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Mendeliome v1.1325 SAT1 Chirag Patel Classified gene: SAT1 as Green List (high evidence)
Mendeliome v1.1325 SAT1 Chirag Patel Gene: sat1 has been classified as Green List (High Evidence).
Mendeliome v1.1324 SAT1 Chirag Patel reviewed gene: SAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35977808; Phenotypes: Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v1.1324 GPR156 Zornitza Stark Phenotypes for gene: GPR156 were changed from Sensorineural hearing loss, MONDO:60700002, GPR156-related to Deafness, autosomal recessive 121, MIM# 620551
Mendeliome v1.1323 GPR156 Zornitza Stark reviewed gene: GPR156: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 121, MIM# 620551; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1323 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia to Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia; Neuronopathy, distal hereditary motor, autosomal recessive 10, MIM# 620542
Mendeliome v1.1322 VRK1 Zornitza Stark edited their review of gene: VRK1: Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia, Neuronopathy, distal hereditary motor, autosomal recessive 10, MIM# 620542
Mendeliome v1.1322 HAND2 Zornitza Stark Phenotypes for gene: HAND2 were changed from Congenital heart disease to Congenital heart disease, MONDO:0005453, HAND2-related
Mendeliome v1.1321 KDM5B Zornitza Stark Phenotypes for gene: KDM5B were changed from Mental retardation, autosomal recessive 65 MIM#618109; Intellectual disability and/or autism, autosomal dominant to Mental retardation, autosomal recessive 65 MIM#618109; Neurodevelopmental disorder (MONDO#0700092), KDM5B-related, autosomal dominant
Mendeliome v1.1320 KDM5B Lauren Rogers reviewed gene: KDM5B: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), KDM5B-related, Intellectual developmental disorder, autosomal recessive 65 (MIM#618109); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1320 PTPN4 Bryony Thompson Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Mendeliome v1.1319 PTPN4 Bryony Thompson edited their review of gene: PTPN4: Changed publications: 17953619, 25424712, 30238967, 34527963
Mendeliome v1.1319 PTPN4 Bryony Thompson changed review comment from: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature; to: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
PMID: 34527963 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Mendeliome v1.1319 ZFHX3 Zornitza Stark Deleted their comment
Mendeliome v1.1319 ZFHX3 Zornitza Stark Phenotypes for gene: ZFHX3 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related
Mendeliome v1.1318 ZFHX3 Zornitza Stark edited their review of gene: ZFHX3: Added comment: 41 individuals with protein truncating variants (PTVs) or (partial) deletions of ZFHX3. Presentations included (mild) ID and/or behavioural problems, postnatal growth retardation, feeding difficulties, dysmorphism (rarely cleft palate). Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation in neural stem cells and SH-SY5Y cells, ZFHX3 interacts with the chromatin remodelling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex. ZFHX3 haploinsufficiency associates with a specific DNA methylation profile in leukocyte-derived DNA, and participates in chromatin remodelling and mRNA processing.; Changed publications: 37292950; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related
Mendeliome v1.1318 SMG8 Zornitza Stark Publications for gene: SMG8 were set to PMID: 31130284
Mendeliome v1.1317 EPHA2 Zornitza Stark Publications for gene: EPHA2 were set to 19005574; 19649315; 19306328; 33671840
Mendeliome v1.1316 EPHA2 Zornitza Stark Phenotypes for gene: EPHA2 were changed from cataract 6 multiple types MONDO:0007288 to cataract 6 multiple types MONDO:0007288; microphthalmia, MONDO:0021129, EPHA2-related
Mendeliome v1.1315 EPHA2 Zornitza Stark Mode of inheritance for gene: EPHA2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1314 COG3 Zornitza Stark Phenotypes for gene: COG3 were changed from Neurodevelopmental disorder (MONDO#0700092), COG3-related to Congenital disorder of glycosylation, type IIbb, MIM# 620546
Mendeliome v1.1313 COG3 Zornitza Stark reviewed gene: COG3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IIbb, MIM# 620546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1313 ADAMTS15 Zornitza Stark Phenotypes for gene: ADAMTS15 were changed from Arthrogryposis (MONDO:0008779), ADMATS15-related to Arthrogryposis, distal, type 12, MIM# 620545
Mendeliome v1.1312 ADAMTS15 Zornitza Stark reviewed gene: ADAMTS15: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, distal, type 12, MIM# 620545; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1312 DNAJB2 Elena Savva Phenotypes for gene: DNAJB2 were changed from Spinal muscular atrophy, distal, autosomal recessive, 5, MIM# 614881; MONDO:0014866 to Neuronopathy, distal hereditary motor, autosomal recessive 5 (MIM#614881)
Mendeliome v1.1311 DNAJB2 Lauren Rogers reviewed gene: DNAJB2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 5 (MIM#614881); Mode of inheritance: None
Mendeliome v1.1311 EGF Zornitza Stark commented on gene: EGF: LIMITED by ClinGen.
Mendeliome v1.1311 EPHA2 Sarah Leigh reviewed gene: EPHA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33671840, 35918037; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1311 SMG8 Sarah Leigh reviewed gene: SMG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 34761517; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1311 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528 to Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528; Autosomal dominant spastic paraplegia-91, with or without cerebellar ataxia (SPG91), MIM#620538
Mendeliome v1.1310 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Changed phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477, Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related, Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528, Autosomal dominant spastic paraplegia-91, with or without cerebellar ataxia (SPG91), MIM#620538
Mendeliome v1.1310 COQ7 Zornitza Stark Phenotypes for gene: COQ7 were changed from Coenzyme Q10 deficiency, primary, 8 MIM#616733 to Coenzyme Q10 deficiency, primary, 8 MIM#616733; Neuronopathy, distal hereditary motor, autosomal recessive 9, MIM# 620402
Mendeliome v1.1309 COQ7 Zornitza Stark Publications for gene: COQ7 were set to 26084283; 31240163; 33215859; 28409910
Mendeliome v1.1308 COQ7 Zornitza Stark reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: 36758993, 36759155; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 9, MIM# 620402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1308 ZFHX3 Chirag Patel Classified gene: ZFHX3 as Green List (high evidence)
Mendeliome v1.1308 ZFHX3 Chirag Patel Gene: zfhx3 has been classified as Green List (High Evidence).
Mendeliome v1.1307 ZFHX3 Chirag Patel Classified gene: ZFHX3 as Green List (high evidence)
Mendeliome v1.1307 ZFHX3 Chirag Patel Gene: zfhx3 has been classified as Green List (High Evidence).
Mendeliome v1.1306 ZFHX3 Chirag Patel reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37292950; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1306 KDM2B Ain Roesley edited their review of gene: KDM2B: Changed phenotypes: neurodevelopmental disorder MONDO#0700092, KDM2B-related
Mendeliome v1.1306 KDM2B Ain Roesley Phenotypes for gene: KDM2B were changed from neurodevelopmental disorder MONDO#070009, KDM2B-related to neurodevelopmental disorder MONDO#0700092, KDM2B-related
Mendeliome v1.1305 FAM83G Zornitza Stark Phenotypes for gene: FAM83G were changed from Palmoplantar keratoderma, curly scalp hair and toenail dystrophy to Hereditary palmoplantar keratoderma, MONDO:0019272, FAM83G-related
Mendeliome v1.1304 FAM83G Zornitza Stark edited their review of gene: FAM83G: Changed phenotypes: Hereditary palmoplantar keratoderma, MONDO:0019272, FAM83G-related
Mendeliome v1.1304 FAAP24 Zornitza Stark Phenotypes for gene: FAAP24 were changed from EBV infection-driven lymphoproliferative disease to Immunodeficiency-associated lymphoproliferative disease, MONDO:0020083, FAAP24-related
Mendeliome v1.1303 FAAP24 Zornitza Stark edited their review of gene: FAAP24: Changed phenotypes: Immunodeficiency-associated lymphoproliferative disease, MONDO:0020083, FAAP24-related
Mendeliome v1.1303 IL23R Zornitza Stark Phenotypes for gene: IL23R were changed from Immunodeficiency disease, MONDO:0021094; Susceptibility to mycobacteria and Salmonella to Immunodeficiency disease, MONDO:0021094; Inherited susceptibility to mycobacterial disease, MONDO:0019146, IL23R-related
Mendeliome v1.1302 IL23R Zornitza Stark Publications for gene: IL23R were set to 30578351; 35829840
Mendeliome v1.1301 IL23R Zornitza Stark Classified gene: IL23R as Green List (high evidence)
Mendeliome v1.1301 IL23R Zornitza Stark Gene: il23r has been classified as Green List (High Evidence).
Mendeliome v1.1300 IL23R Zornitza Stark edited their review of gene: IL23R: Added comment: PMID 36763636: Six individuals from four unrelated Iranian kindreds with AR complete IL-23R deficiency presenting MSMD with complete penetrance. Also some patients with susceptibility to CMC with incomplete penetrance.; Changed rating: GREEN; Changed publications: 30578351, 35829840, 36763636; Changed phenotypes: Immunodeficiency disease, MONDO:0021094, Inherited susceptibility to mycobacterial disease, MONDO:0019146, IL23R-related
Mendeliome v1.1300 IRF1 Zornitza Stark Phenotypes for gene: IRF1 were changed from to Inherited susceptibility to mycobacterial disease, MONDO:0019146, IRF1-related
Mendeliome v1.1299 IRF1 Zornitza Stark Publications for gene: IRF1 were set to
Mendeliome v1.1298 IRF1 Zornitza Stark Mode of inheritance for gene: IRF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1297 IRF1 Zornitza Stark Classified gene: IRF1 as Green List (high evidence)
Mendeliome v1.1297 IRF1 Zornitza Stark Gene: irf1 has been classified as Green List (High Evidence).
Mendeliome v1.1296 IRF1 Zornitza Stark edited their review of gene: IRF1: Added comment: PMID 36736301: Two unrelated children with recurrent early-onset life-threatening mycobacterial diseases due to multiple mycobacteria (BCG, M. avium). Homozygous LoF vairiants with extensive supporting functional data.; Changed rating: GREEN; Changed publications: 36736301; Changed phenotypes: Inherited susceptibility to mycobacterial disease, MONDO:0019146, IRF1-related; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1296 IRF4 Zornitza Stark Phenotypes for gene: IRF4 were changed from Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724; Combined immunodeficiency to Combined immunodeficiency, MONDO:0015131, IRF4-related
Mendeliome v1.1295 IRF4 Zornitza Stark Publications for gene: IRF4 were set to 29537367; 29408330
Mendeliome v1.1294 IRF4 Zornitza Stark Classified gene: IRF4 as Green List (high evidence)
Mendeliome v1.1294 IRF4 Zornitza Stark Gene: irf4 has been classified as Green List (High Evidence).
Mendeliome v1.1293 IRF4 Zornitza Stark edited their review of gene: IRF4: Added comment: PMID 36662884: Seven individuals with profound CID from six kindreds of diverse ethnic origins (Fig. 1A). All affected individuals suffered with early onset (<1 year of age) recurrent sinopulmonary infections, with the opportunistic pathogen Pneumocystis jirovecii causing pneumonia in most individuals. p.T95R variant found in all patients. Extensive functional data including knockout mouse model. The heterozygous IRF4T95R variant found in multiple unrelated families caused a fully penetrant, severe very early-onset immunodeficiency characterized by greatly enhanced susceptibility to opportunistic pathogens such as P. jirovecii and weakly pathogenic mycobacteria.; Changed rating: GREEN; Changed publications: 29537367, 36662884; Changed phenotypes: Combined immunodeficiency, MONDO:0015131, IRF4-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1293 MCM9 Zornitza Stark Publications for gene: MCM9 were set to 25480036; 26771056; 33538981; 33095795
Mendeliome v1.1292 MCM9 Zornitza Stark Phenotypes for gene: MCM9 were changed from Ovarian dysgenesis 4, MIM# 616185 to Ovarian dysgenesis 4, MIM# 616185; Hereditary neoplastic syndrome MONDO:0015356
Mendeliome v1.1291 CR2 Zornitza Stark Publications for gene: CR2 were set to 22035880; 26325596
Mendeliome v1.1290 CR2 Zornitza Stark Classified gene: CR2 as Green List (high evidence)
Mendeliome v1.1290 CR2 Zornitza Stark Gene: cr2 has been classified as Green List (High Evidence).
Mendeliome v1.1289 CR2 Zornitza Stark edited their review of gene: CR2: Added comment: PMID:28499783 reported two siblings from consanguineous parents, both with a homozygous frameshift variant in CR2 and with recurrent respiratory infections and hypogammaglobulinaemia.; Changed rating: GREEN; Changed publications: 22035880, 26325596, 28499783
Mendeliome v1.1289 HMOX1 Zornitza Stark Publications for gene: HMOX1 were set to 21088618; 9884342; 20844238
Mendeliome v1.1288 HMOX1 Zornitza Stark Classified gene: HMOX1 as Green List (high evidence)
Mendeliome v1.1288 HMOX1 Zornitza Stark Gene: hmox1 has been classified as Green List (High Evidence).
Mendeliome v1.1287 HMOX1 Zornitza Stark edited their review of gene: HMOX1: Added comment: PMID:33066778 provides a third case in support of promoting HMOX1 to green rating. This third case is a boy born to nonconsanguineous parents who presented with early onset asplenia, recurrent infections, and associated flares with bone marrow histiocyte activation with worsening interstitial lung disease and joint pain. This boy harboured compound heterozygous variants (p.L89Sfs*24 and p.Ala88Profs*51).; Changed rating: GREEN; Changed publications: 21088618, 9884342, 20844238, 33066778
Mendeliome v1.1287 HYOU1 Zornitza Stark Classified gene: HYOU1 as Green List (high evidence)
Mendeliome v1.1287 HYOU1 Zornitza Stark Gene: hyou1 has been classified as Green List (High Evidence).
Mendeliome v1.1286 HYOU1 Zornitza Stark changed review comment from: PMID:35549617 reported another case with homozgyous variant (p.Arg486Cys) and anemia, thrombocytopenia and severe panleukopenia and immunodeficiency.; to: PMID:35549617 reported another case with homozgyous variant (p.Arg486Cys) and anaemia, thrombocytopenia and severe panleukopenia and immunodeficiency.
Mendeliome v1.1286 HYOU1 Zornitza Stark edited their review of gene: HYOU1: Added comment: PMID:35549617 reported another case with homozgyous variant (p.Arg486Cys) and anemia, thrombocytopenia and severe panleukopenia and immunodeficiency.; Changed rating: GREEN; Changed publications: 27913302, 35822684, 35549617
Mendeliome v1.1286 KCNH5 Zornitza Stark edited their review of gene: KCNH5: Changed phenotypes: Developmental and epileptic encephalopathy 112, MIM# 620537
Mendeliome v1.1286 KCNH5 Zornitza Stark reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 36307226; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1286 KCNH5 Zornitza Stark Phenotypes for gene: KCNH5 were changed from Neurodevelopmental disorder MONDO#0700092, KCNH5-related to Developmental and epileptic encephalopathy 112, MIM# 620537
Mendeliome v1.1285 ERLIN2 Zornitza Stark Phenotypes for gene: ERLIN2 were changed from hereditary spastic paraplegia 18 MONDO:0012639; Spastic paraplegia 18A, autosomal dominant, MIM# 620512 to Spastic paraplegia 18, autosomal recessive, MIM# 611225; Spastic paraplegia 18A, autosomal dominant, MIM# 620512
Mendeliome v1.1284 ERLIN2 Zornitza Stark edited their review of gene: ERLIN2: Changed phenotypes: Spastic paraplegia 18, autosomal recessive, MIM# 611225, Spastic paraplegia 18A, autosomal dominant, MIM# 620512; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1284 ERLIN2 Zornitza Stark Phenotypes for gene: ERLIN2 were changed from hereditary spastic paraplegia 18 MONDO:0012639 to hereditary spastic paraplegia 18 MONDO:0012639; Spastic paraplegia 18A, autosomal dominant, MIM# 620512
Mendeliome v1.1283 ERLIN2 Zornitza Stark reviewed gene: ERLIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 18A, autosomal dominant, MIM# 620512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1283 MCM9 Natalie Tan changed review comment from: Emerging association in individuals with biallelic variants of a combined phenotype of primary ovarian insufficiency and a Lynch-like syndrome/early-onset colorectal cancer (PMID: 26806154, 34556653). Monoallelic carriers have also been reported with a Lynch-like syndrome (32841224). Association of primary ovarian insufficiency with other malignancies is less clear (32613604, 34556653). See PMID 37378315 for review of literature to April 2023.; to: Emerging association in individuals with biallelic variants of a combined phenotype of primary ovarian insufficiency and a Lynch-like syndrome/early-onset colorectal cancer (PMID: 26806154, 34556653). Monoallelic carriers have also been reported with a Lynch-like syndrome (32841224). Association of primary ovarian insufficiency with other malignancies is less clear (32613604, 34556653). See PMID 37378315 for review of literature to April 2023.
Mendeliome v1.1283 MCM9 Natalie Tan reviewed gene: MCM9: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26806154, 34556653, 32841224, 32613604, 37378315); Phenotypes: Primary ovarian insufficiency, Lynch-like syndrome/colorectal cancer; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1283 U2AF2 Zornitza Stark Phenotypes for gene: U2AF2 were changed from Neurodevelopmental disorder MONDO:0700092, U2AF2-related to Developmental delay, dysmorphic facies, and brain anomalies, MIM# 620535
Mendeliome v1.1282 EYA3 Zornitza Stark Phenotypes for gene: EYA3 were changed from Oculo-auriculo-vertebral spectrum (OAVS) to Oculo-auriculo-vertebral spectrum (OAVS), MONDO:0015397, EYA3-related
Mendeliome v1.1281 ETS1 Zornitza Stark Phenotypes for gene: ETS1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ETS1-related
Mendeliome v1.1280 ETS1 Zornitza Stark edited their review of gene: ETS1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ETS1-related
Mendeliome v1.1280 ERBIN Zornitza Stark Phenotypes for gene: ERBIN were changed from Recurrent respiratory infections; Susceptibility to S.aureus; Eczema; Hyperextensible joints; Scoliosis; Arterial dilatation in some to Combined immunodeficiency, MONDO:0015131, ERBIN-related; Recurrent respiratory infections; Susceptibility to S.aureus; Eczema; Hyperextensible joints; Scoliosis; Arterial dilatation in some
Mendeliome v1.1279 ERBIN Zornitza Stark edited their review of gene: ERBIN: Changed phenotypes: Combined immunodeficiency, MONDO:0015131, ERBIN-related, Recurrent respiratory infections, Susceptibility to S.aureus, Eczema, Hyperextensible joints, Scoliosis, Arterial dilatation in some
Mendeliome v1.1279 EPHX1 Zornitza Stark Phenotypes for gene: EPHX1 were changed from Lipoatrophic diabetes to Hereditary lipodystrophy, MONDO:0020087, EPHX1-related
Mendeliome v1.1278 EPHX1 Zornitza Stark edited their review of gene: EPHX1: Changed phenotypes: Hereditary lipodystrophy, MONDO:0020087, EPHX1-related
Mendeliome v1.1278 EPHA7 Zornitza Stark Phenotypes for gene: EPHA7 were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092,EPHA7-related
Mendeliome v1.1277 EPHA7 Zornitza Stark edited their review of gene: EPHA7: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092,EPHA7-related
Mendeliome v1.1277 EOMES Zornitza Stark Phenotypes for gene: EOMES were changed from Microcephaly to Microcephaly, MONDO:0001149, EOMES-related
Mendeliome v1.1276 EOMES Zornitza Stark edited their review of gene: EOMES: Changed phenotypes: Microcephaly, MONDO:0001149, EOMES-related
Mendeliome v1.1276 ENO1 Zornitza Stark Phenotypes for gene: ENO1 were changed from Polymicrogyria to Polymicrogyria, MONDO:0000087, ENO1-related
Mendeliome v1.1275 ELMOD1 Zornitza Stark Phenotypes for gene: ELMOD1 were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092,ELMOD1-related
Mendeliome v1.1274 ELMOD1 Zornitza Stark edited their review of gene: ELMOD1: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092,ELMOD1-related
Mendeliome v1.1274 EIF4ENIF1 Zornitza Stark Phenotypes for gene: EIF4ENIF1 were changed from Primary ovarian insufficiency to Primary ovarian insufficiency, MONDO:0005387, EIF4ENIF1-related
Mendeliome v1.1273 EHBP1L1 Zornitza Stark Phenotypes for gene: EHBP1L1 were changed from Non-immune hydrops fetalis to Non-immune hydrops fetalis, MONDO:0015193, EHBP1l1-related
Mendeliome v1.1272 EEF1D Zornitza Stark Phenotypes for gene: EEF1D were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092, EEF1D-related
Mendeliome v1.1271 EEF1D Zornitza Stark edited their review of gene: EEF1D: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, EEF1D-related
Mendeliome v1.1271 DYNC1I1 Zornitza Stark Phenotypes for gene: DYNC1I1 were changed from Split-hand/split-foot malformation (SHFM) to Split-hand/split-foot malformation (SHFM) MONDO:0016576, DYNC1I1-related
Mendeliome v1.1270 DSCR3 Zornitza Stark Phenotypes for gene: DSCR3 were changed from Intellectual disability, no OMIM # yet to Neurodevelopmental disorder (MONDO:0700092), DSCR3-related
Mendeliome v1.1269 DSCR3 Zornitza Stark edited their review of gene: DSCR3: Changed phenotypes: Neurodevelopmental disorder (MONDO:0700092), DSCR3-related
Mendeliome v1.1269 STAT6 Zornitza Stark Phenotypes for gene: STAT6 were changed from Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies to Hyper-IgE syndrome 6, autosomal dominant, with atopy and allergies, MIM# 620532
Mendeliome v1.1268 STAT6 Zornitza Stark edited their review of gene: STAT6: Changed phenotypes: Hyper-IgE syndrome 6, autosomal dominant, with atopy and allergies, MIM# 620532
Mendeliome v1.1268 SRP68 Zornitza Stark Marked gene: SRP68 as ready
Mendeliome v1.1268 SRP68 Zornitza Stark Gene: srp68 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1268 SRP68 Zornitza Stark Classified gene: SRP68 as Amber List (moderate evidence)
Mendeliome v1.1268 SRP68 Zornitza Stark Gene: srp68 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1267 SRP68 Zornitza Stark gene: SRP68 was added
gene: SRP68 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SRP68 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP68 were set to 32273475
Phenotypes for gene: SRP68 were set to Neutropenia, severe congenital, 10, autosomal recessive, MIM# 620534
Review for gene: SRP68 was set to AMBER
Added comment: Single individual reported with bi-allelic LoF variants and presenting with infantile-onset severe neutropenia and recurrent infections. Multiple lines of functional evidence provided.
Sources: Expert list
Mendeliome v1.1266 PLS3 Zornitza Stark Phenotypes for gene: PLS3 were changed from Bone mineral density QTL18, osteoporosis - MIM#300910 to Bone mineral density QTL18, osteoporosis - MIM#300910; congenital diaphragmatic hernia MONDO:0005711, PLS3-related
Mendeliome v1.1265 PLS3 Zornitza Stark Publications for gene: PLS3 were set to 32655496; 25209159; 29736964; 29884797; 28777485; 24088043
Mendeliome v1.1264 PLS3 Zornitza Stark Mode of inheritance for gene: PLS3 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 v1.1263 PLS3 Zornitza Stark edited their review of gene: PLS3: Added comment: PMID 37751738: 8 unrelated families with affected males with an X-linked condition characterised by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. All were missense variants. A mouse knock in model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Gain-of-function is a suggested mechanism.; Changed publications: 32655496, 25209159, 29736964, 29884797, 28777485, 24088043, 37751738; Changed phenotypes: Bone mineral density QTL18, osteoporosis - MIM#300910, congenital diaphragmatic hernia MONDO:0005711, PLS3-related; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1263 EFCAB7 Zornitza Stark Marked gene: EFCAB7 as ready
Mendeliome v1.1263 EFCAB7 Zornitza Stark Gene: efcab7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1263 EFCAB7 Zornitza Stark Classified gene: EFCAB7 as Amber List (moderate evidence)
Mendeliome v1.1263 EFCAB7 Zornitza Stark Gene: efcab7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1262 MYCN Elena Savva Phenotypes for gene: MYCN were changed from Feingold syndrome 1; megalencephaly; ventriculomegaly; hypoplastic corpus callosum; intellectual disability; polydactyly; neuroblastoma to Neurodevelopmental disorder (MONDO:0700092), MYCN-related; Feingold syndrome 1 MIM#164280
Mendeliome v1.1261 CDC23 Zornitza Stark Marked gene: CDC23 as ready
Mendeliome v1.1261 CDC23 Zornitza Stark Gene: cdc23 has been classified as Green List (High Evidence).
Mendeliome v1.1261 MYCN Elena Savva Publications for gene: MYCN were set to 21224895; 8470948; 30573562
Mendeliome v1.1260 CDC23 Zornitza Stark Classified gene: CDC23 as Green List (high evidence)
Mendeliome v1.1260 CDC23 Zornitza Stark Gene: cdc23 has been classified as Green List (High Evidence).
Mendeliome v1.1259 CFAP20 Ain Roesley Marked gene: CFAP20 as ready
Mendeliome v1.1259 CFAP20 Ain Roesley Gene: cfap20 has been classified as Green List (High Evidence).
Mendeliome v1.1259 CFAP20 Ain Roesley Phenotypes for gene: CFAP20 were changed from Retinitis pigmentosa (MONDO:0019200) to Retinitis pigmentosa (MONDO:0019200), CFAP20-related
Mendeliome v1.1258 CFAP20 Ain Roesley Classified gene: CFAP20 as Green List (high evidence)
Mendeliome v1.1258 CFAP20 Ain Roesley Gene: cfap20 has been classified as Green List (High Evidence).
Mendeliome v1.1257 COG3 Elena Savva Classified gene: COG3 as Amber List (moderate evidence)
Mendeliome v1.1257 COG3 Elena Savva Gene: cog3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1256 COG3 Elena Savva Classified gene: COG3 as Amber List (moderate evidence)
Mendeliome v1.1256 COG3 Elena Savva Gene: cog3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1255 COG3 Elena Savva Marked gene: COG3 as ready
Mendeliome v1.1255 COG3 Elena Savva Gene: cog3 has been removed from the panel.
Mendeliome v1.1255 EFCAB7 Melanie Marty gene: EFCAB7 was added
gene: EFCAB7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EFCAB7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB7 were set to PMID: 37684519
Phenotypes for gene: EFCAB7 were set to Polydactyly (MONDO:0021003), EFCAB7-related
Review for gene: EFCAB7 was set to AMBER
Added comment: PMID: 37684519: two homozygous frameshift variants were identified by exome sequencing in four consanguinous Pakistani families, 3 families with p.(Gly277Valfs*5) and 1 family with p.(Asn451Phefs*2). Variants segregated with disease and het carriers were unaffected. Counting as 2 families to be conservative.
Sources: Literature
Mendeliome v1.1254 CFAP20 Sarah Pantaleo gene: CFAP20 was added
gene: CFAP20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP20 were set to PMID:36329026
Phenotypes for gene: CFAP20 were set to Retinitis pigmentosa (MONDO:0019200)
Review for gene: CFAP20 was set to GREEN
Added comment: CFAP20 is a ciliopathy candidate. Demonstrate in zebrafish that cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development.

Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy (retinitis pigments). Hence, CFAP20 functions within a structural./functional hub centred on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associaetd domains or macromolecular complexes.

Describe 8 individuals from 4 independent families with damaging biallelic variants (homozygous or compound heterozygous) in CFAP20 that segregate with retinal dystrophy. All variants cluster to one side of the protein, with two of the residues directly contacting alpha-tubullin.

Family 1 - consanguineous set of 3 siblings from Sudan, homozygous for CFAP20 c.305G>A; p.Arg102His (they also had a homozygous variant in DYNC1LI2 however CFAP20 was considered the better candidate.
Family 2 - 3 siblings from Spain, 2 with retinal dystrophy, 1 genetically tested and has c.337C>T; p.(Arg113Trp) and c.397delC; p.(Gln133Serfs*5)
Family 3 - single affected family member compound het for c.164+1G>A and c.457A>G; p.(Arg153Gly).
Family 4 - 3 affected siblings with generalised retinopathy and variable neurological deficits with c.164+1G>A and c.257G>A; p.(Tyr86Cys)

For all families, no individuals had signs of polycystic kidney disease; however, not all individuals had kidney imaging. Visual defecit phenotype presented between adolescence and adulthood (17-56 years old).

Used HEK293T cell expression studies to demonstrate a statistically significant decline of mutated CFAP20 protein levels (with the exception of p.Arg102His). To test the specific variants, they used the C.elegans orthologues.
Sources: Literature
Mendeliome v1.1255 GPRASP1 Elena Savva Classified gene: GPRASP1 as Amber List (moderate evidence)
Mendeliome v1.1255 GPRASP1 Elena Savva Gene: gprasp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1254 GPRASP1 Elena Savva Classified gene: GPRASP1 as Amber List (moderate evidence)
Mendeliome v1.1254 GPRASP1 Elena Savva Gene: gprasp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1253 GPRASP1 Elena Savva Classified gene: GPRASP1 as Amber List (moderate evidence)
Mendeliome v1.1253 GPRASP1 Elena Savva Gene: gprasp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1252 GPRASP1 Elena Savva Marked gene: GPRASP1 as ready
Mendeliome v1.1252 GPRASP1 Elena Savva Gene: gprasp1 has been removed from the panel.
Mendeliome v1.1252 MYCN Naomi Baker reviewed gene: MYCN: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:37710961; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), MYCN-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1252 MAST4 Ain Roesley Marked gene: MAST4 as ready
Mendeliome v1.1252 MAST4 Ain Roesley Gene: mast4 has been classified as Green List (High Evidence).
Mendeliome v1.1252 MAST4 Ain Roesley Classified gene: MAST4 as Green List (high evidence)
Mendeliome v1.1252 MAST4 Ain Roesley Gene: mast4 has been classified as Green List (High Evidence).
Mendeliome v1.1251 CDC23 Michelle Torres gene: CDC23 was added
gene: CDC23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC23 were set to 37768355
Phenotypes for gene: CDC23 were set to inherited oocyte maturation defect MONDO#0014769, CDC23-related
Review for gene: CDC23 was set to GREEN
Added comment: Two missense variants, p.(Y329C) and p.(R330C), detected in three unrelated homozygous infertile females characterised by oocyte maturation defects.

In vitro studies using HeLa cells showed either decreased protein levels (Y329C) or impaired localisation (R330C). In vivo studies in mice homozygous for Y329C reproduced patient’s phenotype.
Sources: Literature
Mendeliome v1.1251 GPRASP1 Paul De Fazio gene: GPRASP1 was added
gene: GPRASP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPRASP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GPRASP1 were set to 37787182
Phenotypes for gene: GPRASP1 were set to Arteriovenous hemangioma/malformation, GPRASP1-related, MONDO:0001256
Penetrance for gene: GPRASP1 were set to unknown
Review for gene: GPRASP1 was set to AMBER
gene: GPRASP1 was marked as current diagnostic
Added comment: Two hemizygous germline missense variants, p.Arg1167Trp and p.Trp553Cys, were identified in three male patients presenting with spinal AVM, Cobb syndrome, or scalp AVM. The variants were inherited from unaffected heterozygous mothers. Note that p.Arg1167Trp has hemizygous (>70) and homozygous individuals reported in gnomAD.

The variants were found to result in LoF in endothelial cells. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral hemorrhage, AVMs, and exhibited vascular anomalies in multiple organs.
Sources: Literature
Mendeliome v1.1251 COG3 Daniel Flanagan gene: COG3 was added
gene: COG3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to PMID: 37711075
Phenotypes for gene: COG3 were set to Neurodevelopmental disorder (MONDO#0700092), COG3-related
Review for gene: COG3 was set to AMBER
Added comment: Two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings.
Sources: Expert list
Mendeliome v1.1251 ATP2B2 Zornitza Stark Phenotypes for gene: ATP2B2 were changed from Deafness, autosomal dominant 82, MIM# 619804; {Deafness, autosomal recessive 12, modifier of}, MIM# 601386 to Deafness, autosomal dominant 82, MIM# 619804; Neurodevelopmental Disorder, MONDO:0700092, ATP2B2-related
Mendeliome v1.1250 ATP2B2 Zornitza Stark Publications for gene: ATP2B2 were set to 30535804; 15829536
Mendeliome v1.1249 MAST4 Ain Roesley gene: MAST4 was added
gene: MAST4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST4 were set to 36910266; 33057194
Phenotypes for gene: MAST4 were set to neurodevelopmental disorder MONDO:0700092, MAST4-related
Penetrance for gene: MAST4 were set to Complete
Review for gene: MAST4 was set to GREEN
gene: MAST4 was marked as current diagnostic
Added comment: PMID: 36910266 - 4 families with 4 affecteds, all de novo missense

2x borderline microcephaly (-2SD)
2x gross motor delay
2x dysmorphism
4x ID + seizures
3x abnormal brain MRI findings

PMID: 33057194 - 5x de novos, 4x missense + 1x PTC
Cohort of individuals with severe developmental disorder
individual phenotypic information not provided


Recurrent variants are Thr1471Ile (3x) and Ser1181Phe)
Sources: Literature
Mendeliome v1.1248 ZBTB47 Elena Savva Marked gene: ZBTB47 as ready
Mendeliome v1.1248 ZBTB47 Elena Savva Gene: zbtb47 has been classified as Green List (High Evidence).
Mendeliome v1.1248 ZBTB47 Elena Savva Classified gene: ZBTB47 as Green List (high evidence)
Mendeliome v1.1248 ZBTB47 Elena Savva Gene: zbtb47 has been classified as Green List (High Evidence).
Mendeliome v1.1247 ZBTB47 Elena Savva gene: ZBTB47 was added
gene: ZBTB47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZBTB47 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB47 were set to 37743782
Phenotypes for gene: ZBTB47 were set to Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related
Review for gene: ZBTB47 was set to GREEN
Added comment: PMID 37743782:
- 5 patients with de novo missense, 4/5 have a recurring p.Gly477Lys. Probands have intellectual disability (5/5), seizures (5/5), hypotonia (5/5), gait abnormalities, and variable movement abnormalities (5/5).
- Missense variants are positioned close to His and Cys residues involved in forming C2H2 zinc fingers.
- No functional studies performed
- Minimal PTCs in gnomAD
Sources: Literature
Mendeliome v1.1246 KIF4A Zornitza Stark Phenotypes for gene: KIF4A were changed from Mental retardation, X-linked 100, MIM# 300923 to Mental retardation, X-linked 100, MIM# 300923; Taurodontism, microdontia, and dens invaginatus (MIM#313490)
Mendeliome v1.1245 ATP2B2 Andrew Fennell reviewed gene: ATP2B2: 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: 37675773; Phenotypes: Neurodevelopmental Disorder, MONDO:0700092, ATP2B2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1245 KIF4A Lucy Spencer reviewed gene: KIF4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31616463; Phenotypes: Taurodontism, microdontia, and dens invaginatus (MIM#313490); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1245 ATRX Zornitza Stark Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome, MIM# 301040; Intellectual disability-hypotonic facies syndrome, X-linked, MIM# 309580 to ATR-X-related syndrome MONDO:0016980
Mendeliome v1.1244 DLG5 Zornitza Stark Phenotypes for gene: DLG5 were changed from Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations to Ciliopathy, MONDO:0016044, DLG5-related; Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations
Mendeliome v1.1243 DHX32 Zornitza Stark Phenotypes for gene: DHX32 were changed from Intellectual disability, spastic diplegia, dystonia, brain abnormalities to Neurodevelopmental disorder, MONDO:0700092, DHX32-related
Mendeliome v1.1242 DGAT2 Zornitza Stark Phenotypes for gene: DGAT2 were changed from axonal Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease, MONDO:0015626, DGAT2-related
Mendeliome v1.1241 DDX54 Zornitza Stark Phenotypes for gene: DDX54 were changed from Intellectual disability; congenital anomalies to Neurodevelopmental disorder, MONDO:0700092, DDX54-related
Mendeliome v1.1240 DDX54 Zornitza Stark edited their review of gene: DDX54: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, DDX54-related
Mendeliome v1.1240 DDX23 Zornitza Stark Phenotypes for gene: DDX23 were changed from DDX23-associated neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, DDX23-related
Mendeliome v1.1239 DDX23 Zornitza Stark edited their review of gene: DDX23: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, DDX23-related
Mendeliome v1.1239 CSNK1G1 Zornitza Stark Phenotypes for gene: CSNK1G1 were changed from Global developmental delay; Intellectual disability; Autism; Seizures to Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related
Mendeliome v1.1238 CSNK1G1 Zornitza Stark edited their review of gene: CSNK1G1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related
Mendeliome v1.1238 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; hereditary motor neuropathy to Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528
Mendeliome v1.1237 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Changed phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477, Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related, Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528
Mendeliome v1.1237 DAZL Zornitza Stark Phenotypes for gene: DAZL were changed from Primary ovarian insufficiency to Primary ovarian failure, MONDO:0005387, DAZL-related
Mendeliome v1.1236 DACH2 Zornitza Stark Phenotypes for gene: DACH2 were changed from Primary ovarian insufficiency to Primary ovarian failure, MONDO:0005387, DACH2-related
Mendeliome v1.1235 CYBRD1 Zornitza Stark Phenotypes for gene: CYBRD1 were changed from Iron overload to Iron metabolism disease, MONDO:0002279, CYBRD1-related
Mendeliome v1.1234 CYBRD1 Zornitza Stark edited their review of gene: CYBRD1: Changed phenotypes: Iron metabolism disease, MONDO:0002279, CYBRD1-related
Mendeliome v1.1234 CTNND2 Zornitza Stark Phenotypes for gene: CTNND2 were changed from Intellectual disability; Autism; Epilepsy to Neurodevelopmental disorder, MONDO:0700092, CTNND2-related
Mendeliome v1.1233 CTNNBL1 Zornitza Stark Phenotypes for gene: CTNNBL1 were changed from Primary Immunodeficiency; Autoimmune Cytopenias; Common variable immunodeficiency to Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, MIM# 619846
Mendeliome v1.1232 CTNNBL1 Zornitza Stark edited their review of gene: CTNNBL1: Changed phenotypes: Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, MIM# 619846
Mendeliome v1.1232 CSNK1E Zornitza Stark Phenotypes for gene: CSNK1E were changed from Epileptic encephalopathy to Developmental and epileptic encephalopathy, MONDO:0100062, CSNK1E-related
Mendeliome v1.1231 CSGALNACT1 Zornitza Stark Phenotypes for gene: CSGALNACT1 were changed from Congenital disorders of glycosylation; skeletal dysplasia; advanced bone age to Skeletal dysplasia, mild, with joint laxity and advanced bone age, MIM# 618870
Mendeliome v1.1230 CSGALNACT1 Zornitza Stark edited their review of gene: CSGALNACT1: Changed phenotypes: Skeletal dysplasia, mild, with joint laxity and advanced bone age, MIM# 618870
Mendeliome v1.1230 CSDE1 Zornitza Stark Phenotypes for gene: CSDE1 were changed from Autism; intellectual disability; seizures; macrocephaly to Neurodevelopmental disorder, MONDO:0700092, CSDE1-related
Mendeliome v1.1229 CSDE1 Zornitza Stark edited their review of gene: CSDE1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSDE1-related
Mendeliome v1.1229 CASP4 Zornitza Stark Marked gene: CASP4 as ready
Mendeliome v1.1229 CASP4 Zornitza Stark Gene: casp4 has been classified as Red List (Low Evidence).
Mendeliome v1.1229 CASP4 Zornitza Stark gene: CASP4 was added
gene: CASP4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CASP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CASP4 were set to 37647624
Phenotypes for gene: CASP4 were set to Hereditary susceptibility to infection, MONDO:0015979, CASP4-related; Susceptibility to meliodiosis
Review for gene: CASP4 was set to RED
Added comment: Single patient with severe disease secondary to B. pseudomallei requiring ECMO. Adjunctive IFN-γ administration as replacement for its failed induction by IL-18 promptly led to clearance of B. pseudomallei and subsequent weaning of support. Novel homozygous missense mutation in CASP4, at exon 7 c.1030C > T. Peripheral blood mononuclear cells (PBMC) of the patient and her parents showed reduced IFN-γ production, notably to IL-12 stimulation, and decreased IL-18 in response to LPS and increased IL-1B. Cloned cells show impacts on CASP4 activation and pyroptosis.
Sources: Expert Review
Mendeliome v1.1228 IL36RN Zornitza Stark Phenotypes for gene: IL36RN were changed from Psoriasis 14, pustular, MIM# 614204 to Psoriasis 14, pustular, MIM# 614204; Autoinflammatory syndrome, MONDO:0019751, IL36RN-related
Mendeliome v1.1227 IL36RN Zornitza Stark Mode of inheritance for gene: IL36RN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1226 IL36RN Zornitza Stark edited their review of gene: IL36RN: Added comment: Monoallelic disease: Multiple patients with systemic inflammation with monoallelic variants in IL36RN suggesting a gene dosage effect whereby GPP onset is significantly delayed in subjects with monoallelic mutations but still at high risk of systemic inflammation.; Changed publications: 21848462, 21839423, 22903787, 23648549, 25458002; Changed phenotypes: Psoriasis 14, pustular, MIM# 614204, Autoinflammatory syndrome, MONDO:0019751, IL36RN-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1226 SNAPC4 Zornitza Stark Phenotypes for gene: SNAPC4 were changed from Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related to Neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction, MIM# 620515
Mendeliome v1.1225 PLCG1 Zornitza Stark Phenotypes for gene: PLCG1 were changed from Autoinflammatory syndrome, MONDO:0019751, PLCG1-related; Immune dysregulation to Immune dysregulation, autoimmunity, and autoinflammation, MIM# 620514
Mendeliome v1.1224 PLCG1 Zornitza Stark edited their review of gene: PLCG1: Changed phenotypes: Immune dysregulation, autoimmunity, and autoinflammation, MIM# 620514
Mendeliome v1.1224 CPEB1 Zornitza Stark Phenotypes for gene: CPEB1 were changed from Primary ovarian insufficiency to Primary ovarian insufficiency, MONDO:0005387, CPEB1-related
Mendeliome v1.1223 CPA1 Zornitza Stark Phenotypes for gene: CPA1 were changed from Susceptibility to chronic pancreatitis; Hereditary pancreatitis to Hereditary pancreatitis, MONDO:0008185, CPA1-related
Mendeliome v1.1222 CPA1 Zornitza Stark edited their review of gene: CPA1: Changed phenotypes: Hereditary pancreatitis, MONDO:0008185, CPA1-related
Mendeliome v1.1222 CNTN6 Zornitza Stark Phenotypes for gene: CNTN6 were changed from Intellectual disability; autism; Tourette syndrome; schizophrenia to Neurodevelopmental disorder, MONDO:0700092, CNTN6-related
Mendeliome v1.1221 CNTN6 Zornitza Stark edited their review of gene: CNTN6: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CNTN6-related
Mendeliome v1.1221 CNTN3 Zornitza Stark Phenotypes for gene: CNTN3 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, CNTN3-related
Mendeliome v1.1220 CNTN2 Zornitza Stark Phenotypes for gene: CNTN2 were changed from Epilepsy to Epilepsy, MONDO:0015653, CNTN2-related
Mendeliome v1.1219 CNKSR1 Zornitza Stark Phenotypes for gene: CNKSR1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, CNKSR1-related
Mendeliome v1.1218 CMAS Zornitza Stark Phenotypes for gene: CMAS were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, CMAS-related
Mendeliome v1.1217 CHST8 Zornitza Stark Phenotypes for gene: CHST8 were changed from Peeling skin syndrome to Peeling skin syndrome, MONDO:0019347, CHST8-realted
Mendeliome v1.1216 NCKAP1 Ain Roesley Phenotypes for gene: NCKAP1 were changed from Intellectual disability; autism to Neurodevelopmental disorder (MONDO#0700092)​​​​​​​, NCKAP1-related
Mendeliome v1.1215 PPP1R13L Zornitza Stark Phenotypes for gene: PPP1R13L were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related; Dilated cardiomyopathy, onset in infancy to Arrhythmogenic cardiomyopathy with or without ectodermal abnormalities, MIM#620519
Mendeliome v1.1214 PPP1R13L Zornitza Stark edited their review of gene: PPP1R13L: Changed phenotypes: Arrhythmogenic cardiomyopathy with or without ectodermal abnormalities, MIM#620519
Mendeliome v1.1214 DEPDC5 Zornitza Stark Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, MIM#604364 to Epilepsy, familial focal, with variable foci 1, MIM#604364; Developmental and epileptic encephalopathy 111, MIM# 620504
Mendeliome v1.1213 CELA3B Zornitza Stark Phenotypes for gene: CELA3B were changed from Chronic pancreatitis to Chronic pancreatitis, MONDO:0008185, CELA3B-related
Mendeliome v1.1212 CDK5R1 Zornitza Stark Phenotypes for gene: CDK5R1 were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, CDK5R1-related
Mendeliome v1.1211 CDK5R1 Zornitza Stark edited their review of gene: CDK5R1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CDK5R1-related
Mendeliome v1.1211 ASTN2 Zornitza Stark Phenotypes for gene: ASTN2 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ASTN2-related
Mendeliome v1.1210 ASTN2 Zornitza Stark Publications for gene: ASTN2 were set to 28940097
Mendeliome v1.1209 CBY1 Zornitza Stark Phenotypes for gene: CBY1 were changed from intellectual disability; cerebellar ataxia; molar tooth sign; polydactyly; Joubert syndrome to Joubert syndrome, MONDO:0018772, CBY1-related
Mendeliome v1.1208 CAPZA2 Zornitza Stark Phenotypes for gene: CAPZA2 were changed from intellectual disability to Neurodevelopmental disorder, MONDO:0700092, CAPZA2-related
Mendeliome v1.1207 CACNB1 Zornitza Stark Phenotypes for gene: CACNB1 were changed from Malignant hyperthermia susceptibility to Malignant hyperthermia susceptibility, MONDO:0800188, CACNB1-related
Mendeliome v1.1206 CACNB1 Zornitza Stark edited their review of gene: CACNB1: Changed rating: RED; Changed phenotypes: Malignant hyperthermia susceptibility, MONDO:0800188, CACNB1-related
Mendeliome v1.1206 C1orf194 Zornitza Stark Phenotypes for gene: C1orf194 were changed from Charcot-Marie-Tooth disease, intermediate or demyelinating to Charcot-Marie-Tooth disease, intermediate or demyelinating, MONDO:0015626, C1orf194-related
Mendeliome v1.1205 C1orf194 Zornitza Stark edited their review of gene: C1orf194: Changed rating: AMBER; Changed phenotypes: Charcot-Marie-Tooth disease, intermediate or demyelinating, MONDO:0015626, C1orf194; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1205 BLOC1S1 Zornitza Stark Phenotypes for gene: BLOC1S1 were changed from severe intellectual disability; severe global developmental delay; epilepsy to Neurodevelopmental disorder, MONDO:0700092, BLOC1S1-related
Mendeliome v1.1204 BLOC1S1 Zornitza Stark edited their review of gene: BLOC1S1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BLOC1S1-related
Mendeliome v1.1204 BET1 Zornitza Stark Phenotypes for gene: BET1 were changed from Muscular dystrophy; Epilepsy to Muscular dystrophy, MONDO:0019950, BET1-related; Epilepsy
Mendeliome v1.1203 BCL9L Zornitza Stark Phenotypes for gene: BCL9L were changed from Heterotaxy; Congenital Heart Disease to Heterotaxy syndrome, MONDO:0018677, BCL9L-related
Mendeliome v1.1202 BCL9L Zornitza Stark edited their review of gene: BCL9L: Changed phenotypes: Heterotaxy syndrome, MONDO:0018677, BCL9L
Mendeliome v1.1202 B3GNT2 Zornitza Stark Phenotypes for gene: B3GNT2 were changed from Muscular dystrophy-dystroglycanopathy to Muscular dystrophy-dystroglycanopathy, MONDO:0018276, B3GNT2-related
Mendeliome v1.1201 B3GNT2 Zornitza Stark edited their review of gene: B3GNT2: Changed phenotypes: Muscular dystrophy-dystroglycanopathy, MONDO:0018276, B3GNT2-related
Mendeliome v1.1201 AXL Zornitza Stark Phenotypes for gene: AXL were changed from Kallman syndrome; normosmic idiopathic hypogonadotropic hypogonadism to Kallman syndrome, MONDO:0018800, AXL-related; normosmic idiopathic hypogonadotropic hypogonadism
Mendeliome v1.1200 ATXN2L Zornitza Stark Phenotypes for gene: ATXN2L were changed from macrocephaly; intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ATXN2L-related
Mendeliome v1.1199 ATRIP Zornitza Stark Phenotypes for gene: ATRIP were changed from Seckel Syndrome to Seckel Syndrome, MONDO:0019342, ATRIP-related
Mendeliome v1.1198 ATP2B4 Zornitza Stark Phenotypes for gene: ATP2B4 were changed from Hereditary spastic paraplegia to Hereditary spastic paraplegia, MONDO:0019064, ATP2B4-related
Mendeliome v1.1197 ASTN2 Zornitza Stark Mode of inheritance for gene: ASTN2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Changed publications: 28940097, 34412080, 27138430
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Added comment: Rare CNVs also reported.; Changed publications: 28940097, 34412080
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ASTN2-related
Mendeliome v1.1196 ASTN1 Zornitza Stark Phenotypes for gene: ASTN1 were changed from Polymicrogyria; hypoplastic corpus callosum to Cerebral malformation, MONDO:0016054, ASTN1-related
Mendeliome v1.1195 ASTN1 Zornitza Stark edited their review of gene: ASTN1: Changed phenotypes: Cerebral malformation, MONDO:0016054, ASTN1-related
Mendeliome v1.1195 ARIH1 Zornitza Stark Phenotypes for gene: ARIH1 were changed from Thoracic aortic aneurysm to Thoracic aortic aneurysm, MONDO:0005396, ARIH1-related
Mendeliome v1.1194 ARHGAP29 Zornitza Stark Phenotypes for gene: ARHGAP29 were changed from Cleft palate; cleft lip with or without cleft palate to Clefting disorder, MONDO:0000358, ARHGAP29-related
Mendeliome v1.1193 ARHGAP29 Zornitza Stark edited their review of gene: ARHGAP29: Changed phenotypes: Clefting disorder, MONDO:0000358, ARHGAP29-related
Mendeliome v1.1193 ARHGAP24 Zornitza Stark Phenotypes for gene: ARHGAP24 were changed from FSGS to FSGS, MONDO:0005363, ARHGAP24-related
Mendeliome v1.1192 ARHGAP24 Zornitza Stark edited their review of gene: ARHGAP24: Changed phenotypes: FSGS, MONDO:0005363, ARHGAP24-related
Mendeliome v1.1192 ARFGEF3 Zornitza Stark Phenotypes for gene: ARFGEF3 were changed from Dystonia to Dystonia, MONDO:0044807, ARFGEF3-related
Mendeliome v1.1191 ARF3 Zornitza Stark Phenotypes for gene: ARF3 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Neurodevelopmental disorder, MONDO:0700092, ARF3-related
Mendeliome v1.1190 ARAP3 Zornitza Stark Phenotypes for gene: ARAP3 were changed from Lymphoedema to Lymphoedema, MONDO:0019297, ARAP3-related
Mendeliome v1.1189 ARAP3 Zornitza Stark edited their review of gene: ARAP3: Changed phenotypes: Lymphoedema, MONDO:0019297, ARAP3-related
Mendeliome v1.1189 MCCC1 Bryony Thompson Publications for gene: MCCC1 were set to 27604308; 11170888; 31730530
Mendeliome v1.1188 MCCC1 Bryony Thompson reviewed gene: MCCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36822454, 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1188 MCCC1 Bryony Thompson Deleted their review
Mendeliome v1.1188 AP1B1 Zornitza Stark Phenotypes for gene: AP1B1 were changed from Intellectual disability; enteropathy; deafness; ichthyosis; keratoderma to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, MIM# 242150
Mendeliome v1.1187 AP1B1 Zornitza Stark edited their review of gene: AP1B1: Changed phenotypes: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, MIM# 242150
Mendeliome v1.1187 ANKZF1 Zