ii) PMID: 29661171 (2018)- a novel hemizygous missense variant (W856C) in two brothers with azoospermia (absent in the mother- ?can it be gonadal mosaicism). Their testicular biopsy revealed meiotic arrest and no post-meiotic round spermatids and mature spermatozoa were observed.
iii) PMID: 34621296 (2021)- seven novel hemizygous variants in three familial (one missense, two splice) and four NOA-affected sporadic (three frameshift, one nonsense) cases iv) PMID: 37124723 (2023)- three novel hemizygous variants ( p.R105*, p.K143Q, and p.G859R) in three unrelated NOA males and their histological analysis of testicular biopsy specimens revealed thicker basement membrane of the seminiferous tubules and poorly developed spermatocytes.
Sources: Expert Review
Mendeliome v1.2427 SPAG6 Zornitza Stark Marked gene: SPAG6 as ready
Mendeliome v1.2427 SPAG6 Zornitza Stark Gene: spag6 has been classified as Green List (High Evidence).
Mendeliome v1.2427 SPAG6 Zornitza Stark Classified gene: SPAG6 as Green List (high evidence)
Mendeliome v1.2427 SPAG6 Zornitza Stark Gene: spag6 has been classified as Green List (High Evidence).
Mendeliome v1.2426 SPAG6 Zornitza Stark gene: SPAG6 was added
gene: SPAG6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPAG6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPAG6 were set to 35232447; 38073178; 32124190
Phenotypes for gene: SPAG6 were set to Spermatogenic failure, MONDO:0004983, SPAG6-related
Review for gene: SPAG6 was set to GREEN
Added comment: i) PMID: 35232447- two homozygous variants (F1 II-1: p. A103D; F2 II-1:p. K196Sfs*6) in two unrelated Han Chinese men with nonsyndromic asthenoteratozoospermia with severe multiple morphological abnormalities of the sperm flagella. Immunostaining and WB showed lower SPAG6 expression in spermatozoa of both affected males. The couple with the missense variant as able to conceive successfully after undergoing ICSI.
ii) PMID: 38073178- a homozygous missense p.R310W in three brothers (two brothers with both asthenozoospermia and oligozoospermia, third brother with azoospermia)
iii) PMID: 32124190- a novel compound heterozygous variant (c.143_145del: p.48_49del, c.585delA: p.Lys196Serfs*6) in an infertile PCD patient with severe with asthenoteratozoospermia, presented with morphological defects of sperm flagella and lower mRNA and protein expression in mutant sperm.
Sources: Literature
Mendeliome v1.2425 SEPT12 Zornitza Stark Marked gene: SEPT12 as ready
Mendeliome v1.2425 SEPT12 Zornitza Stark Gene: sept12 has been classified as Green List (High Evidence).
Mendeliome v1.2425 SEPT12 Zornitza Stark Classified gene: SEPT12 as Green List (high evidence)
Mendeliome v1.2425 SEPT12 Zornitza Stark Gene: sept12 has been classified as Green List (High Evidence).
Mendeliome v1.2424 SEPT12 Zornitza Stark gene: SEPT12 was added
gene: SEPT12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEPT12 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SEPT12 were set to 22479503; 22275165; 35547809
Phenotypes for gene: SEPT12 were set to Spermatogenic failure 10, MIM#614822
Review for gene: SEPT12 was set to GREEN
Added comment: i) PMID: 22479503- A homozygous truncating variant (c.474 G>A) in 15 unrelated infertile men and 9 of them had teratozoospermia (88 to 99% of abnormal sperm);Transfection studies also showed that the mutant SEPT12 disrupted filament formation of wildtype SEPT12 in a dose-dependent manner.
ii) PMID:22275165- Two heterozygous missense variants (T89M and D197N) in a man with asthenoteratozoospermia and another man with oligoasthenozoospermia. Functional analysis demonstrated that both mutations adversely affected filament formation of wildtype SEPT12 in a dose-dependent manner.
iii) PMID: 35547809- A heterozygous missense variant (p.Cys24Ter) in the male partner of a patient couple, who had a previous fertilization failure (FF) after intracytoplasmic sperm injection (ICSI) and became pregnant after ICSI together with artificial oocyte activation (AOA). Their Septin12 knockout mice study also showed that Septin12 -/- male mice are infertile with reduced sperm counts and abnormal sperm morphology but male Septin12 +/− mice are fertile. This observation contradicted with the previous studies showed that male Septin12 +/− chimeric mice are infertile (Lin et al., 2009, PMID: 19359518). The main difference is that the Septin12 +/− chimeric mice were generated in Lin et al., 2009 (PMID: 19359518) was by blastocyst injection of Septin12 +/− embryonic stem cells (ESCs), while their Septin12 +/− founder mice were established by CRISPR/Cas9 mediated gene editing in the zygote. The quality of injected Septin12 +/− ESCs might affect the experimental result.
Sources: Literature
Mendeliome v1.2423 PLCZ1 Zornitza Stark Marked gene: PLCZ1 as ready
Mendeliome v1.2423 PLCZ1 Zornitza Stark Gene: plcz1 has been classified as Green List (High Evidence).
Mendeliome v1.2423 PLCZ1 Zornitza Stark Classified gene: PLCZ1 as Green List (high evidence)
Mendeliome v1.2423 PLCZ1 Zornitza Stark Gene: plcz1 has been classified as Green List (High Evidence).
Mendeliome v1.2422 PLCZ1 Zornitza Stark gene: PLCZ1 was added
gene: PLCZ1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLCZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCZ1 were set to 26721930; 31463947; 36593593; 37004249
Phenotypes for gene: PLCZ1 were set to Spermatogenic failure 17, MIM# 617214
Review for gene: PLCZ1 was set to GREEN
Added comment: i) PMID:26721930- homozygous missense variant (I489F) in 2 Tunisian brothers with infertility due to oocyte activation failure.
ii) PMID:31463947- 3 homozygous variants (C196X, S350P, L246F) in 4 Chinese men from 3 consanguineous families with SPGF17 and total fertilization failure of oocytes after intracytoplasmic sperm injection.
iii) PMID: 36593593- compound heterozygosity for splice site and missense variants (c.1174+3A-C and N425S in case 2; c.136-1G-C and G453D in case 3) in 2 unrelated Chinese men with infertility due to acrosomal abnormalities and total fertilization failure.
iv) PMID: 37004249- previously reported homozygous variant (C196X) in two unrelated men with infertility due to total fertilization failure
Sources: Literature
Mendeliome v1.2421 EXO1 Zornitza Stark Marked gene: EXO1 as ready
Mendeliome v1.2421 EXO1 Zornitza Stark Gene: exo1 has been classified as Green List (High Evidence).
Mendeliome v1.2421 EXO1 Zornitza Stark Classified gene: EXO1 as Green List (high evidence)
Mendeliome v1.2421 EXO1 Zornitza Stark Gene: exo1 has been classified as Green List (High Evidence).
Mendeliome v1.2420 EXO1 Zornitza Stark gene: EXO1 was added
gene: EXO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EXO1 were set to 39595984; 32772095; 36385415
Phenotypes for gene: EXO1 were set to Primary ovarian failure, MONDO:0005387, EXO1-related
Review for gene: EXO1 was set to GREEN
Added comment: 1. PMID:39595984- heterozygous nonsense variant (p.Glu829Ter) in an European female with diminished ovarian reserve
2. PMID:32772095- heterozygous missense variant (p.Thr52Ser) in a Chinese patient with POI, which impaired the meiotic process in budding yeast cells and analysis of transfected HEK293 cells demonstrated impaired efficiency of homologous recombination repair for DNA double-stranded breaks with the mutant compared to wildtype EXO1
3. PMID:36385415- heterozygous nonsense variant (p.Tyr742Ter) in a case (C23) with recurrent pregnancy loss (RPL), primary infertility (PI), recurrent implantation failure (RIF)
Sources: Literature
Mendeliome v1.2419 DDX3Y Zornitza Stark Marked gene: DDX3Y as ready
Mendeliome v1.2419 DDX3Y Zornitza Stark Gene: ddx3y has been classified as Green List (High Evidence).
Mendeliome v1.2419 DDX3Y Zornitza Stark Classified gene: DDX3Y as Green List (high evidence)
Mendeliome v1.2419 DDX3Y Zornitza Stark Gene: ddx3y has been classified as Green List (High Evidence).
Mendeliome v1.2418 DDX3Y Zornitza Stark gene: DDX3Y was added
gene: DDX3Y was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DDX3Y was set to Other
Publications for gene: DDX3Y were set to 36997603
Phenotypes for gene: DDX3Y were set to Azoospermia, MONDO:0100459, DDX3Y-related
Review for gene: DDX3Y was set to GREEN
Added comment: PMID:36997603- Four (3 German, 1 Estonian) unrelated men with non-obstructive azoospermia carrying different LOF variants- absent in the gnomAD database (v2.1.1), abrogate at least the sequence of the C-terminal helicase domain, and are predicted to lead to degradation of the transcripts by nonsense-mediated decay. All four patients shared histological phenotype of Sertoli cell-only (SCO), reduced testicular volume, and had elevated FSH upon primary or later presentation indicative of spermatogenic failure.

Mode of inheritance: Y-linked
Sources: Expert Review
Mendeliome v1.2417 CFAP221 Achchuthan Shanmugasundram reviewed gene: CFAP221: Rating: AMBER; Mode of pathogenicity: None; Publications: 31636325, 39362668; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2417 EZR Zornitza Stark Marked gene: EZR as ready
Mendeliome v1.2417 EZR Zornitza Stark Gene: ezr has been classified as Red List (Low Evidence).
Mendeliome v1.2417 EZR Zornitza Stark Classified gene: EZR as Red List (low evidence)
Mendeliome v1.2417 EZR Zornitza Stark Gene: ezr has been classified as Red List (Low Evidence).
Mendeliome v1.2416 IDH3G Zornitza Stark Marked gene: IDH3G as ready
Mendeliome v1.2416 IDH3G Zornitza Stark Gene: idh3g has been classified as Green List (High Evidence).
Mendeliome v1.2416 IDH3G Zornitza Stark Classified gene: IDH3G as Green List (high evidence)
Mendeliome v1.2416 IDH3G Zornitza Stark Gene: idh3g has been classified as Green List (High Evidence).
Mendeliome v1.2415 C19orf44 Zornitza Stark Marked gene: C19orf44 as ready
Mendeliome v1.2415 C19orf44 Zornitza Stark Gene: c19orf44 has been classified as Green List (High Evidence).
Mendeliome v1.2415 C19orf44 Zornitza Stark Classified gene: C19orf44 as Green List (high evidence)
Mendeliome v1.2415 C19orf44 Zornitza Stark Gene: c19orf44 has been classified as Green List (High Evidence).
Mendeliome v1.2414 TIMM29 Zornitza Stark Marked gene: TIMM29 as ready
Mendeliome v1.2414 TIMM29 Zornitza Stark Gene: timm29 has been classified as Red List (Low Evidence).
Mendeliome v1.2414 TIMM29 Zornitza Stark Classified gene: TIMM29 as Red List (low evidence)
Mendeliome v1.2414 TIMM29 Zornitza Stark Gene: timm29 has been classified as Red List (Low Evidence).
Mendeliome v1.2413 TIMM29 Sangavi Sivagnanasundram gene: TIMM29 was added
gene: TIMM29 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TIMM29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIMM29 were set to 40022150
Phenotypes for gene: TIMM29 were set to Sengers syndrome MONDO:0008922, TIMM29-related
Review for gene: TIMM29 was set to RED
Added comment: One large Arab family presenting with a range of clinical and biochemical phenotypes suggestive of Sengers Syndrome.
Biallelic p.Trp172Arg was identified that segregated through the family - this variant is absent from gnomADv4.1
Knockdown drosophillia assay recapitulated the phenotype and pathology observed in the cohort of senger syndrome affected patients.
Sources: Literature
Mendeliome v1.2413 C19orf44 Sangavi Sivagnanasundram edited their review of gene: C19orf44: Changed phenotypes: Late onset retinal dystrophy, MONDO:0019118
Mendeliome v1.2413 C19orf44 Sangavi Sivagnanasundram gene: C19orf44 was added
gene: C19orf44 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C19orf44 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C19orf44 were set to 40079362
Phenotypes for gene: C19orf44 were set to Late onset retinal dystrophy; MONDO:0019118
Review for gene: C19orf44 was set to GREEN
Added comment: 5 biallelic LoF variants were identified in 11 unrelated families of Jewish or Israeli ancestry. All affected individuals present with a form of retinal disorder including perifoveal chorioretinal atrophy and electroretinographic features of rod-cone degeneration.
All 5 variants were present in gnomAD v4.1 with varying AF (p.Ser325PhefsTer16 being the most common).
Sources: Literature
Mendeliome v1.2413 IDH3G Sangavi Sivagnanasundram gene: IDH3G was added
gene: IDH3G was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IDH3G was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IDH3G were set to 40119724
Phenotypes for gene: IDH3G were set to X-linked retinitis pigmentosa, MONDO:0019200
Review for gene: IDH3G was set to GREEN
Added comment: PMID: 40119724
5 unrelated male probands with retinal pigmentosa (RP) identifed with hemizygous variants in IDH3G and was shown to segregate with disease in some families.
Sources: Literature
Mendeliome v1.2413 TFRC Zornitza Stark Phenotypes for gene: TFRC were changed from Immunodeficiency 46, MIM# 616740; T cells: normal number, poor proliferation; B cells: normal number, low memory B cells; recurrent infections, neutorpaenia; thrombocytopaenia to TFRC-related combined immunodeficiency MONDO:0014760; Immunodeficiency 46, MIM# 616740; T cells: normal number, poor proliferation; B cells: normal number, low memory B cells; recurrent infections, neutorpaenia; thrombocytopaenia
Mendeliome v1.2412 TFRC Zornitza Stark Classified gene: TFRC as Green List (high evidence)
Mendeliome v1.2412 TFRC Zornitza Stark Gene: tfrc has been classified as Green List (High Evidence).
Mendeliome v1.2411 TAX1BP3 Zornitza Stark Marked gene: TAX1BP3 as ready
Mendeliome v1.2411 TAX1BP3 Zornitza Stark Gene: tax1bp3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2411 TAX1BP3 Zornitza Stark Classified gene: TAX1BP3 as Amber List (moderate evidence)
Mendeliome v1.2411 TAX1BP3 Zornitza Stark Gene: tax1bp3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2410 TAX1BP3 Zornitza Stark gene: TAX1BP3 was added
gene: TAX1BP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAX1BP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAX1BP3 were set to 39963794
Phenotypes for gene: TAX1BP3 were set to Familial cardiomyopathy, MONDO:0005217, TAX1BP3-related
Review for gene: TAX1BP3 was set to AMBER
Added comment: Biallelic variants (1 x del, 1 x missense) in TAX1BP3 cause a novel autosomal recessive form of arrhythmogenic cardiomyopathy. One family only, but 3 affected sibs had the bialleic variants which were absent in an unaffected sister. Carrier parents were normal. Experimental work on patient-derived induced pluripotent stem cell cardiac myocytes and a knockout mouse showed that show loss of TAX1BP3 causes calcium dysregulation in cardiomyocytes, a known mechanism for arrhythmia. AMBER until more case level data evolves.
Sources: Literature
Mendeliome v1.2409 CFAP54 Zornitza Stark Phenotypes for gene: CFAP54 were changed from Spermatogenic failure 98, MIM# 621124; Hydrocephalus, male infertility, mucus accumulation to Ciliary dyskinesia, primary, 54, MIM:621125; Spermatogenic failure 98, MIM# 621124; Hydrocephalus, male infertility, mucus accumulation
Mendeliome v1.2408 CFAP54 Zornitza Stark Publications for gene: CFAP54 were set to 26224312; 36593121
Mendeliome v1.2407 CFAP54 Zornitza Stark Classified gene: CFAP54 as Green List (high evidence)
Mendeliome v1.2407 CFAP54 Zornitza Stark Gene: cfap54 has been classified as Green List (High Evidence).
Mendeliome v1.2406 EZR Sangavi Sivagnanasundram gene: EZR was added
gene: EZR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EZR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EZR were set to 40137958
Phenotypes for gene: EZR were set to Congenital enteropathy, MONDO:0009173
Review for gene: EZR was set to RED
Added comment: Homozygous LoF variant c. 356dup (p. Glu120*) - present in gnomAD v4.1 (rare enough for AR condition)
Infant from consanguineous parents with intractable diarrhea and failure to thrive.
A supportive functional assay showing the variant is predicted to result in NMD was conducted.
No other reports of other variants in this gene to support this gene disease association as of yet.
Sources: Literature
Mendeliome v1.2406 CELF4 Zornitza Stark Marked gene: CELF4 as ready
Mendeliome v1.2406 CELF4 Zornitza Stark Gene: celf4 has been classified as Green List (High Evidence).
Mendeliome v1.2406 CELF4 Zornitza Stark Classified gene: CELF4 as Green List (high evidence)
Mendeliome v1.2406 CELF4 Zornitza Stark Gene: celf4 has been classified as Green List (High Evidence).
Mendeliome v1.2405 CELF4 Zornitza Stark gene: CELF4 was added
gene: CELF4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CELF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF4 were set to 40108438
Phenotypes for gene: CELF4 were set to Neurodevelopmental disorder, MONDO:0700092, CELF4-related
Review for gene: CELF4 was set to GREEN
Added comment: 15 individuals with de novo missense variants clustering in the N-terminal reported, LoF is the likely mechanism. Most individuals presented with neurodevelopmental disorders including global developmental delay/intellectual disability (11/14), seizures (9/15) and overweight/obesity (10/14). Clinical features are similar to the reported celf4-mouse mutant phenotype.
Sources: Literature
Mendeliome v1.2404 CSNK1A1 Zornitza Stark Marked gene: CSNK1A1 as ready
Mendeliome v1.2404 CSNK1A1 Zornitza Stark Gene: csnk1a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2404 CSNK1A1 Zornitza Stark Classified gene: CSNK1A1 as Amber List (moderate evidence)
Mendeliome v1.2404 CSNK1A1 Zornitza Stark Gene: csnk1a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2403 CSNK1A1 Zornitza Stark gene: CSNK1A1 was added
gene: CSNK1A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSNK1A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK1A1 were set to 40156289
Phenotypes for gene: CSNK1A1 were set to Infantile spasms, MONDO:0018097, CSNK1A1-related
Review for gene: CSNK1A1 was set to AMBER
Added comment: Two individuals with de novo variants and some supportive functional data.
Sources: Literature
Mendeliome v1.2402 SVBP Zornitza Stark Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly; OMIM #618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MIM #618569; Spastic paraplegia 94, autosomal recessive, MIM# 621150
Mendeliome v1.2401 SVBP Zornitza Stark Publications for gene: SVBP were set to 31363758; 30607023
Mendeliome v1.2400 SVBP Zornitza Stark edited their review of gene: SVBP: Added comment: PMID 39412222: 6 individuals from 3 families with spastic paraplegia and the same homozygous missense (L49P). Presented from birth or childhood with DD/ID and spastic paraplegia. Additional features: verbal apraxia, axonal neuropathy, ataxia, nystagmus, epilepsy, and aggressive behaviour. Brain MRIs were performed in 3 individuals and showed thinning of the corpus callosum, cerebellar atrophy, and ventriculomegaly; frontal ventricular hyperintensities suggestive of the 'ear of the lynx' sign in 2. Three individuals had a history of cancer of epithelial origin, including adenocarcinoma (patient 1), colonic tubular adenoma (patient 2), and breast cancer (patient 3).; Changed publications: 31363758, 30607023, 39412222; Changed phenotypes: Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MIM #618569, Spastic paraplegia 94, autosomal recessive, MIM# 621150
Mendeliome v1.2400 CFAP54 Achchuthan Shanmugasundram reviewed gene: CFAP54: Rating: GREEN; Mode of pathogenicity: None; Publications: 39362668; Phenotypes: Ciliary dyskinesia, primary, 54, OMIM:621125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2400 NR2F2 Elena Savva Phenotypes for gene: NR2F2 were changed from 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Current 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Edit; 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 to Syndromic disease, MONDO:0002254, NR2F2-related
Mendeliome v1.2399 NR2F2 Elena Savva Phenotypes for gene: NR2F2 were changed from Krithika Murali (Victorian Clinical Genetics Services) 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Current 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Edit; 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 to 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Current 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Edit; 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779
Mendeliome v1.2398 CFAP74 Achchuthan Shanmugasundram reviewed gene: CFAP74: Rating: GREEN; Mode of pathogenicity: None; Publications: 32555313, 36047773, 39362668; Phenotypes: Ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2398 NEB Sangavi Sivagnanasundram reviewed gene: NEB: Rating: AMBER; Mode of pathogenicity: None; Publications: 39802796, 30679003, 33933294; Phenotypes: congenital structural myopathy MONDO:0002921; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2398 FAM126A Sangavi Sivagnanasundram commented on gene: FAM126A
Mendeliome v1.2398 TFRC Sangavi Sivagnanasundram reviewed gene: TFRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32851577, 38270687; Phenotypes: TFRC-related combined immunodeficiency MONDO:0014760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2398 CRMP1 Zornitza Stark Marked gene: CRMP1 as ready
Mendeliome v1.2398 CRMP1 Zornitza Stark Gene: crmp1 has been classified as Green List (High Evidence).
Mendeliome v1.2398 CRMP1 Zornitza Stark Phenotypes for gene: CRMP1 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092, CRMP2-related
Mendeliome v1.2397 CRMP1 Zornitza Stark Classified gene: CRMP1 as Green List (high evidence)
Mendeliome v1.2397 CRMP1 Zornitza Stark Gene: crmp1 has been classified as Green List (High Evidence).
Mendeliome v1.2396 CRMP1 Zornitza Stark reviewed gene: CRMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, MONDO:0700092, CRMP2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2396 PIGQ Sangavi Sivagnanasundram reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008756; Phenotypes: developmental and epileptic encephalopathy, 77 MONDO:0032808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2396 HEPHL1 Sangavi Sivagnanasundram changed review comment from: Classified as LIMITED by General Inborn Errors of Metabolism GCEP on 28/03/2025 - https://search.clinicalgenome.org/CCID:008755

Reported in a proband with chet variant. The variant was shown to affect ferroxidase activity result in abnormal hair phenotype. ?inborn error of iron metabolism; to: Classified as LIMITED by General Inborn Errors of Metabolism GCEP on 28/03/2025 - https://search.clinicalgenome.org/CCID:008755

Reported in a proband with biallelic variant. The variant was shown to affect ferroxidase activity result in abnormal hair phenotype. ?inborn error of iron metabolism
Mendeliome v1.2396 HEPHL1 Sangavi Sivagnanasundram changed review comment from: Classified as LIMITED by General Inborn Errors of Metabolism GCEP on 28/03/2025 - https://search.clinicalgenome.org/CCID:008755

Reported in a proband with chet variants. The variant was shown to affect ferroxidase activity result in abnormal hair phenotype. ?inborn error of iron metabolism; to: Classified as LIMITED by General Inborn Errors of Metabolism GCEP on 28/03/2025 - https://search.clinicalgenome.org/CCID:008755

Reported in a proband with chet variant. The variant was shown to affect ferroxidase activity result in abnormal hair phenotype. ?inborn error of iron metabolism
Mendeliome v1.2396 HEPHL1 Sangavi Sivagnanasundram reviewed gene: HEPHL1: Rating: RED; Mode of pathogenicity: None; Publications: 31125343; Phenotypes: pili torti-developmental delay-neurological abnormalities syndrome MONDO:0009871; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2396 MAN2B2 Zornitza Stark Phenotypes for gene: MAN2B2 were changed from Congenital disorder of glycosylation, MONDO:0015286, MAN2B2-related; immunodeficiency to Congenital disorder of glycosylation type 1EE with or without immunodeficiency, MIM# 621140
Mendeliome v1.2395 MAN2B2 Zornitza Stark Classified gene: MAN2B2 as Green List (high evidence)
Mendeliome v1.2395 MAN2B2 Zornitza Stark Gene: man2b2 has been classified as Green List (High Evidence).
Mendeliome v1.2394 MAN2B2 Zornitza Stark edited their review of gene: MAN2B2: Added comment: Third individual reported PMID 38622837 with compound het missense variants, supportive functional data.; Changed rating: GREEN; Changed publications: 31775018, 35637269, 38622837; Changed phenotypes: Congenital disorder of glycosylation type 1EE with or without immunodeficiency, MIM# 621140
Mendeliome v1.2394 MKKS Zornitza Stark Phenotypes for gene: MKKS were changed from Bardet-Biedl syndrome 6 (MIM#605231); McKusick-Kaufman syndrome, MIM# 236700; Retinitis pigmentosa to Ciliopathy, MONDO:0005308, MKKS-related; Bardet-Biedl syndrome 6 (MIM#605231); McKusick-Kaufman syndrome, MIM# 236700; Retinitis pigmentosa
Mendeliome v1.2393 MEPE Zornitza Stark Phenotypes for gene: MEPE were changed from hereditary congenital facial paresis; otosclerosis to Nonsyndromic genetic hearing loss, MONDO:0019497, MEPE-related; hereditary congenital facial paresis; otosclerosis
Mendeliome v1.2392 MEPE Zornitza Stark edited their review of gene: MEPE: Changed phenotypes: Nonsyndromic genetic hearing loss, MONDO:0019497, MEPE-related, hereditary congenital facial paresis, otosclerosis
Mendeliome v1.2392 MCM7 Zornitza Stark Phenotypes for gene: MCM7 were changed from Meier-Gorlin syndrome; Microcephaly; Intellectual disability; Lipodystrophy; Adrenal insufficiency to Syndromic disease, MONDO:0002254, MCM7-related; Meier-Gorlin syndrome; Microcephaly; Intellectual disability; Lipodystrophy; Adrenal insufficiency
Mendeliome v1.2391 MCM7 Zornitza Stark reviewed gene: MCM7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, MCM7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2391 MACROD2 Zornitza Stark Phenotypes for gene: MACROD2 were changed from intellectual disability; dysmorphic features; microcephaly to Syndromic disease, MONDO:0002254, MACROD2-related; intellectual disability; dysmorphic features; microcephaly
Mendeliome v1.2390 MACROD2 Zornitza Stark edited their review of gene: MACROD2: Changed phenotypes: Syndromic disease, MONDO:0002254, MACROD2-related, intellectual disability, dysmorphic features, microcephaly
Mendeliome v1.2390 SLC35F1 Zornitza Stark Phenotypes for gene: SLC35F1 were changed from Neruodevelopmental disorder, MONDO:0700092, SLC35F1-associated; Rett-like syndrome to Neurodevelopmental disorder, MONDO:0700092, SLC35F1-associated; Rett-like syndrome
Mendeliome v1.2389 SIX5 Zornitza Stark Classified gene: SIX5 as Red List (low evidence)
Mendeliome v1.2389 SIX5 Zornitza Stark Gene: six5 has been classified as Red List (Low Evidence).
Mendeliome v1.2388 SLC30A5 Zornitza Stark Phenotypes for gene: SLC30A5 were changed from Perinatal lethal cardiomyopathy to Cardiomyopathy MONDO:0004994, SLC30A5-related; Perinatal lethal cardiomyopathy
Mendeliome v1.2387 SLC2A1 Zornitza Stark Phenotypes for gene: SLC2A1 were changed from GLUT1 deficiency syndrome 1, infantile onset, severe, MIM#606777; Dystonia 9, MIM#601042; Stomatin-deficient cryohydrocytosis with neurologic defects, MIM#608885; GLUT1 deficiency syndrome 2, childhood onset, MIM#612126; {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM#614847 to GLUT1 deficiency syndrome, MONDO:0000188; GLUT1 deficiency syndrome 1, infantile onset, severe, MIM#606777; Dystonia 9, MIM#601042; Stomatin-deficient cryohydrocytosis with neurologic defects, MIM#608885; GLUT1 deficiency syndrome 2, childhood onset, MIM#612126; {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM#614847
Mendeliome v1.2386 RALGAPB Lucy Spencer reviewed gene: RALGAPB: Rating: RED; Mode of pathogenicity: None; Publications: 35830182; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), RALGAPB-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2386 CRMP1 Achchuthan Shanmugasundram changed review comment from: PMID:36511780 reported the identification of three different heterozygous de novo variants in the CRMP1 gene (p.(Pro589Leu), p.(Thr427Met) & p.(Phe351Ser)) in three unrelated individuals with a neurodevelopmental disorder presenting with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. ID was moderate in two of them, while IQ was normal in one. There is also functional evidence available for these variants.

PMID:39758889 reported the identification of a novel heterozygous de novo frameshift variant in CRMP1 (p.(Lys586fs)) in a 9-year-old male patient presenting with phenotypes such as autism, language delay, hyperactivity, and learning disabilities. This patient was reported with moderate ID.

There are three unrelated cases reported with moderate intellectual disability and with monoallelic CRMP1 variants. However, one patient with a different monoallelic CRMP1 variant had normal IQ. Hence, this gene should be rated amber with current evidence.
Sources: Literature; to: PMID:36511780 reported the identification of three different heterozygous de novo variants in the CRMP1 gene (p.(Pro589Leu), p.(Thr427Met) & p.(Phe351Ser)) in three unrelated individuals with a neurodevelopmental disorder presenting with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. ID was moderate in two of them, while IQ was normal in one. There is also functional evidence available for these variants.

PMID:39758889 reported the identification of a novel heterozygous de novo frameshift variant in CRMP1 (p.(Lys586fs)) in a 9-year-old male patient presenting with phenotypes such as autism, language delay, hyperactivity, and learning disabilities. This patient was reported with moderate ID.

Summary: There are three unrelated cases reported with moderate intellectual disability and with monoallelic CRMP1 variants. However, one patient with a different monoallelic CRMP1 variant had normal IQ. Hence, this gene should be rated amber with current evidence.
Sources: Literature
Mendeliome v1.2386 CRMP1 Achchuthan Shanmugasundram gene: CRMP1 was added
gene: CRMP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CRMP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRMP1 were set to 36511780; 39758889
Phenotypes for gene: CRMP1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CRMP1 was set to AMBER
Added comment: PMID:36511780 reported the identification of three different heterozygous de novo variants in the CRMP1 gene (p.(Pro589Leu), p.(Thr427Met) & p.(Phe351Ser)) in three unrelated individuals with a neurodevelopmental disorder presenting with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. ID was moderate in two of them, while IQ was normal in one. There is also functional evidence available for these variants.

PMID:39758889 reported the identification of a novel heterozygous de novo frameshift variant in CRMP1 (p.(Lys586fs)) in a 9-year-old male patient presenting with phenotypes such as autism, language delay, hyperactivity, and learning disabilities. This patient was reported with moderate ID.

There are three unrelated cases reported with moderate intellectual disability and with monoallelic CRMP1 variants. However, one patient with a different monoallelic CRMP1 variant had normal IQ. Hence, this gene should be rated amber with current evidence.
Sources: Literature
Mendeliome v1.2386 GAP43 Achchuthan Shanmugasundram gene: GAP43 was added
gene: GAP43 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GAP43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GAP43 were set to 39738362
Phenotypes for gene: GAP43 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: GAP43 was set to RED
Added comment: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.
Sources: Literature
Mendeliome v1.2386 KLC4 Zornitza Stark edited their review of gene: KLC4: Changed phenotypes: Neurodegeneration, early-childhood-onset, with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, MIM# 621129
Mendeliome v1.2386 EXOSC2 Zornitza Stark changed review comment from: LIMITED by ClinGen; to: LIMITED by ClinGen. Two additional patients reported but again, predominantly missense variants.
Mendeliome v1.2386 EXOSC2 Zornitza Stark edited their review of gene: EXOSC2: Changed publications: 26843489, 31628467, 36344539, 36069504
Mendeliome v1.2386 EXOSC2 Zornitza Stark commented on gene: EXOSC2: LIMITED by ClinGen
Mendeliome v1.2386 LSM1 Zornitza Stark Phenotypes for gene: LSM1 were changed from intellectual disability; congenital abnormalities to neurodevelopmental disorder MONDO:0700092, LSM1-related
Mendeliome v1.2385 LSM1 Sangavi Sivagnanasundram reviewed gene: LSM1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO:0700092; Mode of inheritance: None
Mendeliome v1.2385 RP9 Sangavi Sivagnanasundram reviewed gene: RP9: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008710; Phenotypes: retinitis pigmentosa 9 MONDO:0008378; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2385 KMT2C Zornitza Stark Publications for gene: KMT2C were set to
Mendeliome v1.2384 KMT2C Zornitza Stark Phenotypes for gene: KMT2C were changed from Kleefstra syndrome 2, MIM#617768 to Kleefstra syndrome 2, MIM#617768; Neurodevelopmental disorder, MONDO:0700092, KMT2C-related
Mendeliome v1.2383 KMT2C Zornitza Stark reviewed gene: KMT2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 39013459; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, KMT2C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2383 SUPT7L Zornitza Stark Phenotypes for gene: SUPT7L were changed from Lipodystrophy, MONDO:0006573, SUPT7L-related to Fischer-Zirnsak progeroid syndrome, MIM# 621130
Mendeliome v1.2382 SUPT7L Zornitza Stark reviewed gene: SUPT7L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fischer-Zirnsak progeroid syndrome, MIM# 621130; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2382 DZIP1 Bryony Thompson reviewed gene: DZIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33811421, 31118289; Phenotypes: mitral valve prolapse MONDO:0004910; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2382 DYNC1H1 Bryony Thompson Publications for gene: DYNC1H1 were set to 25512093; 28196890
Mendeliome v1.2381 DYNC1H1 Bryony Thompson Phenotypes for gene: DYNC1H1 were changed from Charcot-Marie-Tooth disease, axonal, type 20; Mental retardation, autosomal dominant 13; Spinal muscular atrophy, lower extremity-predominant 1 to dyneinopathy MONDO:1040031
Mendeliome v1.2380 DUOXA2 Bryony Thompson Publications for gene: DUOXA2 were set to
Mendeliome v1.2379 DUOXA2 Bryony Thompson Mode of inheritance for gene: DUOXA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2378 DUOXA1 Bryony Thompson Phenotypes for gene: DUOXA1 were changed from congenital hypothyroidism, No OMIM # to congenital hypothyroidism MONDO:0018612
Mendeliome v1.2377 DUOXA1 Bryony Thompson Publications for gene: DUOXA1 were set to 29650690
Mendeliome v1.2376 DUOXA1 Bryony Thompson Mode of inheritance for gene: DUOXA1 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
Mendeliome v1.2375 DUOX2 Bryony Thompson Added comment: Comment on mode of inheritance: Biallelic evidence for IBD is strong, but the evidence for the monoallelic association is limited. Semidominant inheritance for thyroid dyshormonogenesis.
Mendeliome v1.2375 DUOX2 Bryony Thompson Mode of inheritance for gene: DUOX2 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
Mendeliome v1.2374 LINC01578 Zornitza Stark Tag non-coding gene tag was added to gene: LINC01578.
Mendeliome v1.2374 SNORA31 Zornitza Stark Tag non-coding gene tag was added to gene: SNORA31.
Mendeliome v1.2374 MIR96 Zornitza Stark Tag non-coding gene tag was added to gene: MIR96.
Mendeliome v1.2374 MIR936 Zornitza Stark Tag non-coding gene tag was added to gene: MIR936.
Mendeliome v1.2374 MIR5004 Zornitza Stark Tag non-coding gene tag was added to gene: MIR5004.
Mendeliome v1.2374 MIR204 Zornitza Stark Tag non-coding gene tag was added to gene: MIR204.
Mendeliome v1.2374 MIR184 Zornitza Stark Tag non-coding gene tag was added to gene: MIR184.
Mendeliome v1.2374 MIR183 Zornitza Stark Tag non-coding gene tag was added to gene: MIR183.
Mendeliome v1.2374 MIR182 Zornitza Stark Tag non-coding gene tag was added to gene: MIR182.
Mendeliome v1.2374 MIR17HG Zornitza Stark Tag non-coding gene tag was added to gene: MIR17HG.
Mendeliome v1.2374 MIR145 Zornitza Stark Tag non-coding gene tag was added to gene: MIR145.
Mendeliome v1.2374 MIR140 Zornitza Stark Tag non-coding gene tag was added to gene: MIR140.
Mendeliome v1.2374 RMRP Zornitza Stark Tag non-coding gene tag was added to gene: RMRP.
Mendeliome v1.2374 TERC Zornitza Stark Phenotypes for gene: TERC were changed from Dyskeratosis congenita, autosomal dominant 1, MIM# 127550 to Dyskeratosis congenita, autosomal dominant 1, MIM# 127550; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2, MIM# 614743
Mendeliome v1.2373 TERC Zornitza Stark Tag non-coding gene tag was added to gene: TERC.
Mendeliome v1.2373 TERC Zornitza Stark edited their review of gene: TERC: Changed phenotypes: Dyskeratosis congenita, autosomal dominant 1, MIM# 127550, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2, MIM# 614743
Mendeliome v1.2373 RNU2-2P Zornitza Stark Tag non-coding gene tag was added to gene: RNU2-2P.
Mendeliome v1.2373 SNORD118 Zornitza Stark Tag non-coding gene tag was added to gene: SNORD118.
Mendeliome v1.2373 RNU7-1 Zornitza Stark Tag non-coding gene tag was added to gene: RNU7-1.
Mendeliome v1.2373 RNU4ATAC Zornitza Stark Phenotypes for gene: RNU4ATAC were changed from Microcephalic osteodysplastic primordial dwarfism, type I (MIM# 210710); Roifman syndrome (MIM# 616651); Lowry-Wood syndrome, MIM# 226960 to RNU4ATAC spectrum disorder MONDO:0100558; Microcephalic osteodysplastic primordial dwarfism, type I (MIM# 210710); Roifman syndrome (MIM# 616651); Lowry-Wood syndrome, MIM# 226960
Mendeliome v1.2372 RNU4ATAC Zornitza Stark Tag non-coding gene tag was added to gene: RNU4ATAC.
Mendeliome v1.2372 RNU4-2 Zornitza Stark Tag non-coding gene tag was added to gene: RNU4-2.
Mendeliome v1.2372 RNU12 Zornitza Stark Tag non-coding gene tag was added to gene: RNU12.
Mendeliome v1.2372 DROSHA Zornitza Stark Tag non-coding gene tag was added to gene: DROSHA.
Mendeliome v1.2372 MEG3 Zornitza Stark Marked gene: MEG3 as ready
Mendeliome v1.2372 MEG3 Zornitza Stark Gene: meg3 has been classified as Green List (High Evidence).
Mendeliome v1.2372 MEG3 Zornitza Stark Classified gene: MEG3 as Green List (high evidence)
Mendeliome v1.2372 MEG3 Zornitza Stark Gene: meg3 has been classified as Green List (High Evidence).
Mendeliome v1.2371 MEG3 Zornitza Stark gene: MEG3 was added
gene: MEG3 was added to Mendeliome. Sources: Literature
SV/CNV, non-coding gene tags were added to gene: MEG3.
Mode of inheritance for gene: MEG3 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: MEG3 were set to 33010492; 33746039; 33067531; 38212313
Phenotypes for gene: MEG3 were set to Kagami-Ogata syndrome, MIM# 608149
Review for gene: MEG3 was set to GREEN
Added comment: Small deletions of MAG3 reported in multiple patients as one of the mechanisms of disease.
Sources: Literature
Mendeliome v1.2370 H19 Zornitza Stark Tag non-coding gene tag was added to gene: H19.
Mendeliome v1.2370 CFAP54 Zornitza Stark Classified gene: CFAP54 as Amber List (moderate evidence)
Mendeliome v1.2370 CFAP54 Zornitza Stark Gene: cfap54 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2369 CFAP54 Zornitza Stark edited their review of gene: CFAP54: Added comment: PMID 37725231: three probands from two families with PCD, supportive mouse models x2.; Changed rating: AMBER; Changed publications: 26224312, 36593121, 37725231; Changed phenotypes: Spermatogenic failure 98, MIM# 621124, HCiliary dyskinesia, primary, 54, MIM# 621125
Mendeliome v1.2369 PPFIA3 Zornitza Stark Phenotypes for gene: PPFIA3 were changed from Neurodevelopmental disorder, MONDO:0700092, PPFIA3-related to Paul-Chao neurodevelopmental syndrome, MIM# 621122
Mendeliome v1.2368 PPFIA3 Zornitza Stark edited their review of gene: PPFIA3: Changed phenotypes: Paul-Chao neurodevelopmental syndrome, MIM# 621122
Mendeliome v1.2368 CFAP54 Zornitza Stark Marked gene: CFAP54 as ready
Mendeliome v1.2368 CFAP54 Zornitza Stark Gene: cfap54 has been classified as Red List (Low Evidence).
Mendeliome v1.2368 CFAP54 Zornitza Stark gene: CFAP54 was added
gene: CFAP54 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP54 were set to 26224312; 36593121
Phenotypes for gene: CFAP54 were set to Spermatogenic failure 98, MIM# 621124; Hydrocephalus, male infertility, mucus accumulation
Review for gene: CFAP54 was set to RED
Added comment: PMID 36593121: Three men identified with bi-allelic variants and multiple morphologic abnormalities of the flagella or non-obstructive azoospermia.

PMID: 26224312: Homozygous mice have PCD characterized by hydrocephalus, male infertility (spermatogenesis defects in flagella maturation), and mucus accumulation. Brain analysis showed mild dilatation of the lateral ventricles. Tracheal cilia beat frequency was significantly reduced. The gene was highest expressed in the testis and lungs
Sources: Literature
Mendeliome v1.2367 BUD13 Zornitza Stark Phenotypes for gene: BUD13 were changed from Lipodystrophy, MONDO:0006573 to Achalasia-progeroid syndrome, MIM# 621123
Mendeliome v1.2366 BUD13 Zornitza Stark reviewed gene: BUD13: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Achalasia-progeroid syndrome, MIM# 621123; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2366 KCNQ1OT1 Zornitza Stark Classified gene: KCNQ1OT1 as Amber List (moderate evidence)
Mendeliome v1.2366 KCNQ1OT1 Zornitza Stark Gene: kcnq1ot1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2365 PIGW Zornitza Stark Classified gene: PIGW as Amber List (moderate evidence)
Mendeliome v1.2365 PIGW Zornitza Stark Gene: pigw has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2364 PIGW Zornitza Stark edited their review of gene: PIGW: Added comment: Downgraded to AMBER in light of ClinGen's assessment as LIMITED.; Changed rating: AMBER
Mendeliome v1.2364 KIAA1549 Zornitza Stark Marked gene: KIAA1549 as ready
Mendeliome v1.2364 KIAA1549 Zornitza Stark Gene: kiaa1549 has been classified as Green List (High Evidence).
Mendeliome v1.2364 KIAA1549 Zornitza Stark Classified gene: KIAA1549 as Green List (high evidence)
Mendeliome v1.2364 KIAA1549 Zornitza Stark Gene: kiaa1549 has been classified as Green List (High Evidence).
Mendeliome v1.2363 KIAA1549 Sangavi Sivagnanasundram gene: KIAA1549 was added
gene: KIAA1549 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: KIAA1549 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1549 were set to 30120214; 34027671
Phenotypes for gene: KIAA1549 were set to retinitis pigmentosa 86 MONDO:0032834
Review for gene: KIAA1549 was set to GREEN
Added comment: Classified as STRONG by ClinGen Retina GCEP on 18/02/2025 - https://search.clinicalgenome.org/CCID:008708

Reported in 5 probands with RP - Green according to PanelApp
Sources: ClinGen
Mendeliome v1.2363 IFT74 Sangavi Sivagnanasundram reviewed gene: IFT74: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 PIGW Sangavi Sivagnanasundram reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: None; Publications: 34618440; Phenotypes: hyperphosphatasia with intellectual disability syndrome 5 MONDO:0014457; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 MYL1 Sangavi Sivagnanasundram reviewed gene: MYL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: congenital myopathy MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 DEF6 Sangavi Sivagnanasundram reviewed gene: DEF6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: immunodeficiency 87 and autoimmunity MONDO:0030457; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 ELF4 Zornitza Stark Marked gene: ELF4 as ready
Mendeliome v1.2363 ELF4 Zornitza Stark Gene: elf4 has been classified as Green List (High Evidence).
Mendeliome v1.2363 SLC25A25 Zornitza Stark Marked gene: SLC25A25 as ready
Mendeliome v1.2363 SLC25A25 Zornitza Stark Gene: slc25a25 has been classified as Red List (Low Evidence).
Mendeliome v1.2363 SLC25A25 Zornitza Stark gene: SLC25A25 was added
gene: SLC25A25 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC25A25 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC25A25 were set to 34346195
Phenotypes for gene: SLC25A25 were set to Nephrolithiasis MONDO:0008171,SLC25A25 related
Penetrance for gene: SLC25A25 were set to Incomplete
Review for gene: SLC25A25 was set to RED
Added comment: SLC25A25 encodes mitochondrial ATP-Mg/Pi carrier 3

A single missense variant was reported in 2 families with renal stones in 2021 by Jabalameli et al (PMID: 3436195).
In family 1 there was 4 affected individuals who shared the same heterozygous variant NM_001330988.2 c.1083G>C|p.Gln361His, however this variant was also seen in 7 individuals in the family without stones
In family 2 there were 7 affected individuals who also had p.Gln361His however this variant was also seen in 3 family members without stones.

This variant is located within the mitochondrial carrier domain and functional studies were performed looking at uptake of radioactive ATP compared to wild type. These studies demonstrated the variant protein had approximately 21% activity compared to wild type.

The variant was proposed to have incomplete penetrance and it should be noted there is 4352 heterozygotes in gnomad 4.

At this time there is insufficient evidence for a gene disease association between SLC25A25 and nephrolithiasis.
Sources: Literature
Mendeliome v1.2362 ELF4 Bryony Thompson Classified gene: ELF4 as Green List (high evidence)
Mendeliome v1.2362 ELF4 Bryony Thompson Gene: elf4 has been classified as Green List (High Evidence).
Mendeliome v1.2360 ELF4 Bryony Thompson gene: ELF4 was added
gene: ELF4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELF4 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ELF4 were set to 38231408
Phenotypes for gene: ELF4 were set to autoinflammatory syndrome, familial, X-linked, Behcet-like 2 MONDO:0024770
Mendeliome v1.2359 ATP5A1 Chirag Patel Publications for gene: ATP5A1 were set to 23599390
Mendeliome v1.2358 APOA1 Chirag Patel Mode of inheritance for gene: APOA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2357 APOA1 Chirag Patel Mode of inheritance for gene: APOA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2356 SLC9A6 Zornitza Stark Phenotypes for gene: SLC9A6 were changed from Mental retardation, X-linked syndromic, Christianson type, MIM# 300243; MONDO:0010278 to Intellectual developmental disorder, X-linked syndromic, Christianson type MIM#300243; Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairement, MIM# 301142
Mendeliome v1.2355 SLC9A6 Zornitza Stark Publications for gene: SLC9A6 were set to 18342287; 19377476; 25044251; 33278113; 32569089; 31879735
Mendeliome v1.2354 SLC9A6 Zornitza Stark edited their review of gene: SLC9A6: Added comment: Multiple female carriers reported with adult-onset neurological phenotypes including neurodegerative disease and Parkinsonism. Some had affected sons with ID. Uncertain whether this is a separate entity or manifestation in female carriers of a XL condition.; Changed publications: 18342287, 19377476, 25044251, 33278113, 32569089, 31879735, 35198730, 39810750, 35198730, 31192222; Changed phenotypes: Intellectual developmental disorder, X-linked syndromic, Christianson type MIM#300243, Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairement, MIM# 301142
Mendeliome v1.2354 CFAP47 Zornitza Stark Phenotypes for gene: CFAP47 were changed from Spermatogenic failure, X-linked, 3, MIM# 301059; asthenoteratozoospermia; morphological abnormalities of the flagella (MMAF) to Spermatogenic failure, X-linked, 3, MIM# 301059; Cystic kidney disease MONDO:0002473
Mendeliome v1.2353 CFAP47 Zornitza Stark Publications for gene: CFAP47 were set to PMID: 33472045
Mendeliome v1.2352 BAG3 Chirag Patel reviewed gene: BAG3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37907725, 31853710, 30145633, 28754666; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant MONDO:0015362, Charcot-Marie-Tooth disease type 2 MONDO: 0018993; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2352 PPP2R5E Chirag Patel gene: PPP2R5E was added
gene: PPP2R5E was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP2R5E was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP2R5E were set to PMID: 39284558
Phenotypes for gene: PPP2R5E were set to Mendelian neurodevelopmental disorder MONDO:0100500
Review for gene: PPP2R5E was set to RED
Added comment: One 20yrs old individual with learning issues, motor coordination disorders, hypotonia (myopathy on EMG), and behavioural issues (mood and emotional dysregulation). WES testing identified a de novo heterozygous missense variant (Glu191Lys) in PPP2R5E gene. The variant was not found in the 4 healthy brothers of the individual. The variant is located within a conserved LFDSEDPRER motif common to all PPP2R5 B-subunits. Biochemical assays demonstrated a decreased interaction with the PP2A A and C subunits, leading to disturbances in holoenzyme formation.

Protein phosphatase 2A (PP2A) is a family of multifunctional enzymatic complexes crucial for cellular signalling, playing a pivotal role in brain function and development. Mutations in specific genes encoding PP2A complexes have been associated with neurodevelopmental disorders with hypotonia and high risk of seizures (e.g. PP2AR-1A, 2B, 3C, 5C, 5D).
Sources: Literature
Mendeliome v1.2351 CFAP47 Chirag Patel changed review comment from: 3 individuals with bilateral kidney cysts with mild enlargement of kidneys (mean age at Dx ~70yrs). They were all undergoing treatment for hypertension, had mean eGFR of ~31, None of them had any liver cysts or any family history of cystic kidney disease. WGS after negative clinical diagnostic testing, identified 3 missense variants in CFAP47 gene [p.(Arg870Gln), p.(Phe516Cys), and p.(Gly6Asp)]. The variants were rare in gnomAD but had equivocal in silico prediction scores, and would be reported as VUS using ACMG criteria. Segregation was not possible as their mothers were deceased. CFAP47 encodes cilia and flagella associated protein 47 a protein that plays a role in the formation and function of cilia and flagella. It is is expressed in primary cilia of human kidney tubules. Knockout (KO) mice exhibited larger kidneys with vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation.; to: 3 Japanese individuals with bilateral kidney cysts with mild enlargement of kidneys (mean age at Dx ~70yrs). They were all undergoing treatment for hypertension, had mean eGFR of ~31, None of them had any liver cysts, infertility, or any family history of cystic kidney disease. WGS after negative clinical diagnostic testing, identified 3 missense variants in CFAP47 gene [p.(Arg870Gln), p.(Phe516Cys), and p.(Gly6Asp)]. The variants were rare in gnomAD but had equivocal in silico prediction scores, and would be reported as VUS using ACMG criteria. Segregation was not possible as their mothers were deceased. CFAP47 encodes cilia and flagella associated protein 47 a protein that plays a role in the formation and function of cilia and flagella. It is is expressed in primary cilia of human kidney tubules. Knockout (KO) mice exhibited larger kidneys with vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation.
Mendeliome v1.2351 CFAP47 Chirag Patel reviewed gene: CFAP47: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 39698362; Phenotypes: Cystic kidney disease MONDO:0002473; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2351 GNA13 Zornitza Stark Tag somatic tag was added to gene: GNA13.
Mendeliome v1.2351 DDX39B Zornitza Stark Marked gene: DDX39B as ready
Mendeliome v1.2351 DDX39B Zornitza Stark Gene: ddx39b has been classified as Green List (High Evidence).
Mendeliome v1.2351 DDX39B Zornitza Stark Classified gene: DDX39B as Green List (high evidence)
Mendeliome v1.2351 DDX39B Zornitza Stark Gene: ddx39b has been classified as Green List (High Evidence).
Mendeliome v1.2350 CDO1 Zornitza Stark Marked gene: CDO1 as ready
Mendeliome v1.2350 CDO1 Zornitza Stark Gene: cdo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2350 CDO1 Zornitza Stark Phenotypes for gene: CDO1 were changed from Neurological Disorder MONDO:0100545 to Syndromic disease, MONDO:0002254, CDO1-related
Mendeliome v1.2349 CDO1 Zornitza Stark Classified gene: CDO1 as Amber List (moderate evidence)
Mendeliome v1.2349 CDO1 Zornitza Stark Gene: cdo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2348 CDO1 Zornitza Stark reviewed gene: CDO1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, CDO1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2348 ATF6 Bryony Thompson reviewed gene: ATF6: Rating: AMBER; Mode of pathogenicity: None; Publications: 39570676; Phenotypes: hearing loss disorder MONDO:0005365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2348 PHACTR4 Zornitza Stark Marked gene: PHACTR4 as ready
Mendeliome v1.2348 PHACTR4 Zornitza Stark Gene: phactr4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2348 PHACTR4 Zornitza Stark Phenotypes for gene: PHACTR4 were changed from Abnormality in embryonic development, MONDO:0019755 to Syndromic disease, MONDO:0002254, PHACTR4-related
Mendeliome v1.2347 PHACTR4 Zornitza Stark Classified gene: PHACTR4 as Amber List (moderate evidence)
Mendeliome v1.2347 PHACTR4 Zornitza Stark Gene: phactr4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2346 PHACTR4 Zornitza Stark reviewed gene: PHACTR4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, PHACTR4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2346 C14orf80 Zornitza Stark Tag new gene name tag was added to gene: C14orf80.
Mendeliome v1.2346 C14orf80 Zornitza Stark Marked gene: C14orf80 as ready
Mendeliome v1.2346 C14orf80 Zornitza Stark Gene: c14orf80 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2346 C14orf80 Zornitza Stark Classified gene: C14orf80 as Amber List (moderate evidence)
Mendeliome v1.2346 C14orf80 Zornitza Stark Gene: c14orf80 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2345 MSX1 Sangavi Sivagnanasundram reviewed gene: MSX1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005439; Phenotypes: tooth agenesis, selective, 1 MONDO:0007129; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2345 SPOUT1 Bryony Thompson Marked gene: SPOUT1 as ready
Mendeliome v1.2345 SPOUT1 Bryony Thompson Gene: spout1 has been classified as Green List (High Evidence).
Mendeliome v1.2345 SPOUT1 Bryony Thompson Classified gene: SPOUT1 as Green List (high evidence)
Mendeliome v1.2345 SPOUT1 Bryony Thompson Gene: spout1 has been classified as Green List (High Evidence).
Mendeliome v1.2344 SPOUT1 Bryony Thompson gene: SPOUT1 was added
gene: SPOUT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to complex neurodevelopmental disorder MONDO:0100038, SPOUT1-related
Review for gene: SPOUT1 was set to GREEN
Added comment: Biallelic SPOUT1 variants were identified in 28 individuals with a complex neurodevelopmental disorder from 21 unrelated families. Common phenotypes include microcephaly (18/21), seizures (20/28), intellectual disability (14/14), and varying degrees of developmental delays (28/28). Also, supporting zebrafish model. The suggested name of the disorder is SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature).
Sources: Literature
Mendeliome v1.2343 MRPS28 Sangavi Sivagnanasundram reviewed gene: MRPS28: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: combined oxidative phosphorylation deficiency 47, MONDO:0033537; Mode of inheritance: None
Mendeliome v1.2343 SIX2 Zornitza Stark Phenotypes for gene: SIX2 were changed from CAKUT to CAKUT, MONDO:0019719, SIX2-related
Mendeliome v1.2342 SIX2 Zornitza Stark edited their review of gene: SIX2: Changed rating: RED; Changed phenotypes: CAKUT, MONDO:0019719, SIX2-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2342 SIN3B Zornitza Stark Phenotypes for gene: SIN3B were changed from Syndromic intellectual disability/autism spectrum disorder to Neurodevelopmental disorder, MONDO:0700092, SIN3B-related
Mendeliome v1.2341 SIN3B Zornitza Stark reviewed gene: SIN3B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SIN3B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2341 PHACTR4 Sangavi Sivagnanasundram gene: PHACTR4 was added
gene: PHACTR4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHACTR4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PHACTR4 were set to 40012205
Phenotypes for gene: PHACTR4 were set to Abnormality in embryonic development, MONDO:0019755
Review for gene: PHACTR4 was set to RED
Added comment: The association with human disease phenotype is not yet established - classified as Red.
Two affected individuals present with overlapping phenotypic features including some neurodevelopmental features. Both having de novo variants (p. Arg622Pro and p.Leu623Pro) located in the RPEL3 repeat domain.
p.Leu623Pro was present at 19% VAF in patient two.
Sources: Literature
Mendeliome v1.2341 C14orf80 Sangavi Sivagnanasundram changed review comment from: New Gene Name: TEDC1
Only two families reported with biallelic variants in this gene - Reports of a supportive functional assay however rated as Amber given that one of the reported families are consanguineous

PMID: 39979680 - Male sibs from non-consanguineous parents presenting with a range of phenotypes including growth development abnormalities, microcephaly, DD, ID and endocrine insufficiency. The brothers were found to carry chet variants identified in trans [NM_001134877.1 c.[104-5C>G];[787delG] p.[?];[(Ala263LeufsTer29)].
Homozygous zebrafish model recapitulated the human phenotype and is supportive of the loss of function mechanism of disease.

PMID: 38252227 - Iranian consanguineous families identified with a rare biallelic missense variant (Gln269Arg). The affected brothers presented with a range of developmental phenotypes including cognitive impairment and microcephaly.
Sources: Literature; to: New HGNC approved Gene Name: TEDC1
Only two families reported with biallelic variants in this gene - Reports of a supportive functional assay however rated as Amber given that one of the reported families are consanguineous

PMID: 39979680 - Male sibs from non-consanguineous parents presenting with a range of phenotypes including growth development abnormalities, microcephaly, DD, ID and endocrine insufficiency. The brothers were found to carry chet variants identified in trans [NM_001134877.1 c.[104-5C>G];[787delG] p.[?];[(Ala263LeufsTer29)].
Homozygous zebrafish model recapitulated the human phenotype and is supportive of the loss of function mechanism of disease.

PMID: 38252227 - Iranian consanguineous families identified with a rare biallelic missense variant (Gln269Arg). The affected brothers presented with a range of developmental phenotypes including cognitive impairment and microcephaly.
Sources: Literature
Mendeliome v1.2341 C14orf80 Sangavi Sivagnanasundram gene: C14orf80 was added
gene: C14orf80 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C14orf80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C14orf80 were set to 39979680; 38252227
Phenotypes for gene: C14orf80 were set to Primary microcephaly, MONDO:0016660
Review for gene: C14orf80 was set to AMBER
Added comment: New Gene Name: TEDC1
Only two families reported with biallelic variants in this gene - Reports of a supportive functional assay however rated as Amber given that one of the reported families are consanguineous

PMID: 39979680 - Male sibs from non-consanguineous parents presenting with a range of phenotypes including growth development abnormalities, microcephaly, DD, ID and endocrine insufficiency. The brothers were found to carry chet variants identified in trans [NM_001134877.1 c.[104-5C>G];[787delG] p.[?];[(Ala263LeufsTer29)].
Homozygous zebrafish model recapitulated the human phenotype and is supportive of the loss of function mechanism of disease.

PMID: 38252227 - Iranian consanguineous families identified with a rare biallelic missense variant (Gln269Arg). The affected brothers presented with a range of developmental phenotypes including cognitive impairment and microcephaly.
Sources: Literature
Mendeliome v1.2341 CDO1 Sangavi Sivagnanasundram gene: CDO1 was added
gene: CDO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDO1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDO1 were set to 39949058
Phenotypes for gene: CDO1 were set to Neurological Disorder MONDO:0100545
Review for gene: CDO1 was set to AMBER
Added comment: Three children with overlapping neurological features. Three missense de novo variants were identified and were clustered around exon 3 and exon 4.
The three missense variants identified p.(His147Arg, Ala131Val, Glu143Lys) were classified as VUS due to the insilicos and the lack of other reports and are all absent from gnomAD v4.1.
Sources: Literature
Mendeliome v1.2341 DDX39B Sangavi Sivagnanasundram gene: DDX39B was added
gene: DDX39B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX39B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX39B were set to 39918047
Phenotypes for gene: DDX39B were set to neurodevelopmental disorder MONDO:0700092, DDX39B-related
Review for gene: DDX39B was set to GREEN
Added comment: Established gene-disease association.

6 individuals from 5 families with variable neurological and developmental phenotypes including hypotonia, DD, ID and epilepsy.
4 de novo missense variants and 1 inherited splice variant were identified. All variants are absent from gnomAD v4.1.
In vivo functional assay using Drosophila transgenic flies was supportive of a loss of function phenotype.
Sources: Literature
Mendeliome v1.2341 SMARCA1 Zornitza Stark Phenotypes for gene: SMARCA1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, SMARCA1-related
Mendeliome v1.2340 SMARCA1 Zornitza Stark Publications for gene: SMARCA1 were set to 26740508; 26539891; 29249292
Mendeliome v1.2339 SMARCA1 Zornitza Stark Mode of inheritance for gene: SMARCA1 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2338 SMARCA1 Zornitza Stark Classified gene: SMARCA1 as Green List (high evidence)
Mendeliome v1.2338 SMARCA1 Zornitza Stark Gene: smarca1 has been classified as Green List (High Evidence).
Mendeliome v1.2337 SMARCA1 Zornitza Stark reviewed gene: SMARCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37841849; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SMARCA1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2337 GNA13 Bryony Thompson Marked gene: GNA13 as ready
Mendeliome v1.2337 GNA13 Bryony Thompson Gene: gna13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2337 GNA13 Bryony Thompson Classified gene: GNA13 as Amber List (moderate evidence)
Mendeliome v1.2337 GNA13 Bryony Thompson Added comment: Comment on list classification: Only a single recurrent variant reported at this point.
Mendeliome v1.2337 GNA13 Bryony Thompson Gene: gna13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2336 GNA13 Bryony Thompson gene: GNA13 was added
gene: GNA13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GNA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNA13 were set to 39966435
Phenotypes for gene: GNA13 were set to Ito hypomelanosis MONDO:0010302
Mode of pathogenicity for gene: GNA13 was set to Other
Review for gene: GNA13 was set to AMBER
Added comment: 4 unrelated cases with a recurrent post-zygotic GNA13 variant (NM_006572.4:c.599G>A p.Arg200Lys) with a syndrome including hypomelanosis of Ito associated with developmental anomalies. The variant was identified in one patient via exome sequencing of paired tissue/blood and then targeted GNA13 testing of other cases. In vitro assays demonstrate a gain of function for the variant. Q226L was an artificial variant demonstrating a gain of function similar to R200K. The suggested mechanism of disease is through upregulation of the RHOA/ROCK pathway altering melanocyte function.
Sources: Literature
Mendeliome v1.2335 SPTAN1 Bryony Thompson reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40023774; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2335 MKL1 Zornitza Stark Tag new gene name tag was added to gene: MKL1.
Mendeliome v1.2335 MKL1 Sangavi Sivagnanasundram commented on gene: MKL1
Mendeliome v1.2335 NR5A1 Zornitza Stark Publications for gene: NR5A1 were set to 31513305
Mendeliome v1.2334 NR5A1 Zornitza Stark Mode of inheritance for gene: NR5A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2333 NR5A1 Zornitza Stark edited their review of gene: NR5A1: Added comment: Rare reports of sex reversal with biallelic variants (hmz). RED/AMBER for this MOI.; Changed publications: 31513305, 38650427, 20453312; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2333 MBTPS1 Sangavi Sivagnanasundram reviewed gene: MBTPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008256; Phenotypes: spondyloepiphyseal dysplasia, kondo-fu type MONDO:0032721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2333 MBD5 Sangavi Sivagnanasundram reviewed gene: MBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005344; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2333 MARS2 Sangavi Sivagnanasundram reviewed gene: MARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005338; Phenotypes: mitochondrial disease MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2333 DUOX2 Bryony Thompson Publications for gene: DUOX2 were set to 35429653; 27373512; 26301257; 28683258
Mendeliome v1.2332 CNTN6 Bryony Thompson Phenotypes for gene: CNTN6 were changed from Neurodevelopmental disorder, MONDO:0700092, CNTN6-related to Neurodevelopmental disorder, MONDO:0700092, CNTN6-related; congenital hypothyroidism MONDO:0018612
Mendeliome v1.2331 CNTN6 Bryony Thompson Publications for gene: CNTN6 were set to 30836150; 28641109; 29983269
Mendeliome v1.2330 CNTN6 Bryony Thompson Mode of inheritance for gene: CNTN6 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2329 CNTN6 Bryony Thompson Classified gene: CNTN6 as Amber List (moderate evidence)
Mendeliome v1.2329 CNTN6 Bryony Thompson Gene: cntn6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2328 CNTN6 Bryony Thompson reviewed gene: CNTN6: Rating: AMBER; Mode of pathogenicity: None; Publications: 38183624; Phenotypes: congenital hypothyroidism MONDO:0018612; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2328 DUOX1 Bryony Thompson Phenotypes for gene: DUOX1 were changed from congenital hypothyroidism, No OMIM # to congenital hypothyroidism MONDO:0018612
Mendeliome v1.2327 DUOX1 Bryony Thompson Publications for gene: DUOX1 were set to 29650690
Mendeliome v1.2326 DUOX1 Bryony Thompson Classified gene: DUOX1 as Red List (low evidence)
Mendeliome v1.2326 DUOX1 Bryony Thompson Gene: duox1 has been classified as Red List (Low Evidence).
Mendeliome v1.2325 DUOX1 Bryony Thompson reviewed gene: DUOX1: Rating: RED; Mode of pathogenicity: None; Publications: 29650690, 28633507; Phenotypes: congenital hypothyroidism MONDO:0018612; Mode of inheritance: Unknown
Mendeliome v1.2325 DSTYK Bryony Thompson reviewed gene: DSTYK: Rating: AMBER; Mode of pathogenicity: None; Publications: 23862974, 37746849, 34608560; Phenotypes: congenital anomalies of kidney and urinary tract 1 MONDO:0012561; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2325 DSPP Bryony Thompson Publications for gene: DSPP were set to
Mendeliome v1.2324 DSG3 Bryony Thompson Publications for gene: DSG3 were set to 30528827
Mendeliome v1.2323 DSG3 Bryony Thompson Classified gene: DSG3 as Amber List (moderate evidence)
Mendeliome v1.2323 DSG3 Bryony Thompson Gene: dsg3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2322 DSG3 Bryony Thompson reviewed gene: DSG3: Rating: AMBER; Mode of pathogenicity: None; Publications: 26763450, 37850634, 30528827; Phenotypes: Blistering, acantholytic, of oral and laryngeal mucosa MONDO:0030986; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2322 DRD3 Bryony Thompson Publications for gene: DRD3 were set to 16650084; 16809426; 17339592
Mendeliome v1.2321 DRD3 Bryony Thompson Publications for gene: DRD3 were set to
Mendeliome v1.2320 DPYS Bryony Thompson Publications for gene: DPYS were set to
Mendeliome v1.2319 DPY19L2 Bryony Thompson Publications for gene: DPY19L2 were set to
Mendeliome v1.2318 DRD2 Bryony Thompson Classified gene: DRD2 as Amber List (moderate evidence)
Mendeliome v1.2318 DRD2 Bryony Thompson Gene: drd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2317 DRD2 Bryony Thompson reviewed gene: DRD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36456191, 34145635, 33200438; Phenotypes: Combined dystonia, MONDO:0020065, DRD2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2317 APOA4 Zornitza Stark Phenotypes for gene: APOA4 were changed from Hereditary amyloidosis, MONDO:0018634, APOA4-related to Hereditary amyloidosis, MONDO:0018634, APOA4-related; Tubulointerstitial kidney disease, autosomal dominant 6, MIM# 621106
Mendeliome v1.2316 APOA4 Zornitza Stark edited their review of gene: APOA4: Changed phenotypes: Hereditary amyloidosis, MONDO:0018634, APOA4-related, Tubulointerstitial kidney disease, autosomal dominant 6, MIM# 621106
Mendeliome v1.2316 DAP3 Zornitza Stark Phenotypes for gene: DAP3 were changed from Mitochondrial disease MONDO:0044970, DAP3-related to Perrault syndrome 7, MIM# 621101
Mendeliome v1.2315 DAP3 Zornitza Stark edited their review of gene: DAP3: Changed phenotypes: Perrault syndrome 7, MIM# 621101
Mendeliome v1.2315 IRF4 Zornitza Stark Phenotypes for gene: IRF4 were changed from Combined immunodeficiency, MONDO:0015131, IRF4-related to Immunodeficiency 131, MIM# 621097
Mendeliome v1.2314 IRF4 Zornitza Stark edited their review of gene: IRF4: Changed phenotypes: Immunodeficiency 131, MIM# 621097
Mendeliome v1.2314 TRAF3 Zornitza Stark Phenotypes for gene: TRAF3 were changed from {?Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 5}, MIM# 614849 to Immunodeficiency 132B, MIM# 621096
Mendeliome v1.2313 TRAF3 Zornitza Stark edited their review of gene: TRAF3: Changed phenotypes: Immunodeficiency 132B, MIM# 621096
Mendeliome v1.2313 SH2B3 Zornitza Stark Phenotypes for gene: SH2B3 were changed from Predisposition to haematological malignancies; Myeloproliferation and multi-organ autoimmunity; juvenile myelomonocytic leukemia MONDO:001190, SH2B3-related to Predisposition to haematological malignancies; Myeloproliferation and multi-organ autoimmunity; juvenile myelomonocytic leukemia MONDO:0011908, SH2B3-related
Mendeliome v1.2312 C12orf66 Zornitza Stark Phenotypes for gene: C12orf66 were changed from complex neurodevelopmental disorder MONDO:0100038 to Intellectual developmental disorder, autosomal recessive 83, MIM# 621100
Mendeliome v1.2311 C12orf66 Zornitza Stark Publications for gene: C12orf66 were set to
Mendeliome v1.2310 C12orf66 Zornitza Stark edited their review of gene: C12orf66: Changed rating: GREEN; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 83, MIM# 621100; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2310 ARFGEF3 Zornitza Stark Classified gene: ARFGEF3 as Amber List (moderate evidence)
Mendeliome v1.2310 ARFGEF3 Zornitza Stark Gene: arfgef3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2309 ERBB4 Zornitza Stark Classified gene: ERBB4 as Amber List (moderate evidence)
Mendeliome v1.2309 ERBB4 Zornitza Stark Gene: erbb4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2308 ZFHX3 Zornitza Stark Phenotypes for gene: ZFHX3 were changed from Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related to Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related; developmental and epileptic encephalopathy MONDO:0100062, ZFHX3-related
Mendeliome v1.2307 ZFHX3 Zornitza Stark Mode of inheritance for gene: ZFHX3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2306 ZFHX3 Zornitza Stark edited their review of gene: ZFHX3: Added comment: PMID 38508705: 8 unrelated probands with biallelic variants and a phenotype consistent with DEE and childhood partial epilepsy. Also a supporting Drosophila Zfh2 knockdown model with seizure-like behaviour.; Changed publications: 37292950, 38508705; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related, developmental and epileptic encephalopathy MONDO:0100062, ZFHX3-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2306 RYR3 Zornitza Stark Classified gene: RYR3 as Red List (low evidence)
Mendeliome v1.2306 RYR3 Zornitza Stark Gene: ryr3 has been classified as Red List (Low Evidence).
Mendeliome v1.2305 RYR3 Zornitza Stark changed review comment from: DISPUTED by ClinGen; to: DISPUTED by ClinGen for myopathy. LIMITED for epilepsy.
Mendeliome v1.2305 RYR3 Zornitza Stark edited their review of gene: RYR3: Added comment: DISPUTED by ClinGen; Changed rating: RED
Mendeliome v1.2305 SELENON Zornitza Stark Mode of inheritance for gene: SELENON was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2304 SELENON Zornitza Stark edited their review of gene: SELENON: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2304 EEFSEC Zornitza Stark Phenotypes for gene: EEFSEC were changed from Neurodevelopmental disorder, MONDO:0700092, EEFSEC-related to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, MIM#621102
Mendeliome v1.2303 ALG5 Monique Dunstan reviewed gene: ALG5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: k,jsvz k,ajwbSCNZ, jqHABWDSCZ, ,JHqabwmsc; Mode of inheritance: None
Mendeliome v1.2303 HAT1 Monique Dunstan Added comment: Comment on phenotypes: wkaesdC
esjhdbcmzx
Mendeliome v1.2303 HAT1 Monique Dunstan Phenotypes for gene: HAT1 were changed from sajhavscz to sajhavscz
Mendeliome v1.2302 HAT1 Monique Dunstan Tag STR tag was added to gene: HAT1.
Tag refuted tag was added to gene: HAT1.
Mendeliome v1.2302 ABCB4 Katrina Bell Tag SV/CNV tag was added to gene: ABCB4.
Mendeliome v1.2302 HAT1 Monique Dunstan gene: HAT1 was added
gene: HAT1 was added to Mendeliome. Sources: UKGTN
SV/CNV tags were added to gene: HAT1.
Mode of inheritance for gene: HAT1 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: HAT1 were set to PMID:716253
Phenotypes for gene: HAT1 were set to sajhavscz
Penetrance for gene: HAT1 were set to Complete
Mode of pathogenicity for gene: HAT1 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: HAT1 was set to AMBER
Added comment: mjsfgzdckz.x,n efks.dzjhk. liuksweF<KDCjz lukESABJFC
Sources: UKGTN
Mendeliome v1.2301 ABCA1 Katrina Bell Tag somatic tag was added to gene: ABCA1.
Tag 5'UTR tag was added to gene: ABCA1.
Mendeliome v1.2301 ABCA1 Katrina Bell reviewed gene: ABCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: X VX; Phenotypes: Campomelic dysplasia with autosomal sex reversal 114290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2301 ACBD6 Katrina Bell Tag somatic tag was added to gene: ACBD6.
Mendeliome v1.2301 ACBD6 Katrina Bell reviewed gene: ACBD6: 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: SZ C; Phenotypes: CA; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2301 ABCB6 Katrina Bell reviewed gene: ABCB6: 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: ; Phenotypes: Campomelic dysplasia with autosomal sex reversal 114290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v1.2301 HSPB8 Zornitza Stark Phenotypes for gene: HSPB8 were changed from Distal myopathy; Vacuolar myopathy; Neuropathy, distal hereditary motor type IIA, 158590; Charcot-Marie-Tooth disease, axonal, type 2L, MIM# 608673 to Myopathy, myofibrillar, 13, with rimmed vacuoles, MIM# 621078; Distal myopathy; Vacuolar myopathy; Neuropathy, distal hereditary motor type IIA, 158590; Charcot-Marie-Tooth disease, axonal, type 2L, MIM# 608673
Mendeliome v1.2300 HSPB8 Zornitza Stark edited their review of gene: HSPB8: Changed phenotypes: Myopathy, myofibrillar, 13, with rimmed vacuoles, MIM# 621078, Distal myopathy, Vacuolar myopathy, Neuropathy, distal hereditary motor type IIA, 158590, Charcot-Marie-Tooth disease, axonal, type 2L, MIM# 608673
Mendeliome v1.2300 CLCA2 Bryony Thompson Marked gene: CLCA2 as ready
Mendeliome v1.2300 CLCA2 Bryony Thompson Gene: clca2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2300 CLCA2 Bryony Thompson Classified gene: CLCA2 as Amber List (moderate evidence)
Mendeliome v1.2300 CLCA2 Bryony Thompson Gene: clca2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2299 CLCA2 Bryony Thompson gene: CLCA2 was added
gene: CLCA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLCA2 were set to 31326550
Phenotypes for gene: CLCA2 were set to heart conduction disease MONDO:0000992
Review for gene: CLCA2 was set to AMBER
Added comment: Only a single family reported. A missense (p.Trp575Cys) segregates with conduction disease in 5 individuals from a large Chinese family. Electrocardiogram monitoring of mice with missense introduced induced mild conduction block and ectopic pacemakers.
Sources: Literature
Mendeliome v1.2298 HECTD1 Zornitza Stark Marked gene: HECTD1 as ready
Mendeliome v1.2298 HECTD1 Zornitza Stark Gene: hectd1 has been classified as Green List (High Evidence).
Mendeliome v1.2298 ARHGEF40 Zornitza Stark Marked gene: ARHGEF40 as ready
Mendeliome v1.2298 ARHGEF40 Zornitza Stark Gene: arhgef40 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2298 ARHGEF40 Zornitza Stark Classified gene: ARHGEF40 as Amber List (moderate evidence)
Mendeliome v1.2298 ARHGEF40 Zornitza Stark Gene: arhgef40 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2297 ARHGEF40 Zornitza Stark reviewed gene: ARHGEF40: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2297 C12orf66 Zornitza Stark Marked gene: C12orf66 as ready
Mendeliome v1.2297 C12orf66 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name: KICS2
Mendeliome v1.2297 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.2297 C12orf66 Zornitza Stark Tag new gene name tag was added to gene: C12orf66.
Mendeliome v1.2297 DDX53 Zornitza Stark Marked gene: DDX53 as ready
Mendeliome v1.2297 DDX53 Zornitza Stark Gene: ddx53 has been classified as Green List (High Evidence).
Mendeliome v1.2297 SHROOM3 Chirag Patel reviewed gene: SHROOM3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 39875538; Phenotypes: Craniofacial microsomia MONDO:0015397; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2297 C12orf66 Chirag Patel reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39824192; Phenotypes: Neurodevelopmental disorder MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2297 ARHGEF40 Chirag Patel Classified gene: ARHGEF40 as Red List (low evidence)
Mendeliome v1.2297 ARHGEF40 Chirag Patel Gene: arhgef40 has been classified as Red List (Low Evidence).
Mendeliome v1.2296 ARHGEF40 Chirag Patel Classified gene: ARHGEF40 as Green List (high evidence)
Mendeliome v1.2296 ARHGEF40 Chirag Patel Gene: arhgef40 has been classified as Green List (High Evidence).
Mendeliome v1.2295 ARHGEF40 Chirag Patel gene: ARHGEF40 was added
gene: ARHGEF40 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGEF40 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGEF40 were set to PMID: 39838643
Phenotypes for gene: ARHGEF40 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: ARHGEF40 was set to RED
Added comment: 2 individuals with global developmental delay, hypotonia, short stature, hearing impairment, nystagmus, feeding issues, and dysmorphism (bifid uvula, narrow mouth, high palate, micrognathia). Trio clinical whole exome sequencing identified de novo variants in the ARHGEF40 gene at position p.Arg225, which is fully conserved in mammals and located within the n-terminal keratin binding region (p.Arg225Trp and p.Arg225Gln). Of note, multiple additional probands with rare missense variants at the p.Arg225 residue have been identified by the same laboratory (but there was no consent for publication, providing further evidence of
the importance of this residue.

The ARHGEF40 gene (aka SOLO) is a member of the Rho guanine nucleotide exchange factor (Rho-GEF) family of proteins, which stimulate Rho signal transduction molecules by converting them from inactive GDP-bound form to the active GTP-bound state. No functional studies to characterise disease-gene relationship or disease mechanism.
Sources: Literature
Mendeliome v1.2294 HECTD1 Chirag Patel Classified gene: HECTD1 as Green List (high evidence)
Mendeliome v1.2294 HECTD1 Chirag Patel Gene: hectd1 has been classified as Green List (High Evidence).
Mendeliome v1.2293 HECTD1 Chirag Patel gene: HECTD1 was added
gene: HECTD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HECTD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HECTD1 were set to PMID: 39879987
Phenotypes for gene: HECTD1 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: HECTD1 was set to GREEN
Added comment: 14 unrelated individuals (identified through GeneMatcher) with 15 variants of uncertain significance (VUS) in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant). Of the 15 different variants in HECTD1, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. All variants were absent in gnomAD, and HECTD1 is highly intolerant to loss-of-function variation (loss-of-function-intolerant score of 1). Clinical presentation was variable developmental delay, intellectual disability, autism spectrum disorder, ADHD, and epilepsy.

The one individual with compound heterozygous variants had growth impairment along with NDD. The variants were inherited from apparently healthy parents, suggesting that genetic or environmental modifiers may be required to develop the phenotype. Significant enrichment of de novo variants in HECTD1 was also shown in an independent cohort of 53,305 published trios with NDDs or congenital heart disease.

HECT-domain-containing protein 1 (HECTD1) mediates developmental pathways, including cell signalling, gene expression, and embryogenesis. Conditional knockout of Hectd1 in the neural lineage in mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development. Functional studies of 2 missense variants and 1 nonsense variant in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms.
Sources: Literature
Mendeliome v1.2292 PDGFRB Zornitza Stark Phenotypes for gene: PDGFRB were changed from Basal ganglia calcification, idiopathic, 4, MIM# 615007; Kosaki overgrowth syndrome, MIM# 616592; Myeloproliferative disorder with eosinophilia, MIM# 131440; Myofibromatosis, infantile, 1, MIM# 228550; Premature ageing syndrome, Penttinen type, MIM# 601812 to Basal ganglia calcification, idiopathic, 4, MIM# 615007; Kosaki overgrowth syndrome, MIM# 616592; Myeloproliferative disorder with eosinophilia, MIM# 131440; Myofibromatosis, infantile, 1, MIM# 228550; Premature ageing syndrome, Penttinen type, MIM# 601812; Ocular pterygium-digital keloid dysplasia syndrome, MIM# 621091
Mendeliome v1.2291 PDGFRB Zornitza Stark edited their review of gene: PDGFRB: Added comment: Single family reported with OPDKD phenotype characterised by aggressive circumferential ingrowth of conjunctiva beginning in early childhood that is resistant to treatment, ultimately covering the cornea and resulting in loss of vision. Digital keloid formation after minor trauma, which can become extensive and cause flexion contractures; hardened auricles. RED for this association.; Changed publications: 33450762; Changed phenotypes: Ocular pterygium-digital keloid dysplasia syndrome, MIM# 621091, Basal ganglia calcification, idiopathic, 4, MIM# 615007, Kosaki overgrowth syndrome, MIM# 616592, Myeloproliferative disorder with eosinophilia, MIM# 131440, Myofibromatosis, infantile, 1, MIM# 228550, Premature ageing syndrome, Penttinen type, MIM# 601812
Mendeliome v1.2291 TAF11 Bryony Thompson Marked gene: TAF11 as ready
Mendeliome v1.2291 TAF11 Bryony Thompson Gene: taf11 has been classified as Red List (Low Evidence).
Mendeliome v1.2291 TAF11 Bryony Thompson gene: TAF11 was added
gene: TAF11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAF11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAF11 were set to 39727181
Phenotypes for gene: TAF11 were set to cleft lip MONDO:0004747
Review for gene: TAF11 was set to RED
Added comment: 2 individuals in a single Chinese family with nonsyndromic cleft lip segregating with the missense p.Leu48Phe. The missense has an AF of 1.8% (including 15 homozygotes) in gnomAD v4 in the East Asian population, which is too common for an autosomal dominant disease—also, a supporting zebrafish model with craniofacial abnormalities (however the genetic evidence for this GDA is lacking).
Sources: Literature
Mendeliome v1.2290 PTPMT1 Bryony Thompson Marked gene: PTPMT1 as ready
Mendeliome v1.2290 PTPMT1 Bryony Thompson Gene: ptpmt1 has been classified as Green List (High Evidence).
Mendeliome v1.2290 PTPMT1 Bryony Thompson Classified gene: PTPMT1 as Green List (high evidence)
Mendeliome v1.2290 PTPMT1 Bryony Thompson Gene: ptpmt1 has been classified as Green List (High Evidence).
Mendeliome v1.2289 PTPMT1 Bryony Thompson gene: PTPMT1 was added
gene: PTPMT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645; 37672386
Phenotypes for gene: PTPMT1 were set to inborn mitochondrial metabolism disorder MONDO:0004069
Review for gene: PTPMT1 was set to GREEN
Added comment: 6 cases from 3 independent families with biallelic variants in PTPMT1 (a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis). All cases presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome including developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Supporting knockout zebrafish and mouse models.
Sources: Literature
Mendeliome v1.2288 NR6A1 Bryony Thompson Marked gene: NR6A1 as ready
Mendeliome v1.2288 NR6A1 Bryony Thompson Gene: nr6a1 has been classified as Green List (High Evidence).
Mendeliome v1.2288 NR6A1 Bryony Thompson Classified gene: NR6A1 as Green List (high evidence)
Mendeliome v1.2288 NR6A1 Bryony Thompson Gene: nr6a1 has been classified as Green List (High Evidence).
Mendeliome v1.2287 NR6A1 Bryony Thompson gene: NR6A1 was added
gene: NR6A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NR6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR6A1 were set to 39606382
Phenotypes for gene: NR6A1 were set to Craniofacial microsomia MONDO:0015397
Review for gene: NR6A1 was set to GREEN
Added comment: 6 unrelated families with heterozygous rare variants (missense, nonsense, frameshift, or large deletion) with incomplete penetrance and variable expressivity. Colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities characterised the phenotype of the families. Also, supporting zebrafish model. Loss of function is the expected mechanism of disease.
Sources: Literature
Mendeliome v1.2286 MRAP2 Zornitza Stark Marked gene: MRAP2 as ready
Mendeliome v1.2286 MRAP2 Zornitza Stark Gene: mrap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2286 MRAP2 Zornitza Stark Classified gene: MRAP2 as Amber List (moderate evidence)
Mendeliome v1.2286 MRAP2 Zornitza Stark Gene: mrap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2285 MRAP2 Zornitza Stark gene: MRAP2 was added
gene: MRAP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRAP2 were set to 23869016; 31700171; 27474872; 26795956
Phenotypes for gene: MRAP2 were set to Susceptibility to obesity, MIM#615457
Review for gene: MRAP2 was set to AMBER
Added comment: Multiple studies supporting association between rare variants and obesity; however ?monogenic vs susceptibility alleles.
Sources: Literature
Mendeliome v1.2284 ITGAV Zornitza Stark Marked gene: ITGAV as ready
Mendeliome v1.2284 ITGAV Zornitza Stark Gene: itgav has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2284 ITGAV Zornitza Stark Classified gene: ITGAV as Amber List (moderate evidence)
Mendeliome v1.2284 ITGAV Zornitza Stark Gene: itgav has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2283 ITGAV Zornitza Stark gene: ITGAV was added
gene: ITGAV was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITGAV was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGAV were set to 39526957
Phenotypes for gene: ITGAV were set to Syndromic disease, MONDO:0002254, ITGAV-related
Review for gene: ITGAV was set to AMBER
Added comment: Three unrelated families reported: two with affected children (one hmz missense; other compound het LoF with missense) and one family with four affected fetuses. Clinical features included brain and eye anomalies and IBD/immune dysregulation. TGF-beta signalling pathway affected. The deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation.
Sources: Literature
Mendeliome v1.2282 RYBP Zornitza Stark Marked gene: RYBP as ready
Mendeliome v1.2282 RYBP Zornitza Stark Gene: rybp has been classified as Green List (High Evidence).
Mendeliome v1.2282 RYBP Zornitza Stark Classified gene: RYBP as Green List (high evidence)
Mendeliome v1.2282 RYBP Zornitza Stark Gene: rybp has been classified as Green List (High Evidence).
Mendeliome v1.2281 RYBP Zornitza Stark gene: RYBP was added
gene: RYBP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RYBP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RYBP were set to 39891528
Phenotypes for gene: RYBP were set to Neurodevelopmental disorder, MONDO:0700092, RYBP-related
Review for gene: RYBP was set to GREEN
Added comment: Seven individuals with heterozygous de novo variants in RYBP reported. Clinical findings include severe developmental delay, dysmorphisms and multiple congenital anomalies. All the single nucleotide variants in RYBP localized to the N-terminal domain of the gene, which encodes the zinc finger domain and ubiquitin binding moiety. Further supportive in vitro and Drosophila functional data.
Sources: Literature
Mendeliome v1.2280 C1orf127 Zornitza Stark Marked gene: C1orf127 as ready
Mendeliome v1.2280 C1orf127 Zornitza Stark Gene: c1orf127 has been classified as Green List (High Evidence).
Mendeliome v1.2280 C1orf127 Zornitza Stark Classified gene: C1orf127 as Green List (high evidence)
Mendeliome v1.2280 C1orf127 Zornitza Stark Gene: c1orf127 has been classified as Green List (High Evidence).
Mendeliome v1.2279 C1orf127 Zornitza Stark gene: C1orf127 was added
gene: C1orf127 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: C1orf127.
Mode of inheritance for gene: C1orf127 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf127 were set to 39753129
Phenotypes for gene: C1orf127 were set to Heterotaxy, visceral, MONDO:0018677, CIROZ-related
Review for gene: C1orf127 was set to GREEN
Added comment: 16 individuals from 10 families reported with bi-allelic variants in this gene and heterotaxy, including CHD. Supportive mouse model. CIROZ is absent or obsolete in select animals with motile cilia at their left-right organiser, including Carnivora, Atherinomorpha fish, or jawless vertebrates. Knockouts in zebrafish and Xenopus did not have observable LR anomalies. Approved HGNC name is CIROZ.
Sources: Literature
Mendeliome v1.2278 DAND5 Zornitza Stark Marked gene: DAND5 as ready
Mendeliome v1.2278 DAND5 Zornitza Stark Gene: dand5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2278 DAND5 Zornitza Stark Classified gene: DAND5 as Amber List (moderate evidence)
Mendeliome v1.2278 DAND5 Zornitza Stark Gene: dand5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2277 DAND5 Zornitza Stark gene: DAND5 was added
gene: DAND5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAND5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAND5 were set to 36316122; 34215651
Phenotypes for gene: DAND5 were set to Heterotaxy, visceral, 13, autosomal, MIM# 621079
Review for gene: DAND5 was set to AMBER
Added comment: Two individuals reported with bi-allelic LoF variants and heterotaxy.
Sources: Literature
Mendeliome v1.2276 SEL1L Zornitza Stark Phenotypes for gene: SEL1L were changed from Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067 to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinaemia, MIM# 621068; Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067
Mendeliome v1.2275 SEL1L Zornitza Stark edited their review of gene: SEL1L: Added comment: Has been split into two conditions by OMIM -- uncertain that these are distinct and not part of a spectrum. Await further reports.; Changed phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinaemia, MIM# 621068, Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067
Mendeliome v1.2275 SEL1L Zornitza Stark Phenotypes for gene: SEL1L were changed from Neurodevelopmental disorder, MONDO:0700092, SEL1L-related to Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067
Mendeliome v1.2274 SEL1L Zornitza Stark reviewed gene: SEL1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2274 PPA1 Zornitza Stark Marked gene: PPA1 as ready
Mendeliome v1.2274 PPA1 Zornitza Stark Gene: ppa1 has been classified as Red List (Low Evidence).
Mendeliome v1.2274 PPA1 Zornitza Stark gene: PPA1 was added
gene: PPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPA1 were set to 37999237
Phenotypes for gene: PPA1 were set to Galactosaemia, MONDO:0018116
Review for gene: PPA1 was set to RED
Added comment: Homozygous missense variant detected in two siblings with increased galactose and galactose-related metabolites ascertained in neonatal screening. Some supportive functional data.
Sources: Literature
Mendeliome v1.2273 DMRT1 Zornitza Stark Phenotypes for gene: DMRT1 were changed from Azoospermia to 46,XY disorder of sex development, MONDO:0020040
Mendeliome v1.2272 DMRT1 Zornitza Stark Classified gene: DMRT1 as Amber List (moderate evidence)
Mendeliome v1.2272 DMRT1 Zornitza Stark Gene: dmrt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2271 DMRT1 Zornitza Stark edited their review of gene: DMRT1: Added comment: DMRT1 gene exclusively expressed in male gonads. Thought not to affect ovarian development.
Gene included three international studies - see PMID: 28295047 supplemental article Fig 1 patient 19, 46XY with hypoplastic labia, uterus present had DMRT1 c.251A>G p.Tyr84Cys maternally inherited VOUS
PMID: 26005864: p.R111G also described in complete gonadal dysgenesis; Changed rating: AMBER; Changed publications: 31479588, 24934491, 29527098, 26005864, 28295047; Changed phenotypes: 46,XY disorder of sex development, MONDO:0020040
Mendeliome v1.2271 GUK1 Zornitza Stark Phenotypes for gene: GUK1 were changed from Mitochondrial DNA depletion syndrome MONDO:0018158, GUK1-related to Mitochondrial DNA depletion syndrome 21, MIM# 621071
Mendeliome v1.2270 GUK1 Zornitza Stark reviewed gene: GUK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 21, MIM# 621071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2270 FLVCR1 Zornitza Stark Phenotypes for gene: FLVCR1 were changed from posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177; neurodevelopmental disorder MONDO:0700092, FLVCR1-related to posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177; Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MIM#621060
Mendeliome v1.2269 FLVCR1 Zornitza Stark reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MIM#621060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2269 MGA Zornitza Stark Marked gene: MGA as ready
Mendeliome v1.2269 MGA Zornitza Stark Gene: mga has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2269 MGA Zornitza Stark Classified gene: MGA as Amber List (moderate evidence)
Mendeliome v1.2269 MGA Zornitza Stark Gene: mga has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2268 MGA Zornitza Stark gene: MGA was added
gene: MGA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MGA were set to 39600096; 20044811; 39545409
Phenotypes for gene: MGA were set to Syndromic disease, MONDO:0002254, MGA-related; Premature ovarian failure 26, MIM# 621065
Review for gene: MGA was set to AMBER
Added comment: Association with syndromic disease: Three individuals with de novo LoF variants reported in individuals with ID and congenital anomalies. Zebrafish model supports role of this transcription factor in organogenesis. Note there are previous, less clear reports of association with NDD/CHD. Gene is constrained for LoF variants in gnomad v4; however, note there are ~30 individuals with LoF variants present. Borderline Green/Amber.

Association with POF: LoF variants enriched in a large POF cohort. Familial testing in a small number of families performed. Mouse model supportive. Also borderline Amber/Green.

Amber rating until phenotypes and mechanisms of disease for these two associations clarified.
Sources: Literature
Mendeliome v1.2267 USP25 Zornitza Stark Phenotypes for gene: USP25 were changed from USP25-related epilepsy (epilepsy, idiopathic generalized, MONDO:0005579) to {Epilepsy, idiopathic generalized, susceptibility to, 19} MIM#621064
Mendeliome v1.2266 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500 to Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM# 169500; Leukodystrophy, demyelinating, adult-onset, autosomal dominan, atypical, MIM#621061
Mendeliome v1.2265 LMNB1 Zornitza Stark edited their review of gene: LMNB1: Changed phenotypes: Microcephaly 26, primary, autosomal dominant, MIM# 619179, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis, Leukodystrophy, adult-onset, autosomal dominant, MIM# 169500, Leukodystrophy, demyelinating, adult-onset, autosomal dominan, atypical, MIM#621061
Mendeliome v1.2265 HYAL2 Zornitza Stark Phenotypes for gene: HYAL2 were changed from Cleft lip and palate; cor triatriatum; congenital cardiac malformations to Muggenthaler-Chowdhury-Chioza syndrome, MIM# 621063
Mendeliome v1.2264 TRPM7 Zornitza Stark Classified gene: TRPM7 as Green List (high evidence)
Mendeliome v1.2264 TRPM7 Zornitza Stark Gene: trpm7 has been classified as Green List (High Evidence).
Mendeliome v1.2263 TRPM7 Zornitza Stark changed review comment from: Protein expressed in the distal tubule, related to TRPM6. Postulated link with hypoMg with secondary hypoCa. PMID 35561741: two families reported with dominant inheritance. F1: three affected individuals with splicing variant; some supportive functional data. F2: single affected individual, de novo missense variant. PMID 35712613: de novo missense variant in an individual with hypoMg. PMID 39099563: three affected individuals with missense variants, all de novo. Probands had DD, two had seizures.; to: Protein expressed in the distal tubule, related to TRPM6. Postulated link with hypoMg with secondary hypoCa. PMID 35561741: two families reported with dominant inheritance. F1: three affected individuals with splicing variant; some supportive functional data. F2: single affected individual, de novo missense variant. PMID 35712613: de novo missense variant in an individual with hypoMg. PMID 39099563: three affected individuals with missense variants, all de novo. Probands had DD, two had seizures.

Overall, Green for association with HypoMg.

Red for ALS and stillbirth.
Mendeliome v1.2263 TRPM7 Zornitza Stark edited their review of gene: TRPM7: Added comment: Protein expressed in the distal tubule, related to TRPM6. Postulated link with hypoMg with secondary hypoCa. PMID 35561741: two families reported with dominant inheritance. F1: three affected individuals with splicing variant; some supportive functional data. F2: single affected individual, de novo missense variant. PMID 35712613: de novo missense variant in an individual with hypoMg. PMID 39099563: three affected individuals with missense variants, all de novo. Probands had DD, two had seizures.; Changed rating: GREEN; Changed publications: 32503408, 31423533, 35561741, 35712613, 39099563; Changed phenotypes: Familial primary hypomagnesemia, MONDO:0018100, TRPM7-related, {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500, Cardiac arrhythmia, stillbirth
Mendeliome v1.2263 TAOK2 Zornitza Stark Phenotypes for gene: TAOK2 were changed from Generalized verrucosis; abnormal T cell activation; autism to neurodevelopmental disorder, MONDO:0700092, TAOK2-related; Generalized verrucosis; abnormal T cell activation; autism
Mendeliome v1.2262 TAOK2 Zornitza Stark Publications for gene: TAOK2 were set to 28385331; 29467497
Mendeliome v1.2261 TAOK2 Zornitza Stark Classified gene: TAOK2 as Green List (high evidence)
Mendeliome v1.2261 TAOK2 Zornitza Stark Gene: taok2 has been classified as Green List (High Evidence).
Mendeliome v1.2260 SLC13A1 Zornitza Stark Classified gene: SLC13A1 as Amber List (moderate evidence)
Mendeliome v1.2260 SLC13A1 Zornitza Stark Gene: slc13a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2259 INPP4A Chirag Patel Classified gene: INPP4A as Green List (high evidence)
Mendeliome v1.2259 INPP4A Chirag Patel Gene: inpp4a has been classified as Green List (High Evidence).
Mendeliome v1.2258 INPP4A Chirag Patel reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39315527; Phenotypes: INPP4A-related neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2258 DDX58 Zornitza Stark Marked gene: DDX58 as ready
Mendeliome v1.2258 DDX58 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is RIGI.
Mendeliome v1.2258 DDX58 Zornitza Stark Gene: ddx58 has been classified as Green List (High Evidence).
Mendeliome v1.2258 DDX58 Zornitza Stark Tag new gene name tag was added to gene: DDX58.
Mendeliome v1.2258 LRRC45 Zornitza Stark Marked gene: LRRC45 as ready
Mendeliome v1.2258 LRRC45 Zornitza Stark Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2258 LRRC45 Zornitza Stark Classified gene: LRRC45 as Amber List (moderate evidence)
Mendeliome v1.2258 LRRC45 Zornitza Stark Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2257 LRRC45 Zornitza Stark gene: LRRC45 was added
gene: LRRC45 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 39638757
Phenotypes for gene: LRRC45 were set to Neurodevelopmental disorder MONDO:0700092, LRRC45-related
Review for gene: LRRC45 was set to AMBER
Added comment: Three individuals from two families reported with two homozygous variants, one splice site and the other missense. Features of a neurological ciliopathy with some supportive experimental evidence.
Sources: Literature
Mendeliome v1.2256 WASHC3 Zornitza Stark Marked gene: WASHC3 as ready
Mendeliome v1.2256 WASHC3 Zornitza Stark Gene: washc3 has been classified as Red List (Low Evidence).
Mendeliome v1.2256 WASHC3 Zornitza Stark Phenotypes for gene: WASHC3 were changed from neurodevelopmental disorder MONDO:0700092 to neurodevelopmental disorder MONDO:0700092, WASHC3 related
Mendeliome v1.2255 WASHC3 Zornitza Stark Mode of inheritance for gene: WASHC3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2254 WASHC3 Zornitza Stark Classified gene: WASHC3 as Red List (low evidence)
Mendeliome v1.2254 WASHC3 Zornitza Stark Gene: washc3 has been classified as Red List (Low Evidence).
Mendeliome v1.2253 WASHC3 Zornitza Stark reviewed gene: WASHC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO:0700092, WASHC3 related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2253 NAV3 Zornitza Stark Marked gene: NAV3 as ready
Mendeliome v1.2253 NAV3 Zornitza Stark Gene: nav3 has been classified as Green List (High Evidence).
Mendeliome v1.2253 NAV3 Zornitza Stark Classified gene: NAV3 as Green List (high evidence)
Mendeliome v1.2253 NAV3 Zornitza Stark Gene: nav3 has been classified as Green List (High Evidence).
Mendeliome v1.2252 NAV3 Zornitza Stark gene: NAV3 was added
gene: NAV3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAV3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAV3 were set to 39708122; 38977784
Phenotypes for gene: NAV3 were set to Neurodevelopmental disorder, MONDO:0700092, NAV3-related
Review for gene: NAV3 was set to GREEN
Added comment: 17 individuals from 11 families reported with bi-allelic variants and neurodevelopmental phenotypes, including DD/ID and behavioural abnormalities.
Sources: Literature
Mendeliome v1.2251 EEFSEC Zornitza Stark Marked gene: EEFSEC as ready
Mendeliome v1.2251 EEFSEC Zornitza Stark Gene: eefsec has been classified as Green List (High Evidence).
Mendeliome v1.2251 EEFSEC Zornitza Stark Classified gene: EEFSEC as Green List (high evidence)
Mendeliome v1.2251 EEFSEC Zornitza Stark Gene: eefsec has been classified as Green List (High Evidence).
Mendeliome v1.2250 EEFSEC Zornitza Stark gene: EEFSEC was added
gene: EEFSEC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEFSEC were set to 39753114
Phenotypes for gene: EEFSEC were set to Neurodevelopmental disorder, MONDO:0700092, EEFSEC-related
Review for gene: EEFSEC was set to GREEN
Added comment: Nine individuals from 8 unrelated families reported with bi-allelic variants in this gene and progressive neurodevelopmental disorder manifesting with global developmental delay, progressive spasticity, ataxia, and seizures. Cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. In line with the clinical phenotype, an eEFSec-RNAi Drosophila model displays progressive impairment of motor function, which is reflected in the synaptic defects in this model organisms.
Sources: Literature
Mendeliome v1.2249 DAP3 Zornitza Stark Marked gene: DAP3 as ready
Mendeliome v1.2249 DAP3 Zornitza Stark Gene: dap3 has been classified as Green List (High Evidence).
Mendeliome v1.2249 DAP3 Zornitza Stark Classified gene: DAP3 as Green List (high evidence)
Mendeliome v1.2249 DAP3 Zornitza Stark Gene: dap3 has been classified as Green List (High Evidence).
Mendeliome v1.2248 DAP3 Zornitza Stark gene: DAP3 was added
gene: DAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to 39701103
Phenotypes for gene: DAP3 were set to Mitochondrial disease MONDO:0044970, DAP3-related
Review for gene: DAP3 was set to GREEN
Added comment: DAP3 encodes the mitoribosomal small subunit 29 (MRPS29). Five unrelated individuals reported with bi-allelic variants in DAP3 and variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants.
Sources: Literature
Mendeliome v1.2247 LRRC8C Zornitza Stark Marked gene: LRRC8C as ready
Mendeliome v1.2247 LRRC8C Zornitza Stark Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2247 LRRC8C Zornitza Stark Classified gene: LRRC8C as Amber List (moderate evidence)
Mendeliome v1.2247 LRRC8C Zornitza Stark Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2246 MYMX Chirag Patel Classified gene: MYMX as Green List (high evidence)
Mendeliome v1.2246 MYMX Chirag Patel Gene: mymx has been classified as Green List (High Evidence).
Mendeliome v1.2245 MYMX Chirag Patel reviewed gene: MYMX: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39668186; Phenotypes: congenital myopathy MONDO:0019952, congenital myopathy with facial palsy, growth restriction, and dysmorphism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2245 DDX53 Chirag Patel Classified gene: DDX53 as Green List (high evidence)
Mendeliome v1.2245 DDX53 Chirag Patel Gene: ddx53 has been classified as Green List (High Evidence).
Mendeliome v1.2244 DDX53 Chirag Patel gene: DDX53 was added
gene: DDX53 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX53 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DDX53 were set to PMID: 39706195
Phenotypes for gene: DDX53 were set to autism spectrum disorder MONDO:0005258
Review for gene: DDX53 was set to GREEN
Added comment: The DDX53 gene is a single-exon RNA helicase which lies intronic to PTCHD1-AS (a multi-isoform long noncoding RNA (lncRNA) at the Xp22.11 locus. It is thought to play a role in RNA decay, RNA processing, ribosome biogenesis, and translation initiation. 9 affected males and 3 affected females from 9 unrelated families with ASD and rare, predicted damaging or loss-of-function variants in DDX53 (including a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS). A further 26 individuals with ASD were identified (from Autism Speaks MSSNG and Simons Foundation Autism Research Initiative) with 19 rare, damaging DDX53 variations (mostly maternally inherited). No functional evidence.
Sources: Literature
Mendeliome v1.2243 RBFOX2 Ain Roesley Phenotypes for gene: RBFOX2 were changed from Congenital heart disease MONDO:0005453, RBFOX2-related to RBFOX2-related congenital heart disorder (MONDO:0100557)
Mendeliome v1.2242 RBFOX2 Zornitza Stark Phenotypes for gene: RBFOX2 were changed from Hypoplastic left heart syndrome (HLHS) MONDO:0004933 to Congenital heart disease MONDO:0005453, RBFOX2-related
Mendeliome v1.2241 RBFOX2 Zornitza Stark Classified gene: RBFOX2 as Green List (high evidence)
Mendeliome v1.2241 RBFOX2 Zornitza Stark Gene: rbfox2 has been classified as Green List (High Evidence).
Mendeliome v1.2240 CCT3 Zornitza Stark Phenotypes for gene: CCT3 were changed from neurodevelopmental disorder MONDO:0700092, CCT3-related to Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, MIM# 621034
Mendeliome v1.2239 CCT3 Zornitza Stark reviewed gene: CCT3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, MIM# 621034; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2239 TCP1 Zornitza Stark Phenotypes for gene: TCP1 were changed from neurodevelopmental disorder MONDO:0700092, TCP1-related to Intellectual developmental disorder with polymicrogyria and seizures, MIM# 621021
Mendeliome v1.2238 TCP1 Zornitza Stark reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with polymicrogyria and seizures, MIM# 621021; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2238 TAOK2 Achchuthan Shanmugasundram reviewed gene: TAOK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39737487; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw reviewed gene: RBFOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26785492, 27670201, 32368696, 27485310, 25205790, 35137168, 26785492, 28991257; Phenotypes: RBFOX2-related congenital heart disorder (MONDO:0100557); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw Deleted their review
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw changed review comment from: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.

- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.

- 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data).

- ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication).

- ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease.; to: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.

- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.

- 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data).

- ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication).

- ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease.
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw reviewed gene: RBFOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26785492, 27670201, 32368696, 27485310, 25205790, 35137168, 26785492, 28991257); Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2238 EP400 Bryony Thompson Marked gene: EP400 as ready
Mendeliome v1.2238 EP400 Bryony Thompson Gene: ep400 has been classified as Green List (High Evidence).
Mendeliome v1.2238 EP400 Bryony Thompson Classified gene: EP400 as Green List (high evidence)
Mendeliome v1.2238 EP400 Bryony Thompson Gene: ep400 has been classified as Green List (High Evidence).
Mendeliome v1.2237 LRRC8C Sangavi Sivagnanasundram changed review comment from: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Sources: Literature; to: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Supporting in vitro functional assay was conducted however further evidence is required to upgrade the gene classification.
Sources: Literature
Mendeliome v1.2237 LRRC8C Sangavi Sivagnanasundram edited their review of gene: LRRC8C: Changed rating: AMBER
Mendeliome v1.2237 EP400 Sangavi Sivagnanasundram gene: EP400 was added
gene: EP400 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EP400 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EP400 were set to 39708813
Phenotypes for gene: EP400 were set to neurodevelopmental disorder with or without early-onset generalized epilepsy - MONDO:0030930
Review for gene: EP400 was set to GREEN
Added comment: 6 unrelated probands presenting with epilepsy with NDD had compound heterozygous variants in EP400. They were confirmed in trans and inherited from their asymptomatic parents.

Knockdown of EP400 ortholog in Drosophila showed an increase in seizure-like susceptibility and abnormal neurological behaviour.
Sources: Literature
Mendeliome v1.2237 LDB1 Bryony Thompson Marked gene: LDB1 as ready
Mendeliome v1.2237 LDB1 Bryony Thompson Gene: ldb1 has been classified as Green List (High Evidence).
Mendeliome v1.2237 LDB1 Bryony Thompson Classified gene: LDB1 as Green List (high evidence)
Mendeliome v1.2237 LDB1 Bryony Thompson Gene: ldb1 has been classified as Green List (High Evidence).
Mendeliome v1.2236 LDB1 Bryony Thompson gene: LDB1 was added
gene: LDB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus MONDO:0016349
Review for gene: LDB1 was set to GREEN
Added comment: Exome-wide significant enrichment of LDB1 protein-altering de novo variants (p = 1.11 x 10-15) in a large cerebral ventriculomegaly cohort (>2,697 parent-proband trios). 8 unrelated cases with ventriculomegaly, developmental delay, and dysmorphic features with de novo variants (7 LoF variants truncate LDB1's carboxy-terminal LIM interaction domain & 1 missense).
Sources: Literature
Mendeliome v1.2235 LRRC8C Sangavi Sivagnanasundram gene: LRRC8C was added
gene: LRRC8C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome MIM#621056
Mode of pathogenicity for gene: LRRC8C was set to Other
Review for gene: LRRC8C was set to RED
Added comment: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Sources: Literature
Mendeliome v1.2235 WASHC3 Sangavi Sivagnanasundram gene: WASHC3 was added
gene: WASHC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASHC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WASHC3 were set to DOI: https://doi.org/10.1016/j.gimo.2024.101915
Phenotypes for gene: WASHC3 were set to neurodevelopmental disorder MONDO:0700092
Review for gene: WASHC3 was set to GREEN
Added comment: Three unrelated families with short stature, distinctive facies and neurodevelopmental abnormalities. Two different rare missense variants were identified between the three families (c.207A>C:p.L69F and c.1A>T, p.M1?).
In vitro functional assay was conducted on both variants showing impaired protein function supportive of disease mechanism.
Sources: Literature
Mendeliome v1.2235 SLC13A1 Sangavi Sivagnanasundram reviewed gene: SLC13A1: Rating: AMBER; Mode of pathogenicity: None; Publications: doi: https://doi.org/10.1016/j.gimo.2024.101958; Phenotypes: sulfation-related bone disorder MONDO:0019688; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2235 RICTOR Bryony Thompson Marked gene: RICTOR as ready
Mendeliome v1.2235 RICTOR Bryony Thompson Gene: rictor has been classified as Green List (High Evidence).
Mendeliome v1.2235 RICTOR Bryony Thompson Classified gene: RICTOR as Green List (high evidence)
Mendeliome v1.2235 RICTOR Bryony Thompson Gene: rictor has been classified as Green List (High Evidence).
Mendeliome v1.2234 RICTOR Bryony Thompson gene: RICTOR was added
gene: RICTOR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RICTOR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RICTOR were set to 39738822
Phenotypes for gene: RICTOR were set to Neurodevelopmental disorder MONDO:0700092, RICTOR-related
Review for gene: RICTOR was set to GREEN
Added comment: 8 unrelated cases presenting with ID and/or developmental delay with de novo or heterozygous variants inherited from one affected parent, including three missense variants, four loss-of-function variants and one 3 kb deletion encompassing RICTOR. Possible gain of function and loss of function mechanism of disease.
Sources: Literature
Mendeliome v1.2233 UBR5 Bryony Thompson Marked gene: UBR5 as ready
Mendeliome v1.2233 UBR5 Bryony Thompson Gene: ubr5 has been classified as Green List (High Evidence).
Mendeliome v1.2233 UBR5 Bryony Thompson Classified gene: UBR5 as Green List (high evidence)
Mendeliome v1.2233 UBR5 Bryony Thompson Gene: ubr5 has been classified as Green List (High Evidence).
Mendeliome v1.2232 UBR5 Bryony Thompson gene: UBR5 was added
gene: UBR5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBR5 were set to 39721588
Phenotypes for gene: UBR5 were set to Neurodevelopmental disorder MONDO:0700092, UBR5-related
Review for gene: UBR5 was set to GREEN
Added comment: 29 individuals with a neurodevelopment syndrome (24 de novo variants) with a core phenotype characterised by developmental delay (26/28), autism (16/26), and intellectual disability (56%). Additionally, some individuals presented with epilepsy/seizures (11/27), movement disorders, and/or genital anomalies (35%). Loss of function is the expected mechanism of disease with functional experiments in C. elegans and in vitro ubiquitination assays.
Sources: Literature
Mendeliome v1.2231 MRUPAV_PLIN4 Bryony Thompson Marked STR: MRUPAV_PLIN4 as ready
Mendeliome v1.2231 MRUPAV_PLIN4 Bryony Thompson Str: mrupav_plin4 has been classified as Green List (High Evidence).
Mendeliome v1.2231 MRUPAV_PLIN4 Bryony Thompson Classified STR: MRUPAV_PLIN4 as Green List (high evidence)
Mendeliome v1.2231 MRUPAV_PLIN4 Bryony Thompson Str: mrupav_plin4 has been classified as Green List (High Evidence).
Mendeliome v1.2230 MRUPAV_PLIN4 Bryony Thompson STR: MRUPAV_PLIN4 was added
STR: MRUPAV_PLIN4 was added to Mendeliome. Sources: Literature
STR tags were added to STR: MRUPAV_PLIN4.
Mode of inheritance for STR: MRUPAV_PLIN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: MRUPAV_PLIN4 were set to 32451610; 37145156; 36151849; 35499779
Phenotypes for STR: MRUPAV_PLIN4 were set to myopathy, distal, with rimmed vacuoles MONDO:0014945
Review for STR: MRUPAV_PLIN4 was set to GREEN
STR: MRUPAV_PLIN4 was marked as clinically relevant
Added comment: Expansion of 33-mer (33 amino acids, 99 bp) identified in coding exon 3 (exon 5) of PLIN4 via linkage analysis and long read sequencing in a large Italian cohort with progressive myopathy with specific pathology including rimmed ubiquitin-positive autophagic vacuolation.
Suggested disease name myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV). An additional 4 unrelated Chinese families/probands were reported. The repeat expansion is not detectable using short-read sequencing.
Normal PLIN4 alleles: 27-31 x 33-mer
Pathogenic: ≥39 x 33-mer
Sources: Literature
Mendeliome v1.2229 P2RY8 Zornitza Stark Marked gene: P2RY8 as ready
Mendeliome v1.2229 P2RY8 Zornitza Stark Gene: p2ry8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2229 P2RY8 Zornitza Stark Classified gene: P2RY8 as Amber List (moderate evidence)
Mendeliome v1.2229 P2RY8 Zornitza Stark Gene: p2ry8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2228 P2RY8 Zornitza Stark gene: P2RY8 was added
gene: P2RY8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: P2RY8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: P2RY8 were set to 34889940
Phenotypes for gene: P2RY8 were set to Systemic lupus erythematosus, MONDO:0007915, P2RY8-related
Review for gene: P2RY8 was set to AMBER
Added comment: One de novo variant, p.Leu257Phe, absent from gnomAD v4 identified in an individual with early-onset SLE.

Subsequent search for additional individuals in large cohorts identified:
p. Asn97Lys, inherited from mother, present in 19 individuals in gnomADv4.
p.Glu323Gly identified in 6 Chinese individuals, inheritance not determined, present in 51 individuals in gnomADv4.

Functional data support the role of the gene in immune tolerance. Role in contributing to the development of SLE is plausible, though not necessarily under a monogenic model.
Sources: Literature
Mendeliome v1.2227 PACSIN1 Zornitza Stark Marked gene: PACSIN1 as ready
Mendeliome v1.2227 PACSIN1 Zornitza Stark Gene: pacsin1 has been classified as Red List (Low Evidence).
Mendeliome v1.2227 PACSIN1 Zornitza Stark gene: PACSIN1 was added
gene: PACSIN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PACSIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PACSIN1 were set to 36622335
Phenotypes for gene: PACSIN1 were set to Systemic lupus erythematosus, MONDO:0007915, PACSIN1-related
Review for gene: PACSIN1 was set to RED
Added comment: Single individual with de novo missense variant reported, supportive functional data.
Sources: Literature
Mendeliome v1.2226 CC2D1A Zornitza Stark Phenotypes for gene: CC2D1A were changed from Autosomal recessive mental retardation, (MIM#608443) to Intellectual developmental disorder, autosomal recessive 3, MIM# 608443
Mendeliome v1.2225 CC2D1A Zornitza Stark edited their review of gene: CC2D1A: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 3, MIM# 608443
Mendeliome v1.2225 CUL4B Zornitza Stark Phenotypes for gene: CUL4B were changed from Mental retardation, X-linked, syndromic 15 (Cabezas type), MIM# 300354 to Intellectual developmental disorder, X-linked syndromic, Cabezas type, MIM#300354
Mendeliome v1.2224 CUL4B Zornitza Stark edited their review of gene: CUL4B: Changed phenotypes: Intellectual developmental disorder, X-linked syndromic, Cabezas type, MIM#300354
Mendeliome v1.2224 CRYL1 Andrew Fennell changed review comment from: About 1% of individuals with GJB2-AR NSHL are compound heterozygotes for one GJB2 pathogenic variant and one of several different deletions that include sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression. Occasionally, the deletion also includes GJB2.; to: About 1% of individuals with GJB2-AR NSHL are compound heterozygotes for one GJB2 pathogenic variant and one of several different deletions that include sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression. Occasionally, the deletion also includes GJB2.
See also PMID: 20301449 GeneReviews
Mendeliome v1.2224 CRYL1 Andrew Fennell reviewed gene: CRYL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30455902; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2224 WNT7A Zornitza Stark Phenotypes for gene: WNT7A were changed from Fuhrmann syndrome, MIM# 228930; Ulna and fibula, absence of, with severe limb deficiency, MIM# 276820 to Fuhrmann syndrome, MIM# 228930; Ulna and fibula, absence of, with severe limb deficiency, MIM# 276820; Santos syndrome, MIM# 613005
Mendeliome v1.2223 WNT7A Zornitza Stark Publications for gene: WNT7A were set to 21344627; 20949531; 16826533
Mendeliome v1.2222 WNT7A Zornitza Stark edited their review of gene: WNT7A: Changed publications: 19012338
Mendeliome v1.2222 WNT7A Zornitza Stark reviewed gene: WNT7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 19012338]; Phenotypes: Santos syndrome, MIM# 613005; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2222 FRYL Zornitza Stark Phenotypes for gene: FRYL were changed from neurodevelopmental disorder MONDO:0700092, FRYL-related to Pan-Chung-Bellen syndrome, MIM# 621049
Mendeliome v1.2221 FRYL Zornitza Stark reviewed gene: FRYL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pan-Chung-Bellen syndrome, MIM# 621049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2221 PIGG Ain Roesley Phenotypes for gene: PIGG were changed from Mental retardation, autosomal recessive 53, MIM#616917 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy MIM#616917
Mendeliome v1.2220 RFWD3 Bryony Thompson Publications for gene: RFWD3 were set to 28691929
Mendeliome v1.2219 RFWD3 Bryony Thompson Classified gene: RFWD3 as Amber List (moderate evidence)
Mendeliome v1.2219 RFWD3 Bryony Thompson Gene: rfwd3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2218 RFWD3 Bryony Thompson reviewed gene: RFWD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 28691929, 38058754; Phenotypes: Fanconi anemia MONDO:0019391; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2218 GNAT1 Sangavi Sivagnanasundram reviewed gene: GNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2218 ATG4A Bryony Thompson Marked gene: ATG4A as ready
Mendeliome v1.2218 ATG4A Bryony Thompson Gene: atg4a has been classified as Red List (Low Evidence).
Mendeliome v1.2218 ATG4A Bryony Thompson gene: ATG4A was added
gene: ATG4A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATG4A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATG4A were set to 33310865
Phenotypes for gene: ATG4A were set to infectious meningitis MONDO:0004796
Review for gene: ATG4A was set to RED
Added comment: Single case with recurrent HSV2 lymphocytic Mollaret’s meningitis heterozygous for a missense variant (p.Leu90Ile).
Sources: Expert list
Mendeliome v1.2217 IFNG Bryony Thompson Publications for gene: IFNG were set to 32163377
Mendeliome v1.2216 IFNG Bryony Thompson Classified gene: IFNG as Amber List (moderate evidence)
Mendeliome v1.2216 IFNG Bryony Thompson Gene: ifng has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2215 IFNG Bryony Thompson reviewed gene: IFNG: Rating: AMBER; Mode of pathogenicity: None; Publications: 32163377, 38363432; Phenotypes: inherited susceptibility to mycobacterial diseases MONDO:0019146; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2215 TMEM173 Bryony Thompson Publications for gene: TMEM173 were set to 25401470; 25029335
Mendeliome v1.2214 TMEM173 Bryony Thompson Mode of inheritance for gene: TMEM173 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2213 TMEM173 Bryony Thompson reviewed gene: TMEM173: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32673614, 36275728; Phenotypes: STING-associated vasculopathy with onset in infancy MONDO:0014405; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.2213 GTF3A Bryony Thompson Marked gene: GTF3A as ready
Mendeliome v1.2213 GTF3A Bryony Thompson Gene: gtf3a has been classified as Red List (Low Evidence).
Mendeliome v1.2213 GTF3A Bryony Thompson gene: GTF3A was added
gene: GTF3A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GTF3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3A were set to 36399538
Phenotypes for gene: GTF3A were set to herpes simplex encephalitis MONDO:0012521
Review for gene: GTF3A was set to RED
Added comment: A single case is reported with common variable immunodeficiency and HSE, and some supporting functional assays.
Sources: Expert list
Mendeliome v1.2212 TLR4 Bryony Thompson Phenotypes for gene: TLR4 were changed from to Inflammatory bowel disease MONDO:0005265
Mendeliome v1.2211 TLR4 Bryony Thompson Publications for gene: TLR4 were set to
Mendeliome v1.2210 TLR4 Bryony Thompson Mode of inheritance for gene: TLR4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2209 TLR4 Bryony Thompson reviewed gene: TLR4: Rating: RED; Mode of pathogenicity: None; Publications: 32042729, 31442584; Phenotypes: Inflammatory bowel disease MONDO:0005265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2209 RNASEL Bryony Thompson Marked gene: RNASEL as ready
Mendeliome v1.2209 RNASEL Bryony Thompson Gene: rnasel has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2209 RNASEL Bryony Thompson Classified gene: RNASEL as Amber List (moderate evidence)
Mendeliome v1.2209 RNASEL Bryony Thompson Gene: rnasel has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2208 RNASEL Bryony Thompson gene: RNASEL was added
gene: RNASEL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNASEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNASEL were set to 36538032; 9351818
Phenotypes for gene: RNASEL were set to Multisystem inflammatory syndrome, MONDO:0035375, RNASEL-related
Review for gene: RNASEL was set to AMBER
Added comment: A single case reported with a homozygous variant reported and a supporting null mouse model.
Sources: Literature
Mendeliome v1.2207 OAS1 Bryony Thompson Added comment: Comment on mode of inheritance: The monoallelic association is definitive (with a GoF mechanism of disease) and biallelic variants (LoF) have only been reported in a single family (limited evidence).
Mendeliome v1.2207 OAS1 Bryony Thompson Mode of inheritance for gene: OAS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2206 OAS1 Bryony Thompson reviewed gene: OAS1: Rating: RED; Mode of pathogenicity: None; Publications: 36538032; Phenotypes: Multisystem inflammatory syndrome in children and adults MONDO:0035375; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2206 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from Services; Australian Genomics) Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, MIM# 621030; Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986 to Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, MIM# 621030; Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.2205 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986 to Services; Australian Genomics) Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, MIM# 621030; Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.2204 OTULIN Zornitza Stark edited their review of gene: OTULIN: Changed phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, MIM# 621030, Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099, Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.2204 RUNX1T1 Zornitza Stark Marked gene: RUNX1T1 as ready
Mendeliome v1.2204 RUNX1T1 Zornitza Stark Gene: runx1t1 has been classified as Green List (High Evidence).
Mendeliome v1.2204 RUNX1T1 Zornitza Stark Phenotypes for gene: RUNX1T1 were changed from Neurodevelopmental disorder MONDO:0700092 to Neurodevelopmental disorder MONDO:0700092, RUNX1T1-related
Mendeliome v1.2203 RUNX1T1 Zornitza Stark Publications for gene: RUNX1T1 were set to PMID: 39568205, 19172993, 22644616, 31223340
Mendeliome v1.2202 PDE12 Zornitza Stark Marked gene: PDE12 as ready
Mendeliome v1.2202 PDE12 Zornitza Stark Gene: pde12 has been classified as Green List (High Evidence).
Mendeliome v1.2202 PDE12 Zornitza Stark Phenotypes for gene: PDE12 were changed from Mitochondrial disease MONDO:0044970 to Mitochondrial disease MONDO:0044970, PDE12-related
Mendeliome v1.2201 PDE12 Chirag Patel Classified gene: PDE12 as Green List (high evidence)
Mendeliome v1.2201 PDE12 Chirag Patel Gene: pde12 has been classified as Green List (High Evidence).
Mendeliome v1.2200 CHUK Chirag Patel Classified gene: CHUK as Green List (high evidence)
Mendeliome v1.2200 CHUK Chirag Patel Gene: chuk has been classified as Green List (High Evidence).
Mendeliome v1.2199 CHUK Chirag Patel reviewed gene: CHUK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34533979; Phenotypes: Combined immunodeficiency, MONDO:0015131, CHUK-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2199 PDE12 Chirag Patel gene: PDE12 was added
gene: PDE12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE12 were set to PMID: 39567835
Phenotypes for gene: PDE12 were set to Mitochondrial disease MONDO:0044970
Review for gene: PDE12 was set to GREEN
Added comment: 3 families (2 consanguineous) with 5 affected individuals with early onset mitochondrial disease presentation (3 liveborn, 2 intrauterine death).
-Family 1: 1 x infant death @3mths (no clinical information), 1 x 7yr old with neonatal respiratory and lactic acidosis, developmental delay, and mitochondrial respiratory chain deficiencies, and marked cytochrome c oxidase (COX) deficiency in muscle.
-Family 2: 1 x neonatal death @2days with metabolic acidosis and lactic acidosis, respiratory failure, lissencephaly, dysgenesis of the corpus callosum and extensive periventricular and subcortical cysts. Normal pyruvate dehydrogenase complex and electron
transfer chain activities in fibroblasts.
-Family 3: 2 x fetuses (13wks and 22wks) with increase nuchal translucency and reduced fetal movements. One had intra-uterine growth retardation, hydrops and cystic hygroma. The other had permanent flexion contractures of four limbs). Western blotting in fetal skeletal muscle showed absent respiratory chain complexes (I, IV, and V).

WES in all 3 families identified 3 different homozygous missense variants in PDE12 gene (p.Tyr155Cys, p.Gly372Glu, and p.Arg41Pro). All variants segregated with disease, were rare in gnomAD, and in silico pathogenicity prediction tools pointed towards a high likelihood of pathogenicity.

PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein.
Sources: Literature
Mendeliome v1.2198 RUNX1T1 Chirag Patel Classified gene: RUNX1T1 as Green List (high evidence)
Mendeliome v1.2198 RUNX1T1 Chirag Patel Gene: runx1t1 has been classified as Green List (High Evidence).
Mendeliome v1.2197 RUNX1T1 Chirag Patel gene: RUNX1T1 was added
gene: RUNX1T1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RUNX1T1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RUNX1T1 were set to PMID: 39568205, 19172993, 22644616, 31223340
Phenotypes for gene: RUNX1T1 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: RUNX1T1 was set to GREEN
Added comment: RUNX1T1 encodes a transcription regulator for hematopoietic genes and is well-known for its involvement in hematologic malignancies. Germline RUNX1T1 variants may also play a role in human congenital neurodevelopmental disorders.

PMID: 39568205
3 unrelated individuals with developmental delay, learning disability, ASD, ADHD, and dysmorphism (1 x heart defects). Trio WES identified de novo variants in RUNX1T1 gene (1 x nonsense variant in 5' region [p.Gln36Ter], 2 x missense variants in C-terminus [p.Gly412Arg and p.His521Tyr]).

PMID: 19172993
1 individual with mild-moderate ID and congenital heart disease, and chromosome t(5;8)(q32;q21.3) translocation. Molecular characterization revealed that one of the break points was within the RUNX1T1 gene. Analysis of RUNX1T1 expression in human embryonic and fetal tissues suggests a role of RUNX1T1 in brain and heart development.

PMID: 22644616
1 individual with mild ID and dysmorphism, and de novo deletion exons 3-7 in RUNX1T1.

PMID: 31223340
1 individual with ID, anaemia, atrial septal defect, dysmorphism, and seizures. Found to have a 2.1 Mb deletion at 8q21.3q22.1 involving entire RUNX1T1 gene (and 2 adjacent genes - SLC26A7 and TRIQK), and a benign familial 4.3 Mb duplication at 1p22.1p21.3 (present in unaffected healthy brother).
Sources: Literature
Mendeliome v1.2196 CAPZA2 Zornitza Stark Publications for gene: CAPZA2 were set to 32338762
Mendeliome v1.2195 CAPZA2 Zornitza Stark Classified gene: CAPZA2 as Green List (high evidence)
Mendeliome v1.2195 CAPZA2 Zornitza Stark Gene: capza2 has been classified as Green List (High Evidence).
Mendeliome v1.2194 CAPZA2 Chris Ciotta reviewed gene: CAPZA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32338762, 38374166, 35856264; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CAPZA2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2194 CCT6A Ain Roesley Marked gene: CCT6A as ready
Mendeliome v1.2194 CCT6A Ain Roesley Gene: cct6a has been classified as Green List (High Evidence).
Mendeliome v1.2194 CCT6A Ain Roesley Classified gene: CCT6A as Green List (high evidence)
Mendeliome v1.2194 CCT6A Ain Roesley Gene: cct6a has been classified as Green List (High Evidence).
Mendeliome v1.2193 CCT6A Ain Roesley gene: CCT6A was added
gene: CCT6A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCT6A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT6A were set to 39480921
Phenotypes for gene: CCT6A were set to neurodevelopmental disorder MONDO:0700092, CCT6A-related
Penetrance for gene: CCT6A were set to Complete
Review for gene: CCT6A was set to GREEN
gene: CCT6A was marked as current diagnostic
Added comment: previously known as CCT6

5x individuals including 4x de novo
3x PTCS + 1x +5C>G + 1x missense

4/5 DD/ID
2/5 visual impairment
2/5 seizures
Sources: Literature
Mendeliome v1.2192 TCP1 Ain Roesley Marked gene: TCP1 as ready
Mendeliome v1.2192 TCP1 Ain Roesley Gene: tcp1 has been classified as Green List (High Evidence).
Mendeliome v1.2192 TCP1 Ain Roesley Marked gene: TCP1 as ready
Mendeliome v1.2192 TCP1 Ain Roesley Gene: tcp1 has been classified as Green List (High Evidence).
Mendeliome v1.2192 TCP1 Ain Roesley Classified gene: TCP1 as Green List (high evidence)
Mendeliome v1.2192 TCP1 Ain Roesley Gene: tcp1 has been classified as Green List (High Evidence).
Mendeliome v1.2191 TCP1 Ain Roesley gene: TCP1 was added
gene: TCP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCP1 were set to 39480921
Phenotypes for gene: TCP1 were set to neurodevelopmental disorder MONDO:0700092, TCP1-related
Penetrance for gene: TCP1 were set to Complete
Review for gene: TCP1 was set to GREEN
gene: TCP1 was marked as current diagnostic
Added comment: previously known as CCT1

8x individuals including 5x de novo
6x PTCs + 2x missense

6/8 DD/ID
2/8 visual impairment
6/8 seizures
6/8 polymicrogyria + 1x Ventriculomegaly, white matter hyperintensities
Sources: Literature
Mendeliome v1.2190 CCT3 Ain Roesley Marked gene: CCT3 as ready
Mendeliome v1.2190 CCT3 Ain Roesley Gene: cct3 has been classified as Green List (High Evidence).
Mendeliome v1.2190 CCT3 Ain Roesley Marked gene: CCT3 as ready
Mendeliome v1.2190 CCT3 Ain Roesley Gene: cct3 has been classified as Green List (High Evidence).
Mendeliome v1.2190 CCT3 Ain Roesley Phenotypes for gene: CCT3 were changed from to neurodevelopmental disorder MONDO:0700092, CCT3-related
Mendeliome v1.2189 CCT3 Ain Roesley Classified gene: CCT3 as Green List (high evidence)
Mendeliome v1.2189 CCT3 Ain Roesley Gene: cct3 has been classified as Green List (High Evidence).
Mendeliome v1.2188 CCT3 Ain Roesley gene: CCT3 was added
gene: CCT3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT3 were set to 39480921
Penetrance for gene: CCT3 were set to Complete
Review for gene: CCT3 was set to GREEN
gene: CCT3 was marked as current diagnostic
Added comment: 4x de novo - 3x PTCs and 1x missense

overlapping phenotypes:
4/4 ID/DD
3/4 visual impairment
2/4 seizures
4/4 Hypomyelination of white matter
Sources: Literature
Mendeliome v1.2187 CLASP1 Ain Roesley Marked gene: CLASP1 as ready
Mendeliome v1.2187 CLASP1 Ain Roesley Gene: clasp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2187 CLASP1 Ain Roesley gene: CLASP1 was added
gene: CLASP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLASP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLASP1 were set to 39040917
Phenotypes for gene: CLASP1 were set to neurodevelopmental disorder MONDO:0700092, CLASP1-related
Review for gene: CLASP1 was set to RED
gene: CLASP1 was marked as current diagnostic
Added comment: 3 siblings from a consanguineous family, homozygous for p.(Arg1481His)
at birth, all had low weight and microcephaly (< 3-4SD), profound dev delay, spasticity, seizures and lissencephaly

Arg1481His - 3 hets 0 Homs in v4
codon is highly conserved with a high REVEL score 0.83
Sources: Literature
Mendeliome v1.2186 GPATCH11 Zornitza Stark Publications for gene: GPATCH11 were set to
Mendeliome v1.2185 HMGCS1 Zornitza Stark Marked gene: HMGCS1 as ready
Mendeliome v1.2185 HMGCS1 Zornitza Stark Gene: hmgcs1 has been classified as Green List (High Evidence).
Mendeliome v1.2185 HMGCS1 Zornitza Stark Classified gene: HMGCS1 as Green List (high evidence)
Mendeliome v1.2185 HMGCS1 Zornitza Stark Gene: hmgcs1 has been classified as Green List (High Evidence).
Mendeliome v1.2184 HMGCS1 Zornitza Stark gene: HMGCS1 was added
gene: HMGCS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGCS1 were set to 39531736
Phenotypes for gene: HMGCS1 were set to Rigid spine syndrome, MONDO:0019951, HMGCS1-related
Review for gene: HMGCS1 was set to GREEN
Added comment: Five individuals from four families reported. All individuals presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some; one individual died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.
HMGCS1 encodes a critical enzyme of the mevalonate pathway. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. Four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays
Sources: Literature
Mendeliome v1.2183 CMPK2 Zornitza Stark Marked gene: CMPK2 as ready
Mendeliome v1.2183 CMPK2 Zornitza Stark Gene: cmpk2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2183 CMPK2 Zornitza Stark Classified gene: CMPK2 as Amber List (moderate evidence)
Mendeliome v1.2183 CMPK2 Zornitza Stark Gene: cmpk2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2182 CMPK2 Zornitza Stark gene: CMPK2 was added
gene: CMPK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CMPK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CMPK2 were set to 36443312
Phenotypes for gene: CMPK2 were set to bilateral striopallidodentate calcinosis, MONDO:0008947, CMPK2-related
Review for gene: CMPK2 was set to AMBER
Added comment: Three individuals from two unrelated families reported. One family (two sibs) with homozygous start loss variant, and the other family with compound het variants. Adult-onset neurodegenerative disorder. Extensive functional data including mouse model. Evidence of underlying mitochondrial dysfunction.
Sources: Literature
Mendeliome v1.2181 MAP3K3 Zornitza Stark Phenotypes for gene: MAP3K3 were changed from Cerebral malformation, MONDO:0016054, MAP3K3-related to Cerebral cavernous malformations 5, MIM# 621032
Mendeliome v1.2180 MAP3K3 Zornitza Stark edited their review of gene: MAP3K3: Changed phenotypes: Cerebral cavernous malformations 5, MIM# 621032
Mendeliome v1.2180 POLA2 Bryony Thompson Phenotypes for gene: POLA2 were changed from Telomere biology disorders; Coats plus syndrome MONDO:0012815 to Telomere biology syndrome MONDO:0100137
Mendeliome v1.2179 POLA2 Bryony Thompson Marked gene: POLA2 as ready
Mendeliome v1.2179 POLA2 Bryony Thompson Gene: pola2 has been classified as Green List (High Evidence).
Mendeliome v1.2179 POLA2 Bryony Thompson Classified gene: POLA2 as Green List (high evidence)
Mendeliome v1.2179 POLA2 Bryony Thompson Gene: pola2 has been classified as Green List (High Evidence).
Mendeliome v1.2178 CTGF Bryony Thompson Marked gene: CTGF as ready
Mendeliome v1.2178 CTGF Bryony Thompson Gene: ctgf has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2178 CTGF Bryony Thompson Phenotypes for gene: CTGF were changed from Kyphomelic dysplasia to Kyphomelic dysplasia MONDO:0008881; Spondyloepimetaphyseal dysplasia MONDO:0100510
Mendeliome v1.2177 CTGF Bryony Thompson Publications for gene: CTGF were set to 39506047
Mendeliome v1.2176 CTGF Bryony Thompson Classified gene: CTGF as Amber List (moderate evidence)
Mendeliome v1.2176 CTGF Bryony Thompson Gene: ctgf has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2175 CTGF Bryony Thompson edited their review of gene: CTGF: Changed publications: 39414788, 20534727
Mendeliome v1.2175 CTGF Bryony Thompson edited their review of gene: CTGF: Changed publications: 39414788, 39414788
Mendeliome v1.2175 CTGF Bryony Thompson reviewed gene: CTGF: Rating: RED; Mode of pathogenicity: None; Publications: 39414788; Phenotypes: Spondyloepimetaphyseal dysplasia MONDO:0100510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2175 GUK1 Bryony Thompson Phenotypes for gene: GUK1 were changed from Mitochondrial DNA depletion syndrome MONDO:0018158 to Mitochondrial DNA depletion syndrome MONDO:0018158, GUK1-related
Mendeliome v1.2174 GUK1 Bryony Thompson Marked gene: GUK1 as ready
Mendeliome v1.2174 GUK1 Bryony Thompson Gene: guk1 has been classified as Green List (High Evidence).
Mendeliome v1.2174 GUK1 Bryony Thompson Classified gene: GUK1 as Green List (high evidence)
Mendeliome v1.2174 GUK1 Bryony Thompson Gene: guk1 has been classified as Green List (High Evidence).
Mendeliome v1.2173 GUK1 Bryony Thompson gene: GUK1 was added
gene: GUK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GUK1 were set to 39230499
Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome MONDO:0018158
Review for gene: GUK1 was set to GREEN
Added comment: 4 adult cases from 3 unrelated families with biallelic variants leading to GUK1 deficiency. Cases presented with ptosis, ophthalmoparesis, myopathic proximal limb weakness, variable hepatopathy, and altered T-lymphocyte profiles. Initial manifestations in childhood or adolescence and developed ptosis and skeletal myopathy. mtDNA depletion/deletions are present in muscle biopsies of reduced activities of mitochondrial respiratory chain enzymes in all 4 cases.
Sources: Literature
Mendeliome v1.2172 PPP2R2B Bryony Thompson Phenotypes for gene: PPP2R2B were changed from to Neurodevelopmental disorder MONDO:0700092, PPP2R2B-related
Mendeliome v1.2171 PPP2R2B Bryony Thompson Publications for gene: PPP2R2B were set to
Mendeliome v1.2170 PPP2R2B Bryony Thompson Mode of inheritance for gene: PPP2R2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2169 PPP2R2B Bryony Thompson Classified gene: PPP2R2B as Amber List (moderate evidence)
Mendeliome v1.2169 PPP2R2B Bryony Thompson Gene: ppp2r2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2168 PPP2R2B Bryony Thompson reviewed gene: PPP2R2B: Rating: AMBER; Mode of pathogenicity: None; Publications: 25356899, 39565297; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PPP2R2B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2168 PPP2R2B Bryony Thompson Deleted their review
Mendeliome v1.2168 PPP2R2B Bryony Thompson Deleted their comment
Mendeliome v1.2168 PPP2R2B Bryony Thompson edited their review of gene: PPP2R2B: Added comment: 5 cases with NDD and heterozygous missense (4/5 confirmed de novo): p.Thr246Lys (unknown inheritance), p.Asn310Lys (confirmed de novo), p.Glu37Lys (confirmed de novo, also had RNU4-2 path de novo Path variant), p.Ile427Thr (confirmed de novo, also had TAOK1 inherited Path variant), p.Arg149Pro (confirmed de novo). 5/5 with intellectual disability and developmental delay, 4/5 with seizures, 2/5 with hearing loss/auditory neuropathy. Study includes in vitro functional assays supporting a possible loss of function mechanism of disease. The 2 missense with additional diagnoses (E37K & I427T) demonstrated a partial reduction in PP2A holoenzyme assembly. Only 3 cases with a possible diagnosis that could be attributed to the PPP2R2B only, and only 2 were confirmed de novo.; Changed rating: AMBER; Changed publications: 25356899, 39565297; Changed phenotypes: Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2168 PPP2R2B Bryony Thompson Deleted their comment
Mendeliome v1.2168 GPATCH11 Sangavi Sivagnanasundram edited their review of gene: GPATCH11: Changed phenotypes: early-onset retinal dystrophy with neurological impairment MONDO:0019118
Mendeliome v1.2168 CTGF Sangavi Sivagnanasundram edited their review of gene: CTGF: Changed phenotypes: Kyphomelic dysplasia, skeletal dysplasia MONDO:0018230
Mendeliome v1.2168 WDR47 Bryony Thompson Marked gene: WDR47 as ready
Mendeliome v1.2168 WDR47 Bryony Thompson Gene: wdr47 has been classified as Green List (High Evidence).
Mendeliome v1.2168 WDR47 Bryony Thompson Classified gene: WDR47 as Green List (high evidence)
Mendeliome v1.2168 WDR47 Bryony Thompson Gene: wdr47 has been classified as Green List (High Evidence).
Mendeliome v1.2167 WDR47 Bryony Thompson gene: WDR47 was added
gene: WDR47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR47 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR47 were set to 39609633; 35474353
Phenotypes for gene: WDR47 were set to Complex neurodevelopmental disorder MONDO:0100038, WDR47-related; Congenital heart disease MONDO:0005453
Review for gene: WDR47 was set to GREEN
Added comment: PMID: 39609633 - 7 cases from 5 unrelated families with biallelic variants and a complex neurodevelopmental syndrome. The most frequent phenotypes were corpus callosum dysgenesis (7/7), microcephaly (7/7), mild to severe intellectual disability (7/7), epilepsy (7/7). Additionally, mouse models recapitulate the human phenotype. Loss of function is the mechanism of disease. Heterozygous parents had no phenotype.

Limited evidence for mono allelic association with congenital heart defects
PMID: 35474353 - rare assumed de novo heterozygous variant (NM_014969.5:c.2056G>A p.(Val686Ile) - 10 hets in gnomAD v4.1) detected in a case with heterotaxy including AVCD, vena azygos continuation, artery lusoria, truncus bicaroticus and polysplenia. Screening of exams for 2,019 individuals with situs inversus totalis, heterotaxy, or isolated CHD detected 2 additional individuals with monoallelic rare missense variants. No functional assays or other supporting evidence. All variants are VUS
Sources: Literature
Mendeliome v1.2166 CTGF Sangavi Sivagnanasundram changed review comment from: CCN2 is the new HGNC approved name.

PMID: 39506047
Three individuals from two unrelated consanguineous families presented with short stature, facial dysmorphism and kyphomelic skeletal dysplasia.

A rare missense variant in family 1 (Cys148Tyr) and novel frameshift variant (Pro260LeufsTer7) in family 2 was identified in homozygous state.
Zebrafish model was also conducted that showed altered body curvature and impaired cartilage formation in craniofacial region resulting in either bent of missing tails.

A missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5.
Sources: Literature; to: CCN2 is the new HGNC approved name.

PMID: 39506047
Three individuals from two unrelated consanguineous families presented with short stature, facial dysmorphism and kyphomelic skeletal dysplasia.

A rare missense variant in family 1 (Cys148Tyr) and novel frameshift variant (Pro260LeufsTer7) in family 2 was identified in homozygous state.
Zebrafish model was also conducted that showed altered body curvature and impaired cartilage formation in craniofacial region resulting in either bent or missing tails.

A missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5.
Sources: Literature
Mendeliome v1.2166 CTGF Sangavi Sivagnanasundram gene: CTGF was added
gene: CTGF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTGF were set to 39506047
Phenotypes for gene: CTGF were set to Kyphomelic dysplasia
Review for gene: CTGF was set to AMBER
Added comment: CCN2 is the new HGNC approved name.

PMID: 39506047
Three individuals from two unrelated consanguineous families presented with short stature, facial dysmorphism and kyphomelic skeletal dysplasia.

A rare missense variant in family 1 (Cys148Tyr) and novel frameshift variant (Pro260LeufsTer7) in family 2 was identified in homozygous state.
Zebrafish model was also conducted that showed altered body curvature and impaired cartilage formation in craniofacial region resulting in either bent of missing tails.

A missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5.
Sources: Literature
Mendeliome v1.2166 GPATCH11 Sangavi Sivagnanasundram reviewed gene: GPATCH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 39572588; Phenotypes: early-onset retinal dystrophy with neurological impairment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2166 POLA2 Sangavi Sivagnanasundram gene: POLA2 was added
gene: POLA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLA2 were set to 39616267
Phenotypes for gene: POLA2 were set to Telomere biology disorders; Coats plus syndrome MONDO:0012815
Review for gene: POLA2 was set to GREEN
Added comment: New gene-disease association.

PMID: 39616267 - Five individuals from two unrelated swedish families presenting with clinical phenotype suggestive of a TBD disorder with Coats plus features including retinal and gastrointestinal telangiectasias. Affected individuals also presented with shortened telomeres.

Compound heterozygous variants were identified in both families.
Family A (Ile96Thr;Pro424Leu) - Both variants are present in gnomAD v4.1 but FAF is rare enough for AR condition [c.287 T > C, p.(Ile96Thr) - FAF 0.002%; c.1271 C > T, p.(Pro424Leu) - FAF 0.0002 %]
Family B (Ile96Thr; intragenic SNV resulting in the deletion of the 5’ terminal and exon 1) - same missense as the other family along with an SNV.

In vitro assay using CRISPR/Cas9 genome engineering into HEK293T to assess whether the p.(Ile96Thr) would affect telomere length. The subclones carrying the missense variant showed telomeric shortening of ~4kb compared to the WT subclones.
Sources: Literature
Mendeliome v1.2166 FGF8 Zornitza Stark edited their review of gene: FGF8: Added comment: Association with CHD: Two individuals reported but extensive functional data. MODERATE by ClinGen.; Changed publications: 32664970, 7768185, 32664970, 10603341, 19509466, 9462741, 10603341, 12223415; Changed phenotypes: Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702, Hypoplastic femurs and pelvis, MIM#619545, Congenital heart disease MONDO:0005453, FGF8-related
Mendeliome v1.2166 ROCK2 Bryony Thompson Marked gene: ROCK2 as ready
Mendeliome v1.2166 ROCK2 Bryony Thompson Gene: rock2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2166 ROCK2 Bryony Thompson Classified gene: ROCK2 as Amber List (moderate evidence)
Mendeliome v1.2166 ROCK2 Bryony Thompson Gene: rock2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2165 PPP5C Bryony Thompson Marked gene: PPP5C as ready
Mendeliome v1.2165 PPP5C Bryony Thompson Gene: ppp5c has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2165 PPP5C Bryony Thompson Classified gene: PPP5C as Amber List (moderate evidence)
Mendeliome v1.2165 PPP5C Bryony Thompson Gene: ppp5c has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2164 RAB35 Bryony Thompson changed review comment from: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays.
PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6).
Sources: Literature; to: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays.
PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6). Cosegergation in 1 affected relative also reported.
Sources: Literature
Mendeliome v1.2164 RAB35 Bryony Thompson Marked gene: RAB35 as ready
Mendeliome v1.2164 RAB35 Bryony Thompson Gene: rab35 has been classified as Red List (Low Evidence).
Mendeliome v1.2164 RAB35 Bryony Thompson gene: RAB35 was added
gene: RAB35 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB35 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: RAB35 were set to 38432637; 36928819
Phenotypes for gene: RAB35 were set to familial hypercholesterolemia MONDO:0005439; neurodevelopmental disorder MONDO:0700092
Review for gene: RAB35 was set to RED
Added comment: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays.
PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6).
Sources: Literature
Mendeliome v1.2163 ARPC3 Bryony Thompson Marked gene: ARPC3 as ready
Mendeliome v1.2163 ARPC3 Bryony Thompson Gene: arpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2163 ARPC3 Bryony Thompson Classified gene: ARPC3 as Amber List (moderate evidence)
Mendeliome v1.2163 ARPC3 Bryony Thompson Gene: arpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2162 ARPC3 Bryony Thompson gene: ARPC3 was added
gene: ARPC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARPC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPC3 were set to 36928819; 26166300
Phenotypes for gene: ARPC3 were set to Charcot-Marie-Tooth disease MONDO:0015626
Review for gene: ARPC3 was set to AMBER
Added comment: Posterior probability association (PPA) 0.995 for Charcot-Marie Tooth disease under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 549 CMT cases and 54,856 controls used in BeviMed analysis. 5 rare variants (missense, splice region, a splice acceptor site) enriched in the CMT cohort (n=14).
Additionally, ArpC3 conditional knockout mice fail to ensheath axons causing axon dysfunction.
Sources: Literature
Mendeliome v1.2161 USP33 Bryony Thompson changed review comment from: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6).
Sources: Literature; to: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 182 early-onset hypertension cases and 55,305 controls used in BeviMed analysis. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6).
Sources: Literature
Mendeliome v1.2161 FMN1 Bryony Thompson changed review comment from: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned); to: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 510 CHI cases assessed and 54,738 controls in BeviMed analysis. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned)
Mendeliome v1.2161 USP33 Bryony Thompson Classified gene: USP33 as Red List (low evidence)
Mendeliome v1.2161 USP33 Bryony Thompson Gene: usp33 has been classified as Red List (Low Evidence).
Mendeliome v1.2160 USP33 Bryony Thompson Marked gene: USP33 as ready
Mendeliome v1.2160 USP33 Bryony Thompson Gene: usp33 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2160 USP33 Bryony Thompson Classified gene: USP33 as Amber List (moderate evidence)
Mendeliome v1.2160 USP33 Bryony Thompson Gene: usp33 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2159 USP33 Bryony Thompson gene: USP33 was added
gene: USP33 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP33 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: USP33 were set to 36928819
Phenotypes for gene: USP33 were set to Renal hypertension MONDO:0001105
Review for gene: USP33 was set to AMBER
Added comment: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6).
Sources: Literature
Mendeliome v1.2158 UCHL1 Bryony Thompson Marked gene: UCHL1 as ready
Mendeliome v1.2158 UCHL1 Bryony Thompson Gene: uchl1 has been classified as Green List (High Evidence).
Mendeliome v1.2158 UCHL1 Bryony Thompson Classified gene: UCHL1 as Green List (high evidence)
Mendeliome v1.2158 UCHL1 Bryony Thompson Gene: uchl1 has been classified as Green List (High Evidence).
Mendeliome v1.2157 UCHL1 Bryony Thompson reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 3340629, 28007905, 32656641, 29735986, 28007905, 35986737, 39030458; Phenotypes: Spastic paraplegia 79A, autosomal dominant, MIM# 620221, Spastic paraplegia 79, autosomal recessive, 615491, MONDO:0014209, Neurodegenerative disease, MONDO:0005559, UCHL1-related; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.2157 UCHL1 Bryony Thompson gene: UCHL1 was added
gene: UCHL1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: UCHL1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: UCHL1 were set to 23359680; 3340629; 28007905; 32656641; 29735986; 28007905; 35986737; 39030458
Phenotypes for gene: UCHL1 were set to Spastic paraplegia 79A, autosomal dominant, MIM# 620221; Spastic paraplegia 79, autosomal recessive, 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related
Mendeliome v1.2156 FMN1 Bryony Thompson Publications for gene: FMN1 were set to 20610440; 19383632; 15202026
Mendeliome v1.2155 FMN1 Bryony Thompson Phenotypes for gene: FMN1 were changed from oligosyndactyly; radioulnar synostosis; hearing loss; renal defects to Hearing loss disorder MONDO:0005365
Mendeliome v1.2154 FMN1 Bryony Thompson edited their review of gene: FMN1: Added comment: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned); Changed publications: 20610440, 19383632, 15202026, 36928819; Changed phenotypes: Hearing loss disorder MONDO:0005365
Mendeliome v1.2154 PPP5C Lucy Spencer gene: PPP5C was added
gene: PPP5C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP5C were set to 35361529; 25363768; 33057194
Phenotypes for gene: PPP5C were set to Neurodevelopmental disorder, MONDO:0700092, PPP5C-related
Review for gene: PPP5C was set to AMBER
Added comment: PMID: 35361529 - reported a de novo missense in a proband with microcephaly, developmental delay and epilepsy. However, after personal communication with the undiagnosed disease network this proband has since been found to have a different diagnosis with a nonsense and a missense in VARS1 identified, so unclear if the PPP5C variant is contributing to their phenotype.

3 more probands with de novo missense variants have been published in large autism or developmental disorder cohort with limited information (PMIDs: 25363768, 33057194)

An internal VCGS proband with intellectual disability and failure to thrive was also found to have a de novo missense variant in this gene.
Sources: Literature
Mendeliome v1.2154 MRVI1 Bryony Thompson Marked gene: MRVI1 as ready
Mendeliome v1.2154 MRVI1 Bryony Thompson Gene: mrvi1 has been classified as Red List (Low Evidence).
Mendeliome v1.2154 MRVI1 Bryony Thompson Phenotypes for gene: MRVI1 were changed from moyamoya syndrome to Moyamoya disease MONDO:0016820
Mendeliome v1.2153 MRVI1 Bryony Thompson edited their review of gene: MRVI1: Changed phenotypes: Moyamoya disease MONDO:0016820
Mendeliome v1.2153 MRVI1 Bryony Thompson gene: MRVI1 was added
gene: MRVI1 was added to Mendeliome. Sources: NHS GMS
new gene name tags were added to gene: MRVI1.
Mode of inheritance for gene: MRVI1 was set to Unknown
Publications for gene: MRVI1 were set to 30001348
Phenotypes for gene: MRVI1 were set to moyamoya syndrome
Review for gene: MRVI1 was set to RED
Added comment: A single report of a variant as a possible modifier of NF1-related Moyamoya disease. The SNP rs35857561 segregates co-occurring with NF1 in 2 families and Moyamoya disease. rs35857561 is a common SNP and IRAG1 (new gene name) hasn't been reported in association with Mendelian disease.
Sources: NHS GMS
Mendeliome v1.2152 DHDDS Zornitza Stark Publications for gene: DHDDS were set to 27343064; 29100083; 21295283; 34382076
Mendeliome v1.2151 DHDDS Zornitza Stark edited their review of gene: DHDDS: Added comment: Bi-allelic variants: ClinGen have lumped the CDG together with the RP -- likely represent a continuum of severity rather than distinct disorders.; Changed publications: 27343064, 29100083, 21295283, 27343064, 21295283, 28130426, 29276052, 32483926, 36046393, 24078709, 28005406, 36046393
Mendeliome v1.2151 SLC35F1 Lucy Spencer changed review comment from: Probable 2nd internal VCGS case 24W004707 with intellectual disability and seizures and a de novo Gly226Arg variant.; to: Probable 2nd internal VCGS case with intellectual disability and seizures and a de novo Gly226Arg variant.
Mendeliome v1.2151 WDR83OS Zornitza Stark Phenotypes for gene: WDR83OS were changed from complex neurodevelopmental disorder MONDO:0100038; neurodevelopmental disorder with hypercholanemia to Neurodevelopmental disorder with variable familial hypercholanemia, MIM# 621016
Mendeliome v1.2150 GARS Zornitza Stark Phenotypes for gene: GARS were changed from Spinal muscular atrophy, infantile, James type, MIM# 619042; Charcot-Marie-Tooth disease, type 2D, MIM# 601472; Neuronopathy, distal hereditary motor, type VA, MIM# 600794; Multi-system mitochondrial disorder to Mitochondrial disease (MONDO:0044970), GARS1-related; Spinal muscular atrophy, infantile, James type, MIM# 619042; Charcot-Marie-Tooth disease, type 2D, MIM# 601472; Neuronopathy, distal hereditary motor, type VA, MIM# 600794; Multi-system mitochondrial disorder
Mendeliome v1.2149 GARS Zornitza Stark edited their review of gene: GARS: Changed phenotypes: Mitochondrial disease (MONDO:0044970), GARS1-related, Spinal muscular atrophy, infantile, James type, MIM# 619042, Charcot-Marie-Tooth disease, type 2D, MIM# 601472, Neuronopathy, distal hereditary motor, type VA, MIM# 600794, Multi-system mitochondrial disorder
Mendeliome v1.2149 SLC35F1 Zornitza Stark Classified gene: SLC35F1 as Amber List (moderate evidence)
Mendeliome v1.2149 SLC35F1 Zornitza Stark Gene: slc35f1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2148 SLC35F1 Lucy Spencer reviewed gene: SLC35F1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SLC35F1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2148 LINC01578 Zornitza Stark Phenotypes for gene: LINC01578 were changed from Neurodevelopmental disorder, MONDO:0700092, CHASERR-related to Neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, MIM# 621012
Mendeliome v1.2147 LINC01578 Zornitza Stark edited their review of gene: LINC01578: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, MIM# 621012
Mendeliome v1.2147 ATP5A1 Lucy Spencer reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34483339, 34954817, 23599390, 23596069; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2147 NFATC2 Bryony Thompson Classified gene: NFATC2 as Amber List (moderate evidence)
Mendeliome v1.2147 NFATC2 Bryony Thompson Gene: nfatc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2146 NFATC2 Bryony Thompson reviewed gene: NFATC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35789258, 38427060; Phenotypes: Lymphoproliferative syndrome, MONDO:0016537, NFATC2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2146 MED12L Zornitza Stark Phenotypes for gene: MED12L were changed from Intellectual disability; Seizures; Autism to Neurodevelopmental disorder, MONDO:0700092, MED12L-related; Intellectual disability; Seizures; Autism
Mendeliome v1.2145 MED12L Zornitza Stark edited their review of gene: MED12L: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, MED12L-related, Intellectual disability, Seizures, Autism
Mendeliome v1.2145 RFC4 Zornitza Stark Marked gene: RFC4 as ready
Mendeliome v1.2145 RFC4 Zornitza Stark Gene: rfc4 has been classified as Green List (High Evidence).
Mendeliome v1.2145 RFC4 Zornitza Stark Phenotypes for gene: RFC4 were changed from RFC4-related multisystem disorder to Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010
Mendeliome v1.2144 DHRSX Zornitza Stark Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type 1DD, MIM# 301133
Mendeliome v1.2143 PDCD1 Zornitza Stark Phenotypes for gene: PDCD1 were changed from PDCD1 deficiency; Inborn errors of immunity, MONDO:0003778 to Autoimmune disease with susceptibility to mycobacterium tuberculosis, MIM# 621004
Mendeliome v1.2142 POMT1 Ain Roesley 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 mental retardation), type B, 1 613155; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308 to 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
Mendeliome v1.2141 SH3KBP1 Bryony Thompson Classified gene: SH3KBP1 as Amber List (moderate evidence)
Mendeliome v1.2141 SH3KBP1 Bryony Thompson Gene: sh3kbp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2140 SH3KBP1 Bryony Thompson edited their review of gene: SH3KBP1: Changed phenotypes: immunodeficiency 61 MONDO:0010296
Mendeliome v1.2140 SH3KBP1 Bryony Thompson reviewed gene: SH3KBP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29636373, 21708930; Phenotypes: Immunodeficiency, common variable, 4 MONDO:0013284; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2140 RFC1 Bryony Thompson Publications for gene: RFC1 were set to 30926972; 33103729; 35883251
Mendeliome v1.2139 RFC1 Bryony Thompson Classified gene: RFC1 as Green List (high evidence)
Mendeliome v1.2139 RFC1 Bryony Thompson Gene: rfc1 has been classified as Green List (High Evidence).
Mendeliome v1.2138 ANAPC1 Zornitza Stark Tag founder tag was added to gene: ANAPC1.
Mendeliome v1.2138 WASHC5 Zornitza Stark Mode of inheritance for gene: WASHC5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2137 WASHC5 Zornitza Stark edited their review of gene: WASHC5: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2137 ZCCHC8 Zornitza Stark Classified gene: ZCCHC8 as Green List (high evidence)
Mendeliome v1.2137 ZCCHC8 Zornitza Stark Gene: zcchc8 has been classified as Green List (High Evidence).
Mendeliome v1.2136 ZCCHC8 Zornitza Stark reviewed gene: ZCCHC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 MONDO:0032865; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2136 RTTN Zornitza Stark Phenotypes for gene: RTTN were changed from Microcephaly, short stature, and polymicrogyria with seizures, MIM# 614833; Intellectual disability; cerebral polymicrogyria; primary microcephaly; growth defects; congenital anomalies to Microcephaly, short stature, and polymicrogyria with seizures, MIM# 614833; microcephalic primordial dwarfism due to RTTN deficiency MONDO:0018764
Mendeliome v1.2135 PLA2G4A Sangavi Sivagnanasundram reviewed gene: PLA2G4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 18451993, 23268370, 25102815; Phenotypes: cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder MONDO:0018794; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 RTTN Sangavi Sivagnanasundram reviewed gene: RTTN: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008471; Phenotypes: microcephalic primordial dwarfism due to RTTN deficiency MONDO:0018764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 ZCCHC8 Sangavi Sivagnanasundram reviewed gene: ZCCHC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31488579, 38375433; Phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 MONDO:0032865; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2135 SLC18A2 Sangavi Sivagnanasundram reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008459; Phenotypes: brain dopamine-serotonin vesicular transport disease MONDO:0018130; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 RFC1 Sangavi Sivagnanasundram reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35883251, 36478048, 36289003; Phenotypes: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome MONDO:0044720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 IQCB1 Sangavi Sivagnanasundram reviewed gene: IQCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008440; Phenotypes: ciliopathy MONDO:0005308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 WASHC5 Sangavi Sivagnanasundram reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006537, https://search.clinicalgenome.org/CCID:006538; Phenotypes: hereditary spastic paraplegia 8 MONDO:0011339, Ritscher-Schinzel syndrome 1 MONDO:0009073; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2135 G6PC Sangavi Sivagnanasundram reviewed gene: G6PC: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008420; Phenotypes: glycogen storage disease I MONDO:0002413; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 PYGL Sangavi Sivagnanasundram reviewed gene: PYGL: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008478; Phenotypes: glycogen storage disease VI MONDO:0009294; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 CAMLG Sangavi Sivagnanasundram reviewed gene: CAMLG: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008383; Phenotypes: congenital disorder of glycosylation, type IIz MONDO:0859357; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 CYP27A1 Sangavi Sivagnanasundram reviewed gene: CYP27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008400; Phenotypes: cerebrotendinous xanthomatosis MONDO:0008948; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 DEGS1 Sangavi Sivagnanasundram reviewed gene: DEGS1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008468; Phenotypes: leukodystrophy, hypomyelinating, 18 MONDO:0032730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 ANAPC1 Sangavi Sivagnanasundram reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008429; Phenotypes: Rothmund-Thomson syndrome type 1 MONDO:0016368; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 COG3 Sangavi Sivagnanasundram reviewed gene: COG3: Rating: AMBER; Mode of pathogenicity: Other; Publications: https://search.clinicalgenome.org/CCID:008379; Phenotypes: congenital disorder of glycosylation MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 POU2AF1 Bryony Thompson Classified gene: POU2AF1 as Amber List (moderate evidence)
Mendeliome v1.2135 POU2AF1 Bryony Thompson Gene: pou2af1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2134 POU2AF1 Bryony Thompson reviewed gene: POU2AF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35603192, 33571536; Phenotypes: Agammaglobulinemia MONDO:0015977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2134 IGKC Bryony Thompson Marked gene: IGKC as ready
Mendeliome v1.2134 IGKC Bryony Thompson Gene: igkc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2134 IGKC Bryony Thompson Classified gene: IGKC as Amber List (moderate evidence)
Mendeliome v1.2134 IGKC Bryony Thompson Gene: igkc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2133 IGKC Bryony Thompson gene: IGKC was added
gene: IGKC was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: IGKC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IGKC were set to https://search.clinicalgenome.org/CCID:005121
Phenotypes for gene: IGKC were set to recurrent infections associated with rare immunoglobulin isotypes deficiency MONDO:0013576
Review for gene: IGKC was set to AMBER
Added comment: Antibody Deficiencies GCEP classify gene-disease association as Limited (18/05/2021) - at least 6 probands https://search.clinicalgenome.org/CCID:005121
Sources: Expert list
Mendeliome v1.2132 FLT3LG Bryony Thompson Classified gene: FLT3LG as Amber List (moderate evidence)
Mendeliome v1.2132 FLT3LG Bryony Thompson Gene: flt3lg has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2131 FLT3LG Bryony Thompson reviewed gene: FLT3LG: Rating: AMBER; Mode of pathogenicity: None; Publications: 10828034, 38701783; Phenotypes: ?Immunodeficiency 125 MIM#620926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2131 TNFSF9 Zornitza Stark Marked gene: TNFSF9 as ready
Mendeliome v1.2131 TNFSF9 Zornitza Stark Gene: tnfsf9 has been classified as Red List (Low Evidence).
Mendeliome v1.2131 TNFSF9 Zornitza Stark gene: TNFSF9 was added
gene: TNFSF9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNFSF9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFSF9 were set to 35657354
Phenotypes for gene: TNFSF9 were set to Hereditary susceptibility to infections, MONDO:0015979, TNFSF9-related
Review for gene: TNFSF9 was set to RED
Added comment: Fournier et al. described one patient with DiGeorge syndrome with a unique susceptibility to EBV with broad EBV infection and smooth muscle tumors. He was found to have a homozygous missense variant (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection.

They show that CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells.
Sources: Literature
Mendeliome v1.2130 APOA4 Zornitza Stark Marked gene: APOA4 as ready
Mendeliome v1.2130 APOA4 Zornitza Stark Gene: apoa4 has been classified as Green List (High Evidence).
Mendeliome v1.2130 APOA4 Zornitza Stark Classified gene: APOA4 as Green List (high evidence)
Mendeliome v1.2130 APOA4 Zornitza Stark Gene: apoa4 has been classified as Green List (High Evidence).
Mendeliome v1.2129 APOA4 Zornitza Stark gene: APOA4 was added
gene: APOA4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOA4 were set to 38096951
Phenotypes for gene: APOA4 were set to Hereditary amyloidosis, MONDO:0018634, APOA4-related
Review for gene: APOA4 was set to GREEN
Added comment: 5 families with autosomal dominant medullary amyloidosis. WGS/WES identified 2 different variants in the APOA4 gene (p.D33N in 3 families and p.L66V in 2 families). The variants were absent in gnomAD, located at the structurally flexible N-terminal domain of APOA4, and segregated with disease. There were 48 genotype +ve individuals with 44/48 having an eGFR <60. All clinically affected individuals presented with a bland urinary sediment, CKD, and no clinical evidence of systemic amyloidosis. Mean age of dialysis/transplantation was 58+/-11yrs. Routine kidney biopsies limited to the kidney cortex showed tubulointerstitial fibrosis and secondary glomerulosclerosis and no amyloid deposition. Four affected individuals were shown to have isolated medullary deposition of amyloid, with mass spectrometry showing the mutated Apoa4 as the primary constituent in 3 available cases. Plasma total ApoA4 levels were increased for patients (n=15) with ApoA4 mutations versus controls (n=49). They hypothesize that the amino acid substitutions alter the tertiary or quaternary structure of the mutated ApoA4, leading to increased plasma and primary urine concentrations and isolated medullary amyloid deposition.
Sources: Literature
Mendeliome v1.2128 TAPBP Bryony Thompson Publications for gene: TAPBP were set to 12149238
Mendeliome v1.2127 TAPBP Bryony Thompson Classified gene: TAPBP as Amber List (moderate evidence)
Mendeliome v1.2127 TAPBP Bryony Thompson Gene: tapbp has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2126 TAPBP Bryony Thompson reviewed gene: TAPBP: Rating: AMBER; Mode of pathogenicity: None; Publications: 38866210, 12149238; Phenotypes: MHC class I deficiency MONDO:0011476; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2126 RHOH Bryony Thompson Publications for gene: RHOH were set to 22850876; 27574848
Mendeliome v1.2125 RHOH Bryony Thompson Classified gene: RHOH as Amber List (moderate evidence)
Mendeliome v1.2125 RHOH Bryony Thompson Gene: rhoh has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2124 RHOH Bryony Thompson reviewed gene: RHOH: Rating: AMBER; Mode of pathogenicity: None; Publications: 38775840, 22850876; Phenotypes: epidermodysplasia verruciformis, susceptibility to, 4 MONDO:0032666; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2124 PRIM1 Bryony Thompson Classified gene: PRIM1 as Green List (high evidence)
Mendeliome v1.2124 PRIM1 Bryony Thompson Gene: prim1 has been classified as Green List (High Evidence).
Mendeliome v1.2123 PRIM1 Bryony Thompson reviewed gene: PRIM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33060134, 38773012; Phenotypes: primordial dwarfism-immunodeficiency-lipodystrophy syndrome MONDO:0859276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2123 MAN2B2 Bryony Thompson Publications for gene: MAN2B2 were set to 31775018; 35637269
Mendeliome v1.2122 MAN2B2 Bryony Thompson reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: None; Publications: 38622837, 35637269, 31775018; Phenotypes: Congenital disorder of glycosylation, MONDO:0015286, MAN2B2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2122 NUDCD3 Bryony Thompson Marked gene: NUDCD3 as ready
Mendeliome v1.2122 NUDCD3 Bryony Thompson Gene: nudcd3 has been classified as Green List (High Evidence).
Mendeliome v1.2122 NUDCD3 Bryony Thompson Classified gene: NUDCD3 as Green List (high evidence)
Mendeliome v1.2122 NUDCD3 Bryony Thompson Gene: nudcd3 has been classified as Green List (High Evidence).
Mendeliome v1.2120 NUDCD3 Bryony Thompson gene: NUDCD3 was added
gene: NUDCD3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NUDCD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDCD3 were set to 38787962
Phenotypes for gene: NUDCD3 were set to severe combined immunodeficiency MONDO:0015974
Mendeliome v1.2119 ATG9A Bryony Thompson Marked gene: ATG9A as ready
Mendeliome v1.2119 ATG9A Bryony Thompson Gene: atg9a has been classified as Red List (Low Evidence).
Mendeliome v1.2119 ATG9A Bryony Thompson gene: ATG9A was added
gene: ATG9A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG9A were set to 35838483
Phenotypes for gene: ATG9A were set to Autophagy-associated immune dysregulation and hyperplasia
Review for gene: ATG9A was set to RED
Added comment: A single case with compound heterozygous variants was reported. After infection with Epstein-Barr virus (EBV), the patient developed hyperplastic proliferation of T and B cells in the lung and brain and exhibited defects in lymphocyte memory cell populations. In vitro functional assays.
Sources: Literature
Mendeliome v1.2118 CCR2 Bryony Thompson Phenotypes for gene: CCR2 were changed from {HIV infection, susceptibility/resistance to} to {HIV infection, susceptibility/resistance to}; Polycystic lung disease MIM#219600
Mendeliome v1.2117 CCR2 Bryony Thompson Publications for gene: CCR2 were set to 34516427; 17504215; 15167933; 17604544
Mendeliome v1.2116 CCR2 Bryony Thompson Mode of inheritance for gene: CCR2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2115 CCR2 Bryony Thompson Classified gene: CCR2 as Green List (high evidence)
Mendeliome v1.2115 CCR2 Bryony Thompson Gene: ccr2 has been classified as Green List (High Evidence).
Mendeliome v1.2114 CCR2 Bryony Thompson reviewed gene: CCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38157855; Phenotypes: Polycystic lung disease MIM#219600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2114 ARHGEF1 Bryony Thompson Classified gene: ARHGEF1 as Amber List (moderate evidence)
Mendeliome v1.2114 ARHGEF1 Bryony Thompson Gene: arhgef1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2113 ME2 Bryony Thompson Marked gene: ME2 as ready
Mendeliome v1.2113 ME2 Bryony Thompson Gene: me2 has been classified as Red List (Low Evidence).
Mendeliome v1.2113 ME2 Bryony Thompson gene: ME2 was added
gene: ME2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ME2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ME2 were set to 39401966
Phenotypes for gene: ME2 were set to inborn disorder of energy metabolism MONDO:0019243
Review for gene: ME2 was set to RED
Added comment: A single individual with a homozygous frameshift variant from a consanguineous family. The phenotype included developmental delay, microcephaly, mild brain atrophy, peripheral
hypotonia, subtle dysmorphic features, ectopic kidney, and mild lactate elevation. Deletion of yeast ortholog of the gene resulted in growth arrest (which could be rescued).
Sources: Literature
Mendeliome v1.2112 TSHZ3 Bryony Thompson Marked gene: TSHZ3 as ready
Mendeliome v1.2112 TSHZ3 Bryony Thompson Gene: tshz3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2112 TSHZ3 Bryony Thompson Classified gene: TSHZ3 as Amber List (moderate evidence)
Mendeliome v1.2112 TSHZ3 Bryony Thompson Gene: tshz3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2111 TSHZ3 Bryony Thompson gene: TSHZ3 was added
gene: TSHZ3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TSHZ3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TSHZ3 were set to 27668656; 34919690; 36553458; 39420202
Phenotypes for gene: TSHZ3 were set to congenital anomaly of kidney and urinary tract MONDO:0019719
Review for gene: TSHZ3 was set to AMBER
Added comment: More evidence for the gene-disease association is required
PMID: 27668656 - TSHZ3 is included in the region deleted in chromosome 19q13.11 Deletion Syndrome, which includes intellectual disability and behavioural issues, congenital anomalies of the kidney and urinary tract (CAKUT)
PMID: 34919690 - haploinsufficient mouse model leads to kidney defects
PMID: 36553458 - heterozygous frameshift variant c.119_120dup p.Pro41SerfsTer79 in a case with intellectual disability, behavioural issues, pyelocaliceal dilatation, and mild urethral stenosis.
PMID: 39420202 - 12 CAKUT patients from 9/301 (3%) families carried 5 different rare heterozygous TSHZ3 missense variants. However, 1 of the variants (p.Ser58Gly) present in 5 of the families is more common in gnomAD v4.1 than you would expect for a dominant disease including 5 homozygotes (1,408/1,612,114 alleles, 5 hom, AF=0.0008734). The authors state this is not unexpected in a condition, such as CAKUT. However, the different missense variants are inherited from unaffected parents in at least 2/9 families (there was no phenotype information available for an additional 3 parents).
Sources: Literature
Mendeliome v1.2110 WDR83OS Bryony Thompson Phenotypes for gene: WDR83OS were changed from Cholestasis to complex neurodevelopmental disorder MONDO:0100038; neurodevelopmental disorder with hypercholanemia
Mendeliome v1.2109 WDR83OS Bryony Thompson Publications for gene: WDR83OS were set to 30250217
Mendeliome v1.2108 WDR83OS Bryony Thompson edited their review of gene: WDR83OS: Changed phenotypes: complex neurodevelopmental disorder MONDO:0100038, neurodevelopmental disorder with hypercholanemia
Mendeliome v1.2108 WDR83OS Bryony Thompson changed review comment from: Now 14 cases from 9 unrelated families with homozygous LoF variants. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Also, supporting null zebrafish model that recapitulates the human phenotype.; to: Now 14 cases from 9 unrelated families with homozygous LoF variants, including the family reported in 2019. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Also, supporting null zebrafish model that recapitulates the human phenotype.
Mendeliome v1.2108 WDR83OS Bryony Thompson Classified gene: WDR83OS as Green List (high evidence)
Mendeliome v1.2108 WDR83OS Bryony Thompson Gene: wdr83os has been classified as Green List (High Evidence).
Mendeliome v1.2107 WDR83OS Bryony Thompson reviewed gene: WDR83OS: Rating: GREEN; Mode of pathogenicity: None; Publications: 39471804, 30250217; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2107 GON4L Bryony Thompson Marked gene: GON4L as ready
Mendeliome v1.2107 GON4L Bryony Thompson Gene: gon4l has been classified as Green List (High Evidence).
Mendeliome v1.2107 GON4L Bryony Thompson Classified gene: GON4L as Green List (high evidence)
Mendeliome v1.2107 GON4L Bryony Thompson Gene: gon4l has been classified as Green List (High Evidence).
Mendeliome v1.2106 GON4L Bryony Thompson gene: GON4L was added
gene: GON4L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GON4L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GON4L were set to 39500882; 21937992; 31785789; 34011629; 33077954
Phenotypes for gene: GON4L were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: GON4L was set to GREEN
Added comment: 2 LoF variants in 4 cases from 3 unrelated consanguineous families, and supporting null zebrafish model
PMID: 39500882 - 2 homozygous truncating GON4L variants [NM_001282860.2: c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in 3 patients from 2 consanguineous families with prenatal-onset growth impairment, developmental delay, mild intellectual disability, speech impairment, progressive and disproportionate microcephaly, facial asymmetry, congenital heart anomaly, and brain structure abnormalities.
Null zebrafish model had distinct morphological and size abnormalities in the craniofacial cartilage of zebrafish larvae
Heterozygous carriers in biallelic families were unaffected
PMID: 21937992 - a case from Iran from a consanguineous family homozygous for c.5517+1G>A with syndromic ID. No other clinical details provided

Limited evidence for AD gene-disease association - heterozygous de novo variants identified in autism studies and a congenital hydrocephalus study. But, heterozygous carriers in families with biallelic LoF variants are healthy
PMID: 31785789 - 4 (3 NS & 1 Silent) de novo GON4L variants in cases with autism (n=3) & neurodevelopmental disorder
PMID: 34011629 - 2 cases with autism spectrum disorder and de novo missense
PMID: 33077954 - a de novo splice site variant identified in a single case with congenital hydrocephalus
Sources: Literature
Mendeliome v1.2105 SGSM3 Zornitza Stark Publications for gene: SGSM3 were set to PMID: 37833060
Mendeliome v1.2104 SGSM3 Zornitza Stark Classified gene: SGSM3 as Green List (high evidence)
Mendeliome v1.2104 SGSM3 Zornitza Stark Gene: sgsm3 has been classified as Green List (High Evidence).
Mendeliome v1.2103 LSM7 Zornitza Stark Phenotypes for gene: LSM7 were changed from Leukodystrophy; foetal death to leukodystrophy MONDO:0019046, LRM7-related
Mendeliome v1.2102 DALRD3 Zornitza Stark Publications for gene: DALRD3 were set to 32427860
Mendeliome v1.2101 UBTF Zornitza Stark Phenotypes for gene: UBTF were changed from Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701 to Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701; Neurodevelopmental disorder, MONDO:0700092, UBTF-related
Mendeliome v1.2100 UBTF Zornitza Stark Publications for gene: UBTF were set to 28777933; 29300972
Mendeliome v1.2099 UBTF Zornitza Stark edited their review of gene: UBTF: Added comment: PMID 39366741: 3 Chinese patients with global developmental delay, intellectual disability, social challenges and dysmorphism (wide forehead, sparse eyebrows, hypertelorism, narrow palpebral fissures, single-fold eyelids, flat nasal bridge, anteverted nares, a long philtrum and a thin upper lip), but no neuroregression (but aged 1.8yrs-4.8yrs). WES with SNV/CNV analysis showed:
-nonsense variant c.1327C>T p. (Arg443Ter) - parental segregation not possible
-de novo ~46 kb deletion at 17q21.31 containing 7 genes but UBTF as only OMIM Morbid gene
-de novo ~106kb deletion at 17q21.31 containing 10 genes but UBTF as only relevant OMIM Morbid gene (other one was SLC4A1)

Propose haploinsufficiency presents with different phenotype to CONDBA which is due to GOF variant.

AMBER for this mechanism and phenotype.; Changed publications: 28777933, 29300972, 39366741; Changed phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672, MONDO:0044701, Neurodevelopmental disorder, MONDO:0700092, UBTF-related
Mendeliome v1.2099 MARK2 Zornitza Stark Marked gene: MARK2 as ready
Mendeliome v1.2099 MARK2 Zornitza Stark Gene: mark2 has been classified as Green List (High Evidence).
Mendeliome v1.2099 IRAK2 Zornitza Stark Marked gene: IRAK2 as ready
Mendeliome v1.2099 IRAK2 Zornitza Stark Gene: irak2 has been classified as Red List (Low Evidence).
Mendeliome v1.2099 IRAK2 Zornitza Stark Phenotypes for gene: IRAK2 were changed from Immune dysregulation, no OMIM # to Immune dysregulation, MONDO:0957790, IRAK2-related
Mendeliome v1.2098 IRAK2 Zornitza Stark reviewed gene: IRAK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immune dysregulation, MONDO:0957790, IRAK2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2098 DTNA Zornitza Stark Publications for gene: DTNA were set to 29118297; 11238270; 16427346
Mendeliome v1.2097 DTNA Zornitza Stark Phenotypes for gene: DTNA were changed from Left ventricular noncompaction 1, with or without congenital heart defects, MIM# 604169 to Muscular dystrophy, MONDO:0020121, DTNA-related; Left ventricular noncompaction 1, with or without congenital heart defects, MIM# 604169
Mendeliome v1.2096 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immunodeficiency, MONDO:0021094, IKZF2-related; Immune dysregulation to Immunodeficiency, MONDO:0021094, IKZF2-related; Immune dysregulation; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related
Mendeliome v1.2095 IKZF2 Zornitza Stark Publications for gene: IKZF2 were set to 34920454; 34826259
Mendeliome v1.2094 CRACR2A Sangavi Sivagnanasundram reviewed gene: CRACR2A: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008378; Phenotypes: combined immunodeficiency MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 DNAH9 Sangavi Sivagnanasundram reviewed gene: DNAH9: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008406; Phenotypes: ciliary dyskinesia, primary, 40 MONDO:0032664; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 FUK Sangavi Sivagnanasundram reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008377; Phenotypes: congenital disorder of glycosylation with defective fucosylation 2 MONDO:0020777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 CTPS1 Sangavi Sivagnanasundram reviewed gene: CTPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008376; Phenotypes: severe combined immunodeficiency due to CTPS1 deficiency MONDO:0014391; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 SOX6 Sangavi Sivagnanasundram reviewed gene: SOX6: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008480; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2094 BHLHE22 Zornitza Stark Marked gene: BHLHE22 as ready
Mendeliome v1.2094 BHLHE22 Zornitza Stark Gene: bhlhe22 has been classified as Green List (High Evidence).
Mendeliome v1.2094 BHLHE22 Zornitza Stark Classified gene: BHLHE22 as Green List (high evidence)
Mendeliome v1.2094 BHLHE22 Zornitza Stark Gene: bhlhe22 has been classified as Green List (High Evidence).
Mendeliome v1.2093 BHLHE22 Zornitza Stark gene: BHLHE22 was added
gene: BHLHE22 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092, BHLHE22-related
Review for gene: BHLHE22 was set to GREEN
Added comment: Four individuals with de novo missense variants within the highly conserved helix-loop-helix domain and seven individuals from five unrelated families with a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Individuals presented with absent or limited speech, severely impaired motor abilities, intellectual disability (ID), involuntary movements, autistic traits with stereotypies, abnormal muscle tone. The majority of individuals had partial or complete agenesis of the corpus callosum (ACC). Additional symptoms comprised epilepsy, variable dysmorphic features, and eye anomalies. One additional individual had spastic paraplegia without delayed development and ACC, expanding the phenotype to milder and later onset forms.

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum.
Sources: Literature
Mendeliome v1.2092 MRPL49 Zornitza Stark Marked gene: MRPL49 as ready
Mendeliome v1.2092 MRPL49 Zornitza Stark Gene: mrpl49 has been classified as Green List (High Evidence).
Mendeliome v1.2092 MRPL49 Zornitza Stark Classified gene: MRPL49 as Green List (high evidence)
Mendeliome v1.2092 MRPL49 Zornitza Stark Gene: mrpl49 has been classified as Green List (High Evidence).
Mendeliome v1.2091 MRPL49 Zornitza Stark gene: MRPL49 was added
gene: MRPL49 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 39417135
Phenotypes for gene: MRPL49 were set to Mitochondrial disease, MONDO:0044970, MRPL49-related
Review for gene: MRPL49 was set to GREEN
Added comment: Five unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly and retinal dystrophy and bi-allelic variants in this gene.
Sources: Literature
Mendeliome v1.2090 SATB1 Sangavi Sivagnanasundram reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008481; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 NT5C2 Sangavi Sivagnanasundram reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008372; Phenotypes: complex hereditary spastic paraplegia MONDO:0015150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 NPTX1 Sangavi Sivagnanasundram reviewed gene: NPTX1: Rating: GREEN; Mode of pathogenicity: Other; Publications: https://search.clinicalgenome.org/CCID:008403; Phenotypes: autosomal dominant cerebellar ataxia MONDO:0020380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 SLC24A1 Sangavi Sivagnanasundram reviewed gene: SLC24A1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008419; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 C1QTNF5 Sangavi Sivagnanasundram reviewed gene: C1QTNF5: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008422; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 EPHB2 Sangavi Sivagnanasundram reviewed gene: EPHB2: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008367; Phenotypes: bleeding disorder, platelet-type, 22 MONDO:0032765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 F12 Sangavi Sivagnanasundram reviewed gene: F12: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary angioedema type 3 MONDO:0012526; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 HOXA11 Sangavi Sivagnanasundram reviewed gene: HOXA11: Rating: AMBER; Mode of pathogenicity: None; Publications: 11101832; Phenotypes: radioulnar synostosis with amegakaryocytic thrombocytopenia 1 MONDO:0024558; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 CCDC115 Sangavi Sivagnanasundram reviewed gene: CCDC115: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008374; Phenotypes: CCDC115-CDG MONDO:0014789; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 IRAK2 Chirag Patel Phenotypes for gene: IRAK2 were changed from Immune dysregulation, no OMIM # to Immune dysregulation, no OMIM #
Mendeliome v1.2090 IRAK2 Chirag Patel Phenotypes for gene: IRAK2 were changed from Immunodeficiency, no OMIM # to Immune dysregulation, no OMIM #
Mendeliome v1.2089 IRAK2 Chirag Patel changed review comment from: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported.

Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens).

Paper does not comment on reasons for disease in biallelic and mono-allelic form.
Sources: Literature; to: PMID: 39299377
2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported. Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens). Paper does not comment on reasons for disease in biallelic and mono-allelic form.


Preprint paper:
2 individuals with immune dysregulation (1 x systemic lupus erythematosus and 1 x autoinflammatory disease) with same homozgyous exon 2 deletion in IRAK2 gene found on WES testing and confirmed with Sanger sequencing. Unaffected family members in trio were heterozygous for variant. Exon 2 encodes a proportion of the death domain, a critical protein domain for Myddosome assembly.

The patients exhibited aberrantly upregulated type I interferon (IFN) response following LPS stimulation, which was further confirmed in bone marrow-derived macrophages (BMDMs) in mice. RNA sequencing analysis indicated that PBMCs from the two patients consistently exhibited defects in activating NFkb signaling in response to LPS or R848 stimulation, as well as impaired activation of the MAPK signaling pathway. RNA sequencing demonstrated that BMDMs from Irak2 ∆ex2/∆ex2 mice exhibited defects in NFkb and MAPK signaling pathways, similar to patients’ PBMCs.
Mendeliome v1.2089 WISP3 Sangavi Sivagnanasundram reviewed gene: WISP3: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008442; Phenotypes: progressive pseudorheumatoid arthropathy of childhood MONDO:0008827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2089 WDR60 Sangavi Sivagnanasundram reviewed gene: WDR60: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008443; Phenotypes: short-rib thoracic dysplasia 8 with or without polydactyly MONDO:0014214; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2089 IRAK2 Chirag Patel gene: IRAK2 was added
gene: IRAK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IRAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: IRAK2 were set to PMID: 39299377
Phenotypes for gene: IRAK2 were set to Immunodeficiency, no OMIM #
Review for gene: IRAK2 was set to RED
Added comment: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported.

Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens).

Paper does not comment on reasons for disease in biallelic and mono-allelic form.
Sources: Literature
Mendeliome v1.2088 MARK2 Chirag Patel Classified gene: MARK2 as Green List (high evidence)
Mendeliome v1.2088 MARK2 Chirag Patel Gene: mark2 has been classified as Green List (High Evidence).
Mendeliome v1.2087 MARK2 Chirag Patel gene: MARK2 was added
gene: MARK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MARK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MARK2 were set to PMID: 39419027, 39436150
Phenotypes for gene: MARK2 were set to Neurodevelopmental disorder MONDO:0700092
Mode of pathogenicity for gene: MARK2 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: MARK2 was set to GREEN
Added comment: 31 individuals with autism spectrum disorder (30/31), intellectual disability/developmental delay (100%), motor delay (62%), speech-language problems (100%), seizure/epilepsy (46%), behaviour disorders (ADHD, aggression, anxiety)(74%), and distinctive facial features (narrow face, abnormal or broad forehead, downslanting palpebral fissures, and large or dysplastic ears).

WES/WGS identified 25 LOF and 6 missense variants in MARK2 gene (Microtubule affinity-regulating kinase 2) which contributes to establishing neuronal polarity and developing dendritic spines. LOF variants were de novo (16/25), inherited (4/25), or unk (5/25). All 6 missense variants were de novo and clustered in the kinase or KA1 domains.

The mRNA and protein expression of MARK2 in PBMCs were significantly lower in affected individuals with LOF variants than in the control group. In vitro expression assay of missense variants supported the effect of MARK2 loss. Proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs) showed MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and disorganization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behaviour. Through the use of RNA sequencing (RNA-seq) and lithium treatment, they linked MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identified lithium as a potential drug for treating MARK2-associated ASD.
Sources: Literature
Mendeliome v1.2086 DTNA Chirag Patel Classified gene: DTNA as Green List (high evidence)
Mendeliome v1.2086 DTNA Chirag Patel Gene: dtna has been classified as Green List (High Evidence).
Mendeliome v1.2085 DTNA Chirag Patel reviewed gene: DTNA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36799992; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis MONDO:0859322; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2085 KAT2B Ain Roesley Marked gene: KAT2B as ready
Mendeliome v1.2085 KAT2B Ain Roesley Gene: kat2b has been classified as Red List (Low Evidence).
Mendeliome v1.2085 KAT2B Ain Roesley Phenotypes for gene: KAT2B were changed from steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related to steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related; cataract MONDO:0005129, KAT2B-related
Mendeliome v1.2084 ROCK2 Sangavi Sivagnanasundram gene: ROCK2 was added
gene: ROCK2 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: ROCK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ROCK2 were set to 28554332, 30622330, 31941532
Phenotypes for gene: ROCK2 were set to congenital heart disease MONDO:0005453
Review for gene: ROCK2 was set to AMBER
Added comment: Reported in 4 unrelated individuals however classified as LIMITED by ClinGen Congenital Heart Disease GCEP on 03/09/2024 - https://search.clinicalgenome.org/CCID:008432
Sources: ClinGen
Mendeliome v1.2084 KAT2B Ain Roesley gene: KAT2B was added
gene: KAT2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KAT2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KAT2B were set to 39366742
Phenotypes for gene: KAT2B were set to steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related
Review for gene: KAT2B was set to RED
gene: KAT2B was marked as current diagnostic
Added comment: 1 family with 2 affected siblings homozygous for an NMD-predicted variant

both have steroid-resistant nephrotic syndrome and bilateral cataract
only 1 has FSGS
Sources: Literature
Mendeliome v1.2083 IKZF2 Ain Roesley edited their review of gene: IKZF2: Changed rating: GREEN
Mendeliome v1.2083 IKZF2 Ain Roesley reviewed gene: IKZF2: Rating: ; Mode of pathogenicity: None; Publications: PMID: 39406892; Phenotypes: nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2083 ANKRD24 Ain Roesley Marked gene: ANKRD24 as ready
Mendeliome v1.2083 ANKRD24 Ain Roesley Gene: ankrd24 has been classified as Red List (Low Evidence).
Mendeliome v1.2083 ANKRD24 Ain Roesley gene: ANKRD24 was added
gene: ANKRD24 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANKRD24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANKRD24 were set to PMID: 39434538
Phenotypes for gene: ANKRD24 were set to sensorineural hearing loss disorder MONDO:0020678, ANKRD24-related
Review for gene: ANKRD24 was set to RED
gene: ANKRD24 was marked as current diagnostic
Added comment: 1 consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL

2 affecteds homozygous for c.1934_1937del; (p.Thr645Lysfs*52), which is NMD-predicted
Sources: Literature
Mendeliome v1.2082 DALRD3 Sangavi Sivagnanasundram reviewed gene: DALRD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 39482881; Phenotypes: developmental and epileptic encephalopathy, 86 MONDO:0030054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2082 ZNF862 Ain Roesley Marked gene: ZNF862 as ready
Mendeliome v1.2082 ZNF862 Ain Roesley Gene: znf862 has been classified as Red List (Low Evidence).
Mendeliome v1.2082 ZNF862 Ain Roesley gene: ZNF862 was added
gene: ZNF862 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF862 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF862 were set to PMID: 35142290
Phenotypes for gene: ZNF862 were set to hereditary gingival fibromatosis MONDO:0016070 , ZNF862 -related
Review for gene: ZNF862 was set to RED
gene: ZNF862 was marked as current diagnostic
Added comment: 13 individuals in a large multi-generational family with hereditary gingival fibromatosis

missense variant with 5 hets in gnomad v4, very low conservation and benign REVEL score
Sources: Literature
Mendeliome v1.2081 LSM7 Sangavi Sivagnanasundram reviewed gene: LSM7: Rating: AMBER; Mode of pathogenicity: None; Publications: 39420558; Phenotypes: leukodystrophy MONDO:0019046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2081 LAMA3 Ain Roesley Phenotypes for gene: LAMA3 were changed from Epidermolysis bullosa, generalized atrophic benign, MIM# 226650; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700 to Epidermolysis bullosa, junctional 2A, intermediate MIM#619783; Epidermolysis bullosa, junctional 2B, severe MIM#619784; Epidermolysis bullosa, junctional 2C, laryngoonychocutaneous MIM#245660
Mendeliome v1.2080 SGSM3 Sangavi Sivagnanasundram reviewed gene: SGSM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39390489; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), SGSM3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2080 GMNN Zornitza Stark changed review comment from: Three unrelated individuals reported, all variants in exon 2 (first coding exon).; to: Three unrelated individuals reported, all variants in exon 2 (first coding exon), leading to the expression of a stable truncated protein.
Mendeliome v1.2080 LINC01578 Zornitza Stark Marked gene: LINC01578 as ready
Mendeliome v1.2080 LINC01578 Zornitza Stark Gene: linc01578 has been classified as Green List (High Evidence).
Mendeliome v1.2080 LINC01578 Zornitza Stark Publications for gene: LINC01578 were set to
Mendeliome v1.2079 LINC01578 Zornitza Stark edited their review of gene: LINC01578: Changed publications: 39442041
Mendeliome v1.2079 LINC01578 Zornitza Stark Classified gene: LINC01578 as Green List (high evidence)
Mendeliome v1.2079 LINC01578 Zornitza Stark Gene: linc01578 has been classified as Green List (High Evidence).
Mendeliome v1.2078 LINC01578 Zornitza Stark gene: LINC01578 was added
gene: LINC01578 was added to Mendeliome. Sources: Literature
SV/CNV, new gene name tags were added to gene: LINC01578.
Mode of inheritance for gene: LINC01578 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LINC01578 were set to Neurodevelopmental disorder, MONDO:0700092, CHASERR-related
Review for gene: LINC01578 was set to GREEN
Added comment: CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Three unrelated children reported with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis, indicating bidirectional dosage sensitivity in human disease.
Sources: Literature
Mendeliome v1.2077 RNU5B-1 Zornitza Stark Marked gene: RNU5B-1 as ready
Mendeliome v1.2077 RNU5B-1 Zornitza Stark Gene: rnu5b-1 has been classified as Green List (High Evidence).
Mendeliome v1.2077 RNU5B-1 Zornitza Stark Classified gene: RNU5B-1 as Green List (high evidence)
Mendeliome v1.2077 RNU5B-1 Zornitza Stark Gene: rnu5b-1 has been classified as Green List (High Evidence).
Mendeliome v1.2076 RNU5B-1 Zornitza Stark gene: RNU5B-1 was added
gene: RNU5B-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5B-1 were set to https://www.medrxiv.org/content/10.1101/2024.10.04.24314692v1.full.pdf; https://www.medrxiv.org/content/10.1101/2024.10.07.24314689v1
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092, RNU5B-1 related
Review for gene: RNU5B-1 was set to GREEN
Added comment: 20 individuals reported in two preprints with de novo variants in this gene and a neurodevelopmental phenotype.
Sources: Literature
Mendeliome v1.2075 SPATA22 Zornitza Stark Phenotypes for gene: SPATA22 were changed from Premature ovarian insufficiency and nonobstructive azoospermia; Genetic infertility MONDO:0017143 to Spermatogenic failure 96, MIM#621001; Premature ovarian failure 25, MIM#621002
Mendeliome v1.2074 SPATA22 Zornitza Stark edited their review of gene: SPATA22: Changed phenotypes: Spermatogenic failure 96, MIM#621001, Premature ovarian failure 25, MIM#621002
Mendeliome v1.2074 SRPK3 Zornitza Stark Phenotypes for gene: SRPK3 were changed from Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related; Neurodevelopmental disorder, MONDO:0700092, SRPK3-related to Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related; Intellectual developmental disorder, X-linked, 114, MIM#301134
Mendeliome v1.2073 SRPK3 Zornitza Stark edited their review of gene: SRPK3: Changed phenotypes: Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related, Intellectual developmental disorder, X-linked, 114, MIM#301134
Mendeliome v1.2073 TOMM7 Eleanor Williams commented on gene: TOMM7
Mendeliome v1.2073 DHX9 Zornitza Stark Phenotypes for gene: DHX9 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; Charcot-Marie-Tooth disease, MONDO:0015626 to Intellectual developmental disorder, autosomal dominant 75, MIM# 620988; Charcot-Marie-Tooth disease, MONDO:0015626
Mendeliome v1.2072 DHX9 Zornitza Stark edited their review of gene: DHX9: Changed rating: GREEN; Changed phenotypes: Intellectual developmental disorder, autosomal dominant 75, MIM# 620988; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2072 ZRSR2 Zornitza Stark Phenotypes for gene: ZRSR2 were changed from Orofacialdigital syndrome MONDO:0015375, ZRSR2-related to Orofaciodigital syndrome XXI, MIM# 301132
Mendeliome v1.2071 ZRSR2 Zornitza Stark edited their review of gene: ZRSR2: Changed phenotypes: Orofaciodigital syndrome XXI, MIM# 301132
Mendeliome v1.2071 ZNF808 Zornitza Stark Phenotypes for gene: ZNF808 were changed from non-syndromic neonatal diabetes; MONDO:0016391 to Pancreatic agenesis 3, MIM# 620991
Mendeliome v1.2070 ZNF808 Zornitza Stark reviewed gene: ZNF808: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pancreatic agenesis 3, MIM# 620991; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2070 AJAP1 Zornitza Stark Marked gene: AJAP1 as ready
Mendeliome v1.2070 AJAP1 Zornitza Stark Gene: ajap1 has been classified as Green List (High Evidence).
Mendeliome v1.2070 AJAP1 Zornitza Stark Classified gene: AJAP1 as Green List (high evidence)
Mendeliome v1.2070 AJAP1 Zornitza Stark Gene: ajap1 has been classified as Green List (High Evidence).
Mendeliome v1.2069 AJAP1 Achchuthan Shanmugasundram gene: AJAP1 was added
gene: AJAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AJAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AJAP1 were set to 38985877
Phenotypes for gene: AJAP1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: AJAP1 was set to GREEN
Added comment: PMID:38985877 reported five unrelated individuals with monoallelic variants or a deletion in AJAP1 gene and they presented with epilepsy, neurodevelopmental problems, or intellectual disability. There is also supporting functional evidence available.
Sources: Literature
Mendeliome v1.2069 DHRSX Zornitza Stark Marked gene: DHRSX as ready
Mendeliome v1.2069 DHRSX Zornitza Stark Gene: dhrsx has been classified as Green List (High Evidence).
Mendeliome v1.2069 DHRSX Zornitza Stark Classified gene: DHRSX as Green List (high evidence)
Mendeliome v1.2069 DHRSX Zornitza Stark Gene: dhrsx has been classified as Green List (High Evidence).
Mendeliome v1.2068 MSL2 Zornitza Stark Phenotypes for gene: MSL2 were changed from Neurodevelopmental disorder, MONDO:0700092, MSL2-related to Karayol-Borroto-Haghshenas neurodevelopmental syndrome, MIM# 620985
Mendeliome v1.2067 MSL2 Zornitza Stark reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Karayol-Borroto-Haghshenas neurodevelopmental syndrome, MIM# 620985; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2067 WFDC2 Zornitza Stark Phenotypes for gene: WFDC2 were changed from bronchiectasis, MONDO:0004822, WFDC2-related to Bronchiectasis and nasal polyposis, MIM# 620984
Mendeliome v1.2066 WFDC2 Zornitza Stark edited their review of gene: WFDC2: Changed phenotypes: Bronchiectasis and nasal polyposis, MIM# 620984
Mendeliome v1.2066 BORCS8 Zornitza Stark Phenotypes for gene: BORCS8 were changed from Neurodevelopmental disorder (MONDO#0700092), BORCS8-related to Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, MIM# 620987
Mendeliome v1.2065 BORCS8 Zornitza Stark reviewed gene: BORCS8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, MIM# 620987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2065 COPG1 Zornitza Stark Phenotypes for gene: COPG1 were changed from Combined immunodeficiency MONDO:0015131, COPG1-related to Immunodeficiency 128, MIM# 620983
Mendeliome v1.2064 COPG1 Zornitza Stark edited their review of gene: COPG1: Changed phenotypes: Immunodeficiency 128, MIM# 620983
Mendeliome v1.2064 MAL Zornitza Stark Phenotypes for gene: MAL were changed from Leukodystrophy MONDO:0019046, MAL-related to Leukodystrophy, hypomyelinating, 28, MIM# 620978
Mendeliome v1.2063 MAL Zornitza Stark edited their review of gene: MAL: Changed phenotypes: Leukodystrophy, hypomyelinating, 28, MIM# 620978
Mendeliome v1.2063 DHRSX Achchuthan Shanmugasundram commented on gene: DHRSX: Note that this gene is located in the pseudoautosomal region 1.
Mendeliome v1.2063 DHRSX Achchuthan Shanmugasundram gene: DHRSX was added
gene: DHRSX was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHRSX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRSX were set to 38821050
Phenotypes for gene: DHRSX were set to congenital disorder of glycosylation, MONDO:0015286
Review for gene: DHRSX was set to GREEN
Added comment: PMID:38821050 reported the identification of biallelic missense variants in DHRSX gene in four patients from three unrelated families with a congenital disorder of glycosylation. They displayed distinct facial features, severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss. These patients also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.2063 UFC1 Zornitza Stark Tag deep intronic tag was added to gene: UFC1.
Mendeliome v1.2063 UFC1 Zornitza Stark reviewed gene: UFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with spasticity and poor growth (MIM#618076); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2063 WFDC2 Zornitza Stark Marked gene: WFDC2 as ready
Mendeliome v1.2063 WFDC2 Zornitza Stark Gene: wfdc2 has been classified as Green List (High Evidence).
Mendeliome v1.2063 WFDC2 Zornitza Stark Classified gene: WFDC2 as Green List (high evidence)
Mendeliome v1.2063 WFDC2 Zornitza Stark Gene: wfdc2 has been classified as Green List (High Evidence).
Mendeliome v1.2062 WFDC2 Zornitza Stark gene: WFDC2 was added
gene: WFDC2 was added to Mendeliome. Sources: Literature
founder tags were added to gene: WFDC2.
Mode of inheritance for gene: WFDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WFDC2 were set to 38626355
Phenotypes for gene: WFDC2 were set to bronchiectasis, MONDO:0004822, WFDC2-related
Review for gene: WFDC2 was set to GREEN
Added comment: 11 individuals from 10 families reported with bi-allelic variants in this gene and bronchiectasis and nasal polyps. p.Cys49Arg is recurrent and may be a founder variant.
Sources: Literature
Mendeliome v1.2061 PTCH1 Zornitza Stark Phenotypes for gene: PTCH1 were changed from Holoprosencephaly 7, MIM# 610828 to Holoprosencephaly 7, MIM# 610828; Bladder exstrophy and epispadias complex (BEEC)
Mendeliome v1.2060 BMP5 Zornitza Stark Marked gene: BMP5 as ready
Mendeliome v1.2060 BMP5 Zornitza Stark Gene: bmp5 has been classified as Red List (Low Evidence).
Mendeliome v1.2060 BMP5 Zornitza Stark Phenotypes for gene: BMP5 were changed from Skeletal dysostosis and atrioventricular septal defect, no OMIM# to Skeletal dysplasia, MONDO:0018230, BMP5-related; Skeletal dysostosis and atrioventricular septal defect, no OMIM#
Mendeliome v1.2059 BMP5 Zornitza Stark Publications for gene: BMP5 were set to
Mendeliome v1.2058 RELB Zornitza Stark Publications for gene: RELB were set to 7834753; 26385063
Mendeliome v1.2057 KLF1 Zornitza Stark Phenotypes for gene: KLF1 were changed from Dyserythropoietic anaemia, congenital, type IV, MIM# 613673; MONDO:0013355 to Dyserythropoietic anaemia, congenital, type IV, MIM# 613673; MONDO:0013355; Anaemia, congenital dyserythropoietic, type IVb, MIM#620969
Mendeliome v1.2056 KLF1 Zornitza Stark Publications for gene: KLF1 were set to 21055716; 33339573; 32815883; 32221653; 32032242; 31818881
Mendeliome v1.2055 KLF1 Zornitza Stark Mode of inheritance for gene: KLF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2054 KLF1 Zornitza Stark edited their review of gene: KLF1: Added comment: Ten individuals reported with bi-allelic variants and congenital dyserythropoietic anaemia.; Changed publications: 21055716, 33339573, 32815883, 32221653, 32032242, 31818881, 24443441, 25724378, 28361594, 34554218; Changed phenotypes: Dyserythropoietic anaemia, congenital, type IV, MIM# 613673, MONDO:0013355, Anaemia, congenital dyserythropoietic, type IVb, MIM#620969; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2054 POLR3K Bryony Thompson Phenotypes for gene: POLR3K were changed from Hypomyelinating leukodystrophy-21, MIM#619310 to POLR3-related leukodystrophy MONDO:0700282
Mendeliome v1.2053 POLR3K Bryony Thompson Publications for gene: POLR3K were set to 30584594; 33659930
Mendeliome v1.2052 POLR3K Bryony Thompson Classified gene: POLR3K as Green List (high evidence)
Mendeliome v1.2052 POLR3K Bryony Thompson Gene: polr3k has been classified as Green List (High Evidence).
Mendeliome v1.2051 POLR3K Bryony Thompson reviewed gene: POLR3K: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1155/2024/8807171, 30584594; Phenotypes: POLR3-related leukodystrophy MONDO:0700282; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2051 RELB Chirag Patel Classified gene: RELB as Green List (high evidence)
Mendeliome v1.2051 RELB Chirag Patel Gene: relb has been classified as Green List (High Evidence).
Mendeliome v1.2050 RELB Chirag Patel reviewed gene: RELB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39231201; Phenotypes: T-cell and B cell immunodeficiency, Immunodeficiency 53, OMIM #617585; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2049 BMP5 Chirag Patel edited their review of gene: BMP5: Changed publications: PMID: 39239663
Mendeliome v1.2048 BMP5 Chirag Patel gene: BMP5 was added
gene: BMP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BMP5 were set to Skeletal dysostosis and atrioventricular septal defect, no OMIM#
Phenotypes for gene: BMP5 were set to Skeletal dysostosis and atrioventricular septal defect, no OMIM#
Review for gene: BMP5 was set to RED
Added comment: 1 patient with skeletal dysostosis, atrioventricular septal defect, hypermobility, laryngo-tracheo-bronchomalacia and dysmorphic features (malar hypoplasia, short palpebral fissures, short nose, low nasal bridge, anteverted nares, long philtrum, small ears with abnormally folded antihelix). Skeletal survey showed mild thoracolumbar scoliosis, four sacral segments, absent ossification of the inferior pubic rami, and patellar aplasia. Trio WGS identified compound heterozygous loss of function variants in BMP5 (c.88_89del, p.(Gly30Argfs*11) and c.1104+2del, p.(?). Abnormal splicing was proven on the suspected splice variant using maternal fibroblasts. BMP5 expression is confined to specific parts of the skeleton and cartilage in mice and is tightly regulated by different enhancers. Previous studies of chicken embryonic heart development showed BMP5 expression in the endoderm underlying the precardiac mesoderm, the myocardium of the atrioventricular canal and outflow tract regions. Other bone morphogenetic proteins are linked to several genetic skeletal disorders.
Sources: Literature
Mendeliome v1.2047 IL7 Zornitza Stark Marked gene: IL7 as ready
Mendeliome v1.2047 IL7 Zornitza Stark Gene: il7 has been classified as Green List (High Evidence).
Mendeliome v1.2047 IL7 Zornitza Stark Classified gene: IL7 as Green List (high evidence)
Mendeliome v1.2047 IL7 Zornitza Stark Gene: il7 has been classified as Green List (High Evidence).
Mendeliome v1.2046 IL7 Zornitza Stark gene: IL7 was added
gene: IL7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL7 were set to 39352394
Phenotypes for gene: IL7 were set to Combined immunodeficiency, MONDO:0015131, IL7-related
Review for gene: IL7 was set to GREEN
Added comment: 6 indviduals from 4 kindreds with combined immune deficiency and recurrent infections. Extensive immunophenotyping revealing IL7 dependent and independent development of T cells.
Sources: Literature
Mendeliome v1.2045 LRRC7 Zornitza Stark Marked gene: LRRC7 as ready
Mendeliome v1.2045 LRRC7 Zornitza Stark Gene: lrrc7 has been classified as Green List (High Evidence).
Mendeliome v1.2045 LRRC7 Zornitza Stark Phenotypes for gene: LRRC7 were changed from neurodevelopmental disorder (MONDO:0700092) to neurodevelopmental disorder (MONDO:0700092), LRRC7-related
Mendeliome v1.2044 LRRC7 Zornitza Stark Classified gene: LRRC7 as Green List (high evidence)
Mendeliome v1.2044 LRRC7 Zornitza Stark Gene: lrrc7 has been classified as Green List (High Evidence).
Mendeliome v1.2043 LRRC7 Zornitza Stark reviewed gene: LRRC7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder (MONDO:0700092), LRRC7-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2043 RPL26 Zornitza Stark Phenotypes for gene: RPL26 were changed from Diamond-Blackfan anemia 11, MIM# 614900 to Diamond-Blackfan anaemia 11, MIM# 614900
Mendeliome v1.2042 RPL26 Zornitza Stark Publications for gene: RPL26 were set to 22431104
Mendeliome v1.2041 RPL26 Zornitza Stark Classified gene: RPL26 as Green List (high evidence)
Mendeliome v1.2041 RPL26 Zornitza Stark Gene: rpl26 has been classified as Green List (High Evidence).
Mendeliome v1.2040 FLVCR1 Zornitza Stark Phenotypes for gene: FLVCR1 were changed from posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177 to posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177; neurodevelopmental disorder MONDO:0700092, FLVCR1-related
Mendeliome v1.2039 NHEJ1 Zornitza Stark Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291; Cernunnos-XLF deficiency MONDO:0012650 to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291; Cernunnos-XLF deficiency MONDO:0012650; Microphthalmia/coloboma, MIM# 13 620968
Mendeliome v1.2038 NHEJ1 Zornitza Stark Publications for gene: NHEJ1 were set to 30898087; 30666249; 28741180; 25288157; 24511403; 21721379; 21535335
Mendeliome v1.2037 NHEJ1 Zornitza Stark changed review comment from: PMID 37580330: Seven individuals from 2 consanguineous families identified with a deep intronic homozygous variant affecting the IHH enhancer within NHEJ1.; to: PMID 37580330: Seven individuals from 2 consanguineous families identified with a deep intronic homozygous variant affecting the IHH enhancer within NHEJ1 -- RED for this association.
Mendeliome v1.2037 NHEJ1 Zornitza Stark edited their review of gene: NHEJ1: Added comment: PMID 37580330: Seven individuals from 2 consanguineous families identified with a deep intronic homozygous variant affecting the IHH enhancer within NHEJ1.; Changed publications: 30898087, 30666249, 28741180, 25288157, 24511403, 21721379, 21535335, 37580330; Changed phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291, Cernunnos-XLF deficiency MONDO:0012650, Microphthalmia/coloboma, MIM# 13 620968
Mendeliome v1.2037 FLVCR1 Bryony Thompson edited their review of gene: FLVCR1: Added comment: A study with 30 patients from 23 unrelated families with biallelic ultra-rare missense and predicted loss-of-function variants in FLVCR1 with a novel FLVCR1-related phenotype characterised by severe developmental disorders with profound developmental delay, microcephaly, brain malformations, epilepsy, spasticity, and premature death. Optic disk atrophy, limb and digital malformations, and macrocytic anaemia can be present.; Changed publications: 21070897, 22279524, 21267618, 39306721; Changed phenotypes: posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177, neurodevelopmental disorder MONDO:0700092, FLVCR1-related
Mendeliome v1.2037 RPL26 Sangavi Sivagnanasundram reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: None; Publications: 39268718; Phenotypes: Diamond-Blackfan anemia MONDO:0015253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2037 LRRC7 Sangavi Sivagnanasundram gene: LRRC7 was added
gene: LRRC7 was added to Mendeliome. Sources: Other,Literature
Mode of inheritance for gene: LRRC7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC7 were set to 39256359
Phenotypes for gene: LRRC7 were set to neurodevelopmental disorder (MONDO:0700092)
Review for gene: LRRC7 was set to GREEN
Added comment: Well established gene-disease association.
Neurodevelopmental disorder with a clinical spectrum - symptoms include ID, ADHD, aggression and in many cases, hyperphagia associate obesity.
Heterozygous missense and LoF variants have been reported and functional assays were conducted on missense and truncating variants that support LoF mechanism of disease.
Sources: Other, Literature
Mendeliome v1.2037 GMPPB Ain Roesley Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 (MIM# 615350); Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 (MIM# 615351); Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 (MIM# 615352)
Mendeliome v1.2036 GMPPA Ain Roesley Phenotypes for gene: GMPPA were changed from Alacrima, achalasia, and mental retardation syndrome, MIM# 615510 to Alacrima, achalasia, and impaired intellectual development syndrome (MIM# 615510)
Mendeliome v1.2035 USP9X Ain Roesley Phenotypes for gene: USP9X were changed from Mental retardation, X-linked 99, XLR (MIM#300919) and XLD (MIM#300968) to Intellectual developmental disorder 99 MIM#300919; syndromic, female-restricted Intellectual developmental disorder 99 MIM#300968
Mendeliome v1.2034 IL7R Ain Roesley Phenotypes for gene: IL7R were changed from Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971; fever; rash; failure to thrive; recurrent respiratory and gastric infections; diarrhoea; lymphadenopathy; pneumonitis; Pancytopaenia; low T-cell numbers; decreased immunoglobulins; normal-high B/NK-cell numbers. to severe combined immunodeficiency 104 MIM#608971
Mendeliome v1.2033 SGPL1 Ain Roesley Phenotypes for gene: SGPL1 were changed from to RENI syndrome (MIM#617575)
Mendeliome v1.2032 PPP2R5D Ain Roesley Phenotypes for gene: PPP2R5D were changed from Mental retardation, autosomal dominant 35, MIM#616355 to Houge-Janssens syndrome 1, MIM#616355
Mendeliome v1.2031 ATAD2B Ain Roesley Marked gene: ATAD2B as ready
Mendeliome v1.2031 ATAD2B Ain Roesley Gene: atad2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2031 ATAD2B Ain Roesley Classified gene: ATAD2B as Amber List (moderate evidence)
Mendeliome v1.2031 ATAD2B Ain Roesley Gene: atad2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2030 ATAD2B Ain Roesley gene: ATAD2B was added
gene: ATAD2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATAD2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD2B were set to 39313616
Phenotypes for gene: ATAD2B were set to neurodevelopmental disorder MONDO:0700092, ATAD2B-related
Review for gene: ATAD2B was set to AMBER
gene: ATAD2B was marked as current diagnostic
Added comment: 3 families including 2 siblings
1 fam is hom for a highly conserved missense

Amber because of the lack of specific phenotypes:
Abnormality of the nervous system and Abnormality of the eye
Sources: Literature
Mendeliome v1.2029 ZDHHC16 Ain Roesley Classified gene: ZDHHC16 as Amber List (moderate evidence)
Mendeliome v1.2029 ZDHHC16 Ain Roesley Gene: zdhhc16 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2028 ZDHHC16 Ain Roesley Marked gene: ZDHHC16 as ready
Mendeliome v1.2028 ZDHHC16 Ain Roesley Gene: zdhhc16 has been classified as Red List (Low Evidence).
Mendeliome v1.2028 ZDHHC16 Ain Roesley gene: ZDHHC16 was added
gene: ZDHHC16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZDHHC16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZDHHC16 were set to 39313616
Phenotypes for gene: ZDHHC16 were set to neurodevelopmental disorder MONDO:0700092, ZDHHC16-related
Review for gene: ZDHHC16 was set to AMBER
gene: ZDHHC16 was marked as current diagnostic
Added comment: 6 families including a pair of siblings

Amber because 5 of the families had non specific phenotypes listed
Abnormality of:
the nervous system, metabolism/homeostasis, head/neck, immune system, the integument, the digestive system, the respiratory system, the endocrine system, Growth abnormality the skeletal system, the musculature, the eye

Specific HPOs were provided for one individual (homoyzygous for a canonical splice)

Abnormality of the face; Cerebellar hypoplasia; Developmental regression; Encephalopathy; Hyperreflexia; Hypertonia; Hypotonia; Inguinal hernia; Laryngomalacia; Microcephaly; Motor delay; Optic atrophy; Seizure; Spastic paraparesis; Spasticity; Talipes equinovarus; Umbilical hernia
Sources: Literature
Mendeliome v1.2027 KBTBD2 Ain Roesley Marked gene: KBTBD2 as ready
Mendeliome v1.2027 KBTBD2 Ain Roesley Gene: kbtbd2 has been classified as Green List (High Evidence).
Mendeliome v1.2027 KBTBD2 Ain Roesley Classified gene: KBTBD2 as Green List (high evidence)
Mendeliome v1.2027 KBTBD2 Ain Roesley Gene: kbtbd2 has been classified as Green List (High Evidence).
Mendeliome v1.2026 KBTBD2 Ain Roesley gene: KBTBD2 was added
gene: KBTBD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KBTBD2 were set to 39313616
Phenotypes for gene: KBTBD2 were set to neurodevelopmental disorder MONDO:0700092, KBTBD2-related
Review for gene: KBTBD2 was set to GREEN
gene: KBTBD2 was marked as current diagnostic
Added comment: 3 families - 2 compound hets and 1 hom

phenotypes include:
Microcephaly, hypotonia, failure to thrive, IUGR, delayed gross motor development, dysmorphism
Sources: Literature
Mendeliome v1.2025 EPB41L3 Bryony Thompson Marked gene: EPB41L3 as ready
Mendeliome v1.2025 EPB41L3 Bryony Thompson Gene: epb41l3 has been classified as Green List (High Evidence).
Mendeliome v1.2025 EPB41L3 Bryony Thompson Classified gene: EPB41L3 as Green List (high evidence)
Mendeliome v1.2025 EPB41L3 Bryony Thompson Gene: epb41l3 has been classified as Green List (High Evidence).
Mendeliome v1.2024 EPB41L3 Bryony Thompson gene: EPB41L3 was added
gene: EPB41L3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPB41L3 were set to 39292993
Phenotypes for gene: EPB41L3 were set to neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities MONDO:0030063
Review for gene: EPB41L3 was set to GREEN
Added comment: 6 cases from 5 unrelated consanguineous families (2nd & 3rd degree) with homozygous LoF variants and a neurodevelopmental condition, including ID and seizures. Epb41l3 shRNA-mediated downregulation in mouse oligodendroglia demonstrated impaired oligodendrocyte function.
Sources: Literature
Mendeliome v1.2023 PSKH1 Zornitza Stark Marked gene: PSKH1 as ready
Mendeliome v1.2023 PSKH1 Zornitza Stark Gene: pskh1 has been classified as Green List (High Evidence).
Mendeliome v1.2023 PSKH1 Zornitza Stark Classified gene: PSKH1 as Green List (high evidence)
Mendeliome v1.2023 PSKH1 Zornitza Stark Gene: pskh1 has been classified as Green List (High Evidence).
Mendeliome v1.2022 PSKH1 Zornitza Stark gene: PSKH1 was added
gene: PSKH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSKH1 were set to 39132680
Phenotypes for gene: PSKH1 were set to Cholestasis, progressive familial intrahepatic, 13, MIM# 620962
Review for gene: PSKH1 was set to GREEN
Added comment: 4 consanguineous families (out of 279 families) with intrahepatic cholestasis:
-1 patient died at 10mths with cholestasis/liver impairment and kidney impairment
-3 cousins with cholestasis (2 with liver failure needing transplant) and kidney features (2 with kidney failure, 1 with renal echogenicity)
-2 siblings with hepatic fibrosis (1 with unilateral renal agenesis)
-2 siblings with unexplained liver cirrhosis (1 needing transplant) but normal kidney function

WES identified 3 different homozygous variants in PSKH1 (Arg121Trp, Ile126Val, Arg183Cys). Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. Human PSKH1 is a poorly understood gene that may play important role in intracellular trafficking, is sensitive to intracellular Ca2+ concentration, and is localized to centrosomes, suggesting a link to cystogenesis.
Sources: Literature
Mendeliome v1.2021 CIAO1 Zornitza Stark Phenotypes for gene: CIAO1 were changed from Neurodegenerative disease, MONDO:0005559, CIAO1-related to Multiple mitochondrial dysfunctions syndrome 10, MIM#620960
Mendeliome v1.2020 CIAO1 Zornitza Stark reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple mitochondrial dysfunctions syndrome 10, MIM#620960; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2020 TREM2 Zornitza Stark Phenotypes for gene: TREM2 were changed from Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193 to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193; {Alzhieimer disease 17, susceptibility to}, MIM# 615080
Mendeliome v1.2019 TREM2 Zornitza Stark edited their review of gene: TREM2: Changed phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193, {Alzhieimer disease 17, susceptibility to}, MIM# 615080
Mendeliome v1.2019 JPH1 Zornitza Stark Phenotypes for gene: JPH1 were changed from Congenital myopathy MONDO:0019952 to Congenital myopathy 25, MIM# 620964
Mendeliome v1.2018 JPH1 Zornitza Stark reviewed gene: JPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 25, MIM# 620964; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2018 AHR Zornitza Stark Phenotypes for gene: AHR were changed from ?Retinitis pigmentosa 85 MIM#618345; foveal hypoplasia and infantile nystagmus to Retinitis pigmentosa 85 MIM#618345; Foveal hypoplasia 3, MIM# 620958
Mendeliome v1.2017 AHR Zornitza Stark edited their review of gene: AHR: Changed phenotypes: Foveal hypoplasia 3, MIM# 620958
Mendeliome v1.2017 PSTPIP1 Zornitza Stark Phenotypes for gene: PSTPIP1 were changed from Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome to Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia, MIMM# 601979; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome
Mendeliome v1.2016 PSTPIP1 Zornitza Stark edited their review of gene: PSTPIP1: Changed phenotypes: Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia, MIMM# 601979, Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome
Mendeliome v1.2016 PNKP Shakira Heerah Deleted their review
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Classified gene: RPS6KB1 as Amber List (moderate evidence)
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Added comment: Comment on list classification: Comment on list classification: ClinGen HCVD GCEP has classified this gene as Limited for HCM on 13/09/2023 - https://search.clinicalgenome.org/CCID:006034
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Gene: rps6kb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2015 DNAH6 Seb Lunke reviewed gene: DNAH6: Rating: AMBER; Mode of pathogenicity: None; Publications: 34215651; Phenotypes: situs inversus, MONDO:0010029, transposition of the great arteries, MONDO:0000153; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2015 EXOC3L2 Zornitza Stark Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation, MONDO:0009072; renal dysplasia; bone marrow failure to Brain malformation renal syndrome, MIM# 620943
Mendeliome v1.2014 EXOC3L2 Zornitza Stark edited their review of gene: EXOC3L2: Changed phenotypes: Brain malformation renal syndrome, MIM# 620943
Mendeliome v1.2014 THAP11 Zornitza Stark Phenotypes for gene: THAP11 were changed from Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related to Methylmalonic aciduria, cblC type-like, MIM# 620940; Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Mendeliome v1.2013 THAP11 Zornitza Stark edited their review of gene: THAP11: Changed phenotypes: Methylmalonic aciduria, cblC type-like, MIM# 620940, Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Mendeliome v1.2013 PHKG2 Sangavi Sivagnanasundram reviewed gene: PHKG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 6962066, 8896567, 9384616, 35549678, 24389071, 25266922, 21646031; Phenotypes: glycogen storage disease IXc MONDO:0013091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2013 PIH1D3 Sangavi Sivagnanasundram reviewed gene: PIH1D3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28041644, 28176794, 32170493, 38051289, 33106461, 38408845, 33635866; Phenotypes: ciliary dyskinesia, primary, 36, X-linked MONDO:0010517; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2013 IFIH1 Sangavi Sivagnanasundram reviewed gene: IFIH1: 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: 24686847, 24995871, 25620204, 30219631, 31898846; Phenotypes: IFIH1-related type 1 interferonopathy MONDO:0700262; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 IRF4 Sangavi Sivagnanasundram reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36662884, 36917008, 29537367, 29408330; Phenotypes: combined immunodeficiency MONDO:0015131; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 AICDA Sangavi Sivagnanasundram reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22992148, 12910268, 14564357, 15893695, 32423680, 35570134, 17560278; Phenotypes: hyper-IgM syndrome type 2 MONDO:0011528; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2013 RBSN Zornitza Stark Phenotypes for gene: RBSN were changed from intellectual disability, MONDO:0001071, RBSN-related to Kariminejad-Reversade neurodevelopmental syndrome, MIM# 620937
Mendeliome v1.2012 RBSN Zornitza Stark edited their review of gene: RBSN: Changed phenotypes: Kariminejad-Reversade neurodevelopmental syndrome, MIM# 620937
Mendeliome v1.2012 B2M Bryony Thompson Mode of inheritance for gene: B2M was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2011 B2M Bryony Thompson reviewed gene: B2M: Rating: GREEN; Mode of pathogenicity: None; Publications: 22693999, 37223323, 24014031, 35575118, 32875920; Phenotypes: variant ABeta2M amyloidosis MONDO:0017810; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2011 RNU2-2P Zornitza Stark Marked gene: RNU2-2P as ready
Mendeliome v1.2011 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Mendeliome v1.2011 RNU2-2P Zornitza Stark Classified gene: RNU2-2P as Green List (high evidence)
Mendeliome v1.2011 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Mendeliome v1.2010 RNU2-2P Zornitza Stark gene: RNU2-2P was added
gene: RNU2-2P was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU2-2P were set to https://www.medrxiv.org/content/10.1101/2024.09.03.24312863v1
Phenotypes for gene: RNU2-2P were set to Neurodevelopmental disorder, MONDO:0700092, RNU2-2P-related
Review for gene: RNU2-2P was set to GREEN
Added comment: 15 individuals reported with de novo, recurrent variants in this gene at nucleotide positions 4 and 35. The disorder is characterized by intellectual disability, neurodevelopmental delay, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.
Sources: Literature
Mendeliome v1.2009 PNKP Shakira Heerah reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31436889, 31707899, 20118933, 23224214, 29243230, 2578773, 27066567; Phenotypes: Ataxia-oculomotor apraxia 4, Microcephaly, seizures, and developmental delay, Charcot-Marie-Tooth disease, type 2B2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2009 NFU1 Zornitza Stark Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711 to Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711; Spastic paraplegia 93, autosomal recessive, MIM# 620938
Mendeliome v1.2008 NFU1 Zornitza Stark edited their review of gene: NFU1: Changed phenotypes: Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711, Spastic paraplegia 93, autosomal recessive, MIM# 620938
Mendeliome v1.2008 SGMS1 Bryony Thompson Marked gene: SGMS1 as ready
Mendeliome v1.2008 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2008 SGMS1 Bryony Thompson Classified gene: SGMS1 as Amber List (moderate evidence)
Mendeliome v1.2008 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 REPS2 Bryony Thompson Marked gene: REPS2 as ready
Mendeliome v1.2007 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 TTL Bryony Thompson Marked gene: TTL as ready
Mendeliome v1.2007 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 REPS2 Bryony Thompson Classified gene: REPS2 as Amber List (moderate evidence)
Mendeliome v1.2007 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2006 TTL Bryony Thompson Classified gene: TTL as Amber List (moderate evidence)
Mendeliome v1.2006 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2005 MRPL42 Bryony Thompson Marked gene: MRPL42 as ready
Mendeliome v1.2005 MRPL42 Bryony Thompson Gene: mrpl42 has been classified as Red List (Low Evidence).
Mendeliome v1.2005 MRPL42 Bryony Thompson Classified gene: MRPL42 as Red List (low evidence)
Mendeliome v1.2005 MRPL42 Bryony Thompson Gene: mrpl42 has been classified as Red List (Low Evidence).
Mendeliome v1.2004 MED16 Bryony Thompson Marked gene: MED16 as ready
Mendeliome v1.2004 MED16 Bryony Thompson Gene: med16 has been classified as Green List (High Evidence).
Mendeliome v1.2004 MED16 Bryony Thompson Classified gene: MED16 as Green List (high evidence)
Mendeliome v1.2004 MED16 Bryony Thompson Gene: med16 has been classified as Green List (High Evidence).
Mendeliome v1.2003 GPN2 Bryony Thompson Marked gene: GPN2 as ready
Mendeliome v1.2003 GPN2 Bryony Thompson Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2003 GPN2 Bryony Thompson Classified gene: GPN2 as Amber List (moderate evidence)
Mendeliome v1.2003 GPN2 Bryony Thompson Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2002 FKBP4 Bryony Thompson Marked gene: FKBP4 as ready
Mendeliome v1.2002 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2002 FKBP4 Bryony Thompson Classified gene: FKBP4 as Amber List (moderate evidence)
Mendeliome v1.2002 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2001 EIF3I Bryony Thompson Marked gene: EIF3I as ready
Mendeliome v1.2001 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2001 EIF3I Bryony Thompson Classified gene: EIF3I as Amber List (moderate evidence)
Mendeliome v1.2001 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2000 DNAH17 Bryony Thompson Marked gene: DNAH17 as ready
Mendeliome v1.2000 DNAH17 Bryony Thompson Gene: dnah17 has been classified as Green List (High Evidence).
Mendeliome v1.2000 DNAH17 Bryony Thompson Classified gene: DNAH17 as Green List (high evidence)
Mendeliome v1.2000 DNAH17 Bryony Thompson Gene: dnah17 has been classified as Green List (High Evidence).
Mendeliome v1.1999 CEP76 Bryony Thompson Marked gene: CEP76 as ready
Mendeliome v1.1999 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Mendeliome v1.1999 CEP76 Bryony Thompson Classified gene: CEP76 as Green List (high evidence)
Mendeliome v1.1999 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Mendeliome v1.1998 CEP76 Mark Cleghorn gene: CEP76 was added
gene: CEP76 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEP76 were set to complex neurodevelopmental disorder MONDO:0100038; Joubert syndrome; Bardet-Biedl syndrome; retinitis pigmentosa
Penetrance for gene: CEP76 were set to unknown
Review for gene: CEP76 was set to GREEN
Added comment: Erica Davis, Stanley Manne Children’s research institute, Chicago
ESHG presentation 4/6/24, unpublished

CEP76 associated with syndromic ciliopathy

CEP76 localizes to centrioles and basal body primary cilia
Role in normal centriolar duplication

Index case
Bardet Biedl syndrome
Compound heterozygous pLoF variants in CEP76

Via Gene matcher
7 cases in 7 families- biallelic CEP76 and various clinical features within ciliopathy spectrum:
Obesity
Ocular phenotype
Structural brain anomalies
Renal?

3/7 families clinical Dx Joubert syndrome
1/7 BBS
1/7 GDD/ID NOS
2/7 retinitis pigmentosa (1 of these with learning difficulties)

Mixture of biallelic pLOF and missense variant

CEP76 knockout zebrafish model shows retinal phenotype w photoreceptor loss, similar to homozygous known BBS4 pathogenic variant

Cell based fx studies with missense variants above, consistent with centriolar duplication dysfunction
Sources: Other
Mendeliome v1.1998 EIF3I Mark Cleghorn gene: EIF3I was added
gene: EIF3I was added to Mendeliome. Sources: Other
Mode of inheritance for gene: EIF3I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EIF3I were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: EIF3I were set to unknown
Review for gene: EIF3I was set to AMBER
Added comment: Marcello Scala, Genoa
ESHG presentation 4/6/24, unpublished

De novo EIF3I missense variants as a cause for novel NDD syndrome

EIF3 complex involved in regulating initiation of mRNA translation
Negative regulator of the TGF beta pathway

8 individuals from 8 families
Mod/severe GDD or ID
Short stature
Midline brain anomalies (hypoplasia/agenesis of corpus callosum and pituitary hypoplasia)
Frontal bossing, hypertelorism, long philtrum
All w rare de novo missense variants in EIF3I, clustering within highly conserved WD repeats

Functional studies
Transfected HEK293 cell studies suggested EIF3I protein from variant alleles (from patients above) had disrupted interaction with other EIF subunits, and cells had reduced protein synthesis overall
No animal models
Sources: Other
Mendeliome v1.1998 MRPL42 Mark Cleghorn gene: MRPL42 was added
gene: MRPL42 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MRPL42 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MRPL42 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MRPL42 were set to unknown
Review for gene: MRPL42 was set to RED
Added comment: Bjorn Fischer-Zirnsak, Charite Berlin
ESHG presentation 4/6/24, unpublished

++ supportive functional data (on patient-derived cells) presented, but only 1 case

Biallelic MRPL42 LoF with lethal mitochondrial disease

Index case, born to consanguineous parents
Small
Hypotonia
Seizures
Conductive hearing impairment
CV: hypertrophic RV, small VSD
Hepatomegaly
Lactic acidosis

Homozygous MRPL42: c.219+6T>A (spliceAI 0.83 donor loss)
RNASeq and RT-PCR supportive of aberrant splicing resulting in out of frame exon 4 skipping
Sources: Other
Mendeliome v1.1998 MED16 Mark Cleghorn gene: MED16 was added
gene: MED16 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MED16 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: MED16 was set to GREEN
Added comment: Charlotte Guillouet, Imagine institute Paris
ESHG presentation 4/6/24, unpublished

MED16 is part of tail of ‘mediator complex’
Plays a role in enhancer/promotor regions

Disruptive variants in other genes encoding proteins within this mediator complex (MED11/12/12/17/20, CDK8) are assoc w neurodevelopmental/neurodegenerative disorders

Cases
index family
Sibs (M/F) to consanguineous parents w NDD/mod ID, tetralogy of Fallot or VSD, bilat deafness, micrognathia, malar hypoplasia, dental AbN, pre auricular tags, hypoplastic nails, brachydactly
WES: biallelic MED16 p.Asp217Asn

Via genematcher
16 families total, 22 individuals, homozygous or compound het rare MED16 variants
Mixture of pLoF and missense variants

Motor delay in 16/17
DD or ID in 17/17
Speech delay in 15/15
6/19 ToF
7/19 other septal/aortic defects
6/18 deafness
11/18 microretrognathia
6/17 cleft palate
8/19 preauricular tags
9/20 puffy eyelids
12/20 nasal dysplasia (most commonly short columella w bulbous nasal tip)
7/20 corpus callosum anomalies

Not clear that functional work recapitulated phenotype as yet?
Immunofluroescence on HeLa cells transfected with variants observed ?conclusion
MED16 knockout mouse > growth delay, pre weaning lethality
MED16 knockout zebrafish > reduced body length, early death, no obvious craniofacial phenotype
Sources: Other
Mendeliome v1.1998 GPN2 Mark Cleghorn gene: GPN2 was added
gene: GPN2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GPN2 were set to complex neurodevelopmental disorder MONDO:0100038; Perrault syndrome
Penetrance for gene: GPN2 were set to unknown
Review for gene: GPN2 was set to AMBER
Added comment: GPN2
ESHG talk 2/6/24, unpublished
Thomas Smith, University of Manchester

Biallelic GPN2 proposed to cause Perrault syndrome (SNHL, ovarian dysfunction, NDD)
RNA polymerase assembly factor

4 families (14 affected individuals) w biallalic GPN2 rare missense variants
Segregated w phenotype
Fam 2 and 3 may be distantly related (leaving 3 distinct kindreds)

Clinical features
13/14 SNHL
3/4 families all females of adolescent age or older had primary ovarian insufficiency
4/4 GDD, ataxia (no data on family w 10 affected indiv.)

Some functional work, not conclusive
Sources: Other
Mendeliome v1.1998 FKBP4 Mark Cleghorn gene: FKBP4 was added
gene: FKBP4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: FKBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FKBP4 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: FKBP4 were set to unknown
Review for gene: FKBP4 was set to AMBER
Added comment: Rebecca Yarwood, University of Manchester
ESHG presentation 4/6/24, unpublished

Bilalleic FKBP4 w NDD + DSD
Protein has functions in hormone receptor trafficking
FKPB4 highly expressed in stem cell and progenitor cells in gonad and neuronal degeneration

Index case
Severe GDD
abN external genitalia
CV AbN
FBBP4 p.E196*

Via GeneMatcher
7 families (12 individuals)

12/12 severe GDD/ID
9/10 microcephaly
11/12 external genital abnormalities (details not provided)

All w homozygous pLoF variants (mixture of canonical splice, frameshift, nonsense)
Sources: Other
Mendeliome v1.1998 SGMS1 Mark Cleghorn gene: SGMS1 was added
gene: SGMS1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: SGMS1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SGMS1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: SGMS1 was set to AMBER
Added comment: SGMS1
Johannes Kopp, Charite Berlin
ESHG presentation 4/6/24, unpublished

Biallelic SGMS1 with novel metabolic disorder

Only 2 families (3 cases) reported
NDD, AbN cerebral myelination, SNHL, ichthyosis

Homozygous or compound het SGMS1 missense

Functional work to support role of SGMS1 in sphingolipid metabolism
Sources: Other
Mendeliome v1.1998 CAPN3 Sangavi Sivagnanasundram reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: muscular dystrophy, limb-girdle, autosomal dominant MONDO:0015151, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1998 BVES Sangavi Sivagnanasundram reviewed gene: BVES: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1998 PTCRA Zornitza Stark Phenotypes for gene: PTCRA were changed from Autoinflammatory syndrome, MONDO:0019751, PTCRA-related to Immunodeficiency 126, MIM# 620931
Mendeliome v1.1997 PTCRA Zornitza Stark edited their review of gene: PTCRA: Changed phenotypes: Immunodeficiency 126, MIM# 620931
Mendeliome v1.1997 ZNRF3 Bryony Thompson Marked gene: ZNRF3 as ready
Mendeliome v1.1997 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Mendeliome v1.1997 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Green List (high evidence)
Mendeliome v1.1997 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Mendeliome v1.1996 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to GREEN
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Mendeliome v1.1995 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Mendeliome v1.1995 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Marked gene: ATP6V1C1 as ready
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Gene: atp6v1c1 has been classified as Red List (Low Evidence).
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Phenotypes for gene: ATP6V1C1 were changed from to neurodevelopmental disorder MONDO:0700092, ATP6V1C1-related
Mendeliome v1.1993 C12orf66 Zornitza Stark Marked gene: C12orf66 as ready
Mendeliome v1.1993 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.1993 C12orf66 Zornitza Stark Classified gene: C12orf66 as Green List (high evidence)
Mendeliome v1.1993 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.1992 RFC4 Chirag Patel gene: RFC4 was added
gene: RFC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to PMID: 39106866
Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder
Review for gene: RFC4 was set to GREEN
gene: RFC4 was marked as current diagnostic
Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Mendeliome v1.1991 COQ8B Zornitza Stark Phenotypes for gene: COQ8B were changed from Nephrotic syndrome, type 9 MIM#615573 to Nephrotic syndrome, type 9 MIM#615573; Retinitis pigmentosa MONDO:0019200
Mendeliome v1.1990 COQ8B Zornitza Stark Publications for gene: COQ8B were set to 24270420
Mendeliome v1.1989 SF3B1 Zornitza Stark Classified gene: SF3B1 as Green List (high evidence)
Mendeliome v1.1989 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Green List (High Evidence).
Mendeliome v1.1988 SF3B1 Zornitza Stark Marked gene: SF3B1 as ready
Mendeliome v1.1988 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1988 SF3B1 Zornitza Stark Classified gene: SF3B1 as Amber List (moderate evidence)
Mendeliome v1.1988 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1987 JPH1 Zornitza Stark Marked gene: JPH1 as ready
Mendeliome v1.1987 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Mendeliome v1.1987 JPH1 Zornitza Stark Classified gene: JPH1 as Green List (high evidence)
Mendeliome v1.1987 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Mendeliome v1.1986 MED22 Zornitza Stark Marked gene: MED22 as ready
Mendeliome v1.1986 MED22 Zornitza Stark Gene: med22 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1986 MED22 Zornitza Stark Classified gene: MED22 as Amber List (moderate evidence)
Mendeliome v1.1986 MED22 Zornitza Stark Gene: med22 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1985 LARP1 Zornitza Stark Marked gene: LARP1 as ready
Mendeliome v1.1985 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Mendeliome v1.1985 LARP1 Zornitza Stark Classified gene: LARP1 as Green List (high evidence)
Mendeliome v1.1985 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Mendeliome v1.1984 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from Mitochondrial myopathy with lactic acidosis (MIM#251950), AR to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related; Mitochondrial myopathy with lactic acidosis (MIM#251950), AR
Mendeliome v1.1983 SPARCL1 Zornitza Stark Marked gene: SPARCL1 as ready
Mendeliome v1.1983 SPARCL1 Zornitza Stark Gene: sparcl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1983 SPARCL1 Zornitza Stark gene: SPARCL1 was added
gene: SPARCL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPARCL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPARCL1 were set to 39169229
Phenotypes for gene: SPARCL1 were set to Corneal dystrophy, MONDO:0018102
Review for gene: SPARCL1 was set to RED
Added comment: 8 affected individuals with corneal dystrophy from 1 family (3 generations). Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue revealed mild stromal textural alterations with alcianophilic deposits.

WGS from 4 affected individuals in family identified a novel heterozygous missense variant in exon 4 of SPARCL1 (c.334G > A; p.(Glu112Lys)) which segregated with disease.

SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Immunohistochemistry showed the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium.
Sources: Literature
Mendeliome v1.1982 NDUFA7 Zornitza Stark Phenotypes for gene: NDUFA7 were changed from to Optic atrophy, MONDO:0003608, NDUFA7-related
Mendeliome v1.1981 NDUFA7 Zornitza Stark Mode of inheritance for gene: NDUFA7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 NDUFA7 Zornitza Stark edited their review of gene: NDUFA7: Changed rating: RED
Mendeliome v1.1980 NDUFA7 Zornitza Stark reviewed gene: NDUFA7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Optic atrophy, MONDO:0003608, NDUFA7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 ABL1 Sangavi Sivagnanasundram reviewed gene: ABL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39155385, 38743093; Phenotypes: Human ABL1 Deficiency Syndrome (HADS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 GMPPB Sangavi Sivagnanasundram reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27147698; Phenotypes: myopathy caused by variation in GMPPB MONDO:0700084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 LARP1 Sangavi Sivagnanasundram gene: LARP1 was added
gene: LARP1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: LARP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LARP1 were set to 39182167
Phenotypes for gene: LARP1 were set to Neurodevelopmental disorder; MONDO:0700092
Review for gene: LARP1 was set to GREEN
Added comment: Seven unrelated probands (6 males and 1 female) with ASD or another variable NDD phenotype (ID, hypotonia, motor delay and/or ASD). Variants were showed to be de novo null variants or missense variants that resulted in haploinsufficiency.

Ex vivo (knockout CRISPR-Cas9) functional assay using lymphoblasts that was collected and immortilised from one proband was conducted to assess the functional impact of the LARP1 variant. The results showed a reduction in protein compared to WT causing reduced rates of aerobic respiration and glycolysis.
Sources: Other
Mendeliome v1.1980 PNPLA8 Chirag Patel edited their review of gene: PNPLA8: Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum.

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.; Set current diagnostic: yes
Mendeliome v1.1980 PNPLA8 Chirag Patel reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39082157; Phenotypes: PNPLA8-related neurological diseases; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 MED22 Mark Cleghorn gene: MED22 was added
gene: MED22 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MED22 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MED22 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MED22 were set to unknown
Review for gene: MED22 was set to AMBER
Added comment: ESHG talk 2/6/24, unpublished
Elisa Cali, UCL

Recurrent homozygous MED22:c.397_399del (p.Glu133del) inframe variant in 8 individuals from 6 families w progressive NDD, microcepahly, cerebellar atrophy, dystonia, seizures

Rare in gnomad v4.1 (9 het alleles, no homozygotes)

Functional work on patient fibroblasts: quantity of protein comparable to controls, did not mentioned assays of protein function (?mechanism proposed)
Drosophilia heterozygous model with equivalent of p.Glu133del variant: structural anomalies, less movements, all died prior to pupae stage
Zebrafish: MED22 mutants less mobile, died prior to adulthood, reduced brain size
Sources: Other
Mendeliome v1.1980 TMEM216 Zornitza Stark Phenotypes for gene: TMEM216 were changed from Joubert syndrome 2, MIM# 608091; MONDO:0011963; Meckel syndrome 2, MIM# 603194; MONDO:0011296 to Joubert syndrome 2, MIM# 608091; MONDO:0011963; Meckel syndrome 2, MIM# 603194; MONDO:0011296; Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Mendeliome v1.1979 TMEM216 Zornitza Stark Publications for gene: TMEM216 were set to 20036350; 20512146
Mendeliome v1.1978 TMEM216 Zornitza Stark Tag founder tag was added to gene: TMEM216.
Tag UTR tag was added to gene: TMEM216.
Mendeliome v1.1978 TMEM216 Zornitza Stark edited their review of gene: TMEM216: Added comment: PMID 39191256: Two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]) found in individuals of South Asian and African ancestry, respectively.

This included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations.

Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted.

Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity.; Changed publications: 20036350, 20512146, 39191256; Changed phenotypes: Joubert syndrome 2, MIM# 608091, MONDO:0011963, Meckel syndrome 2, MIM# 603194, MONDO:0011296, Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Mendeliome v1.1978 JPH1 Sangavi Sivagnanasundram changed review comment from: 4 unrelated probands presented with congenital myopathy with prominent facial and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other; to: 4 unrelated probands presented with congenital myopathy with facial weakness and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other
Mendeliome v1.1978 JPH1 Sangavi Sivagnanasundram gene: JPH1 was added
gene: JPH1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy MONDO:0019952
Review for gene: JPH1 was set to GREEN
Added comment: 4 unrelated probands presented with congenital myopathy with prominent facial and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other
Mendeliome v1.1978 PLEC Zornitza Stark Phenotypes for gene: PLEC were changed from ?Epidermolysis bullosa simplex with nail dystrophy, MIM# 616487; Epidermolysis bullosa simplex with muscular dystrophy, MIM# 226670; Epidermolysis bullosa simplex with pyloric atresia, MIM# 612138; Epidermolysis bullosa simplex, Ogna type MIM#131950; Muscular dystrophy, limb-girdle, autosomal recessive 17, MIM# 613723 to Epidermolysis bullosa simplex with nail dystrophy, MIM# 616487; Epidermolysis bullosa simplex with muscular dystrophy, MIM# 226670; Epidermolysis bullosa simplex with pyloric atresia, MIM# 612138; Epidermolysis bullosa simplex, Ogna type MIM#131950; Muscular dystrophy, limb-girdle, autosomal recessive 17, MIM# 613723; Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related
Mendeliome v1.1977 PLEC Zornitza Stark Publications for gene: PLEC were set to 22144912
Mendeliome v1.1976 PLEC Zornitza Stark reviewed gene: PLEC: Rating: AMBER; Mode of pathogenicity: None; Publications: 39168815; Phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1976 SF3B1 Mark Cleghorn gene: SF3B1 was added
gene: SF3B1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SF3B1 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: SF3B1 were set to unknown
Review for gene: SF3B1 was set to AMBER
Added comment: SF3B1
Delphine Bernard, University of Brest
ESHG talk 2/6/24, unpublished

De novo germline SF3B1 variants, proposed spliceosomopathy/NDD gene

SF3B1 is an RNA binding protein that stabilizes the U2 snRNP complex at branchpoint sequences
Somatic SF3B1 missense commonly occur in haematological malignancy (K700E recurrent)

25 patients with syndromic NDD + de novo heterozygous rare SF3B1 variants identified on WES, genematcher
13 missense (incl recurrent xxx and xxx) within HEAT domain
5 nonsense
4 splicing
1 frameshift

Patients w missense variants may have more severe phenotype incl mircocepahly, palate anomalies, cerebral anomalies, GI/cardiac anomalies

Cellular models of missense variants: erythroleukaemia K562, HEK293T
Suggest missense variants do not cause loss of function, but increase exon skipping and alternative 3’ splice site use
Sources: Other
Mendeliome v1.1976 GBF1 Ain Roesley reviewed gene: GBF1: Rating: RED; Mode of pathogenicity: None; Publications: 39110251; Phenotypes: autosomal dominant cataract MONDO:0022672, GBF1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1976 TLN1 Ain Roesley reviewed gene: TLN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39163585; Phenotypes: idiopathic spontaneous coronary artery dissection MONDO:0007385; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1976 COQ8B Bryony Thompson reviewed gene: COQ8B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39226897, 25967120; Phenotypes: Retinitis pigmentosa MONDO:0019200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1976 C12orf66 Mark Cleghorn gene: C12orf66 was added
gene: C12orf66 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: C12orf66 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: C12orf66 were set to unknown
Review for gene: C12orf66 was set to AMBER
Added comment: KICS2 (previously known as C12ORF66)
Rebecca Buchert, Universitatklinikum Tubingen
ESHG talk 2/6/24, unpublished

Proposed ID + epilepsy gene

8 families w 11 affected individuals
Phenotypes: 11/11 ID, 9/11 epilepsy, 3/11 hearing impairment
3/8 homozygous missense variants (p.Asp296Glu, p.Tyr393Cys, p.Tyr393Cys), all highly conserved
1/8 compound het PTC (p.Lys262*) with 1.1Mb deletion
4/8 homozygous PTC (p.Glu3*, p.Gly79Valfs*18, p.Gly79Valfs*18, p.Lys260Asnfs*18)

Gene appears to be involved in mTOR pathway, and cilia function
mTORC1 activity in CRISPR-HEK293T cells – reduced activity in cells w variants above

Zebrafish model: otolith defects, ciliary dysfunction
?not clear that this truly mimics phenotype observed in patient cohort described
Sources: Other
Mendeliome v1.1976 MYBBP1A Zornitza Stark Marked gene: MYBBP1A as ready
Mendeliome v1.1976 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Mendeliome v1.1976 MYBBP1A Zornitza Stark Classified gene: MYBBP1A as Green List (high evidence)
Mendeliome v1.1976 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Mendeliome v1.1975 MYBBP1A Zornitza Stark gene: MYBBP1A was added
gene: MYBBP1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYBBP1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBBP1A were set to 39191491; 28425981
Phenotypes for gene: MYBBP1A were set to Hydrops fetalis, MONDO:0015193, MYBBP1A-related
Review for gene: MYBBP1A was set to GREEN
Added comment: Three unrelated fetuses with bi-allelic variants in this gene and severe hydrops.
Sources: Literature
Mendeliome v1.1974 ATP6V1C1 Ain Roesley edited their review of gene: ATP6V1C1: Changed phenotypes: neurodevelopmental disorder MONDO:0700092, ATP6V1C1-related
Mendeliome v1.1974 ATP6V1C1 Ain Roesley gene: ATP6V1C1 was added
gene: ATP6V1C1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V1C1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V1C1 were set to 39210597
Review for gene: ATP6V1C1 was set to AMBER
gene: ATP6V1C1 was marked as current diagnostic
Added comment: 1x de novo missense p.Glu289Lys (absent in v4 gnomad). Manual inspection of IGV found the dad was mosaic 7% VAF and he shared some of the clinical features (minor digit anomalies).

Some functional studies using patient fibroblasts were performed, demonstrating similar effects as known pathogenic variants in ATP6V1B2.
- lysosomal morphology
- autophagic flux dysregulation
- increased acidification of lysosome

borderline red/amber
Sources: Literature
Mendeliome v1.1973 REPS2 Mark Cleghorn gene: REPS2 was added
gene: REPS2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: REPS2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: REPS2 were set to complex neurodevelopmental disorder MONDO:0100038; Cerebral palsy HP:0100021
Penetrance for gene: REPS2 were set to unknown
Review for gene: REPS2 was set to AMBER
Added comment: REPS2
Hao Hu, Guangzhou Women and Children’s MC
ESHG talk 1/6/24, unpublished

Proposed X-linked cerebral palsy + NDD gene

4 unrelated males with predicted deleterious hemizygous REPS2 variants, 2 PTC, 2 missense. 2 de novo, 2 maternally inherited
Phenotypes: 2 w CP + moderate ID/ASD, 2 w NDD NOS
Variants described:
c.1050_1052delGAA;p.K351del
c.1040T>C; p.I347T
c.962C>G; p.S321C
c.1736delA; p.N579Tfs*17

In vitro assay of above 4 variants suggest reduced REPS2 protein stability
Zebrafish model: REPS2 expressed in neuronal cells, REPS2 knock down have reduced motor activity and abN neuronal morphology
Mouse model hemizygous w one of above variants (not specified): reduced performance in cognitive tasks, abnormal neuronal migration pattern on post mortem examination
Mechanism may relate to dopamine signalling?
Sources: Other
Mendeliome v1.1973 TTL Mark Cleghorn gene: TTL was added
gene: TTL was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TTL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TTL were set to complex neurodevelopmental disorderMONDO:0100038
Added comment: TTL
Valentina Serpieri, University of Pavia
ESHG talk 1/6/24

FAM1 (Italy)
2 affected sisters born to consanguineous Pakistani parents
GDD, spastic tetraparesis, optic atrophy, brain anomalies resembling tubulinopathies (dysplasia of corpus callosum, basal ganglia, brainstem)
WES: homozygous TTL:c.1013G>A; p.Cys338Tyr in both affected sisters

Via genematcher
5 more families (9 individuals) w similar phenotypes and biallelic variants in TTL

FAM2 (Egypt): homozygous p.Arg46Pro
FAM3 (Egypt): homozygous p.Arg46Pro
FAM4 (Australia): homozygous p.Gln183Arg
FAM5 (France): homozygous p.Trp147*
FAM6 (Saudi Arabia): homozygous p.His243Tyr

TTL KO mice: death soon after birth, no overt malformations, but defects in organisation of cerebral layers

Functional work on patient fibroblasts
FAM1 – reduced quantity of TTL protein compared to control on Western blot, decreased function of TTL protein (increase in detyrosinated tubulin) compared to controls – infer LoF as mechanism
FAM3 – mentioned but no details
FAM4– mentioned but no details
Sources: Other
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Marked gene: PLEKHM2 as ready
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Gene: plekhm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Classified gene: PLEKHM2 as Amber List (moderate evidence)
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Gene: plekhm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1972 PLEKHM2 Bryony Thompson gene: PLEKHM2 was added
gene: PLEKHM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEKHM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHM2 were set to 35862026; 26464484; 38942823; 38490981; 37349842
Phenotypes for gene: PLEKHM2 were set to Dilated cardiomyopathy MONDO:0005021
Review for gene: PLEKHM2 was set to AMBER
Added comment: 2 unrelated families reported with DCM and supporting functional evidence
PMID: 35862026 - 21 yo with DCM with bialleic PLEKHM2 variants. Loss PLEKHM2 expression was found in the proband’s myocardial tissue

PMID: 26464484 - a homozygous frameshift variant (p.Lys645AlafsTer12) segregates with early-onset (adolescent) DCM and LVNC in a large consanguineous Bedouin family

PMID: 38942823 - murine model suggests Plekhm2 acts as an autophagy modulator in cardiofibroblasts

PMID: 38490981, 37349842 - supportive PLEKHM2 knockout iPSC-cardiomyocyte models
Sources: Literature
Mendeliome v1.1971 FLT3LG Zornitza Stark Phenotypes for gene: FLT3LG were changed from Increased susceptibility to infections to Immunodeficiency 125, MIM# 620926
Mendeliome v1.1970 FLT3LG Zornitza Stark reviewed gene: FLT3LG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 125, MIM# 620926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1970 GTPBP1 Zornitza Stark Phenotypes for gene: GTPBP1 were changed from Neurodevelopmental disorder (MONDO#0700092), GTPBP1-related to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888
Mendeliome v1.1969 GTPBP1 Zornitza Stark reviewed gene: GTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1969 LRP1 Zornitza Stark Phenotypes for gene: LRP1 were changed from to Developmental dysplasia of the hip 3, MIM# 620690; Keratosis pilaris atrophicans MIM#604093
Mendeliome v1.1968 LRP1 Zornitza Stark Publications for gene: LRP1 were set to
Mendeliome v1.1967 LRP1 Zornitza Stark Mode of inheritance for gene: LRP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1966 LRP1 Zornitza Stark Classified gene: LRP1 as Amber List (moderate evidence)
Mendeliome v1.1966 LRP1 Zornitza Stark Gene: lrp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1965 LRP1 Zornitza Stark reviewed gene: LRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36067312; Phenotypes: Developmental dysplasia of the hip 3, MIM# 620690; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1965 RAB32 Zornitza Stark Phenotypes for gene: RAB32 were changed from Parkinson disease MONDO:0005180 to {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923
Mendeliome v1.1964 RAB32 Zornitza Stark Publications for gene: RAB32 were set to 38614108
Mendeliome v1.1963 RAB32 Zornitza Stark Classified gene: RAB32 as Amber List (moderate evidence)
Mendeliome v1.1963 RAB32 Zornitza Stark Gene: rab32 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1962 RAB32 Zornitza Stark reviewed gene: RAB32: Rating: AMBER; Mode of pathogenicity: None; Publications: 38858457; Phenotypes: {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1962 VPS52 Bryony Thompson Marked gene: VPS52 as ready
Mendeliome v1.1962 VPS52 Bryony Thompson Gene: vps52 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1962 VPS52 Bryony Thompson Classified gene: VPS52 as Amber List (moderate evidence)
Mendeliome v1.1962 VPS52 Bryony Thompson Gene: vps52 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1961 VPS52 Bryony Thompson gene: VPS52 was added
gene: VPS52 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: VPS52 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VPS52 were set to complex neurodevelopmental disorder with or without congenital anomalies MONDO:0100465
Review for gene: VPS52 was set to AMBER
Added comment: HGSA poster (P110) from Louise Bicknell's group at the University of Otago. 11 cases from 8 families (USA, NZ, Saudi Arabia) with a broad syndromic developmental delay phenotype with biallelic variants (both missense & truncating).
Sources: Other
Mendeliome v1.1960 ELMOD3 Zornitza Stark Classified gene: ELMOD3 as Red List (low evidence)
Mendeliome v1.1960 ELMOD3 Zornitza Stark Gene: elmod3 has been classified as Red List (Low Evidence).
Mendeliome v1.1959 ELMOD3 Zornitza Stark edited their review of gene: ELMOD3: Added comment: Discussed at GenCC: limited.; Changed rating: RED
Mendeliome v1.1959 CFAP57 Zornitza Stark Phenotypes for gene: CFAP57 were changed from to Spermatogenic failure 95, MIM# 620917; Van der Woude Syndrome; Primary ciliary dyskinesia
Mendeliome v1.1958 CFAP57 Zornitza Stark Publications for gene: CFAP57 were set to
Mendeliome v1.1957 CFAP57 Zornitza Stark Classified gene: CFAP57 as Green List (high evidence)
Mendeliome v1.1957 CFAP57 Zornitza Stark Gene: cfap57 has been classified as Green List (High Evidence).
Mendeliome v1.1956 CFAP57 Zornitza Stark edited their review of gene: CFAP57: Added comment: PMID 36752199: 5 individuals from three families reported with biallelic LoF variants (two homozygous variants) and spermatogenic failure. Mouse model recapitulated the phenotype.; Changed rating: GREEN; Changed publications: 21574244, 32764743, 36752199; Changed phenotypes: Spermatogenic failure 95, MIM# 620917, Van der Woude Syndrome, Primary ciliary dyskinesia
Mendeliome v1.1956 FICD Zornitza Stark Phenotypes for gene: FICD were changed from Hereditary motor neurone disease, FICD-related, MONDO:0024257 to Spastic paraplegia 92, autosomal recessive, MIM# 620911
Mendeliome v1.1955 FIG4 Zornitza Stark Marked gene: FIG4 as ready
Mendeliome v1.1955 FIG4 Zornitza Stark Gene: fig4 has been classified as Green List (High Evidence).
Mendeliome v1.1955 FIG4 Zornitza Stark Classified gene: FIG4 as Green List (high evidence)
Mendeliome v1.1955 FIG4 Zornitza Stark Gene: fig4 has been classified as Green List (High Evidence).
Mendeliome v1.1954 FIG4 Zornitza Stark gene: FIG4 was added
gene: FIG4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIG4 were set to 23623387; 17572665; 21705420; 24878229; 18758830; 24598713
Phenotypes for gene: FIG4 were set to Yunis-Varon syndrome - MIM#216340; Polymicrogyria with epilepsy MIM# 612691; Charcot-Marie-Tooth disease, type 4J 611228; Amyotrophic lateral sclerosis 11, MIM# 612577
Review for gene: FIG4 was set to GREEN
Added comment: Associations between biallelic variants and CMT and Yunis Varon syndrome are well established.

Limited evidence for association with brain malformations and with ALS/FTD.
Sources: Expert Review
Mendeliome v1.1953 CSNK1G1 Rylee Peters reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33009664; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1953 REXO2 Zornitza Stark Marked gene: REXO2 as ready
Mendeliome v1.1953 REXO2 Zornitza Stark Gene: rexo2 has been classified as Amber List (Moderate Evidence).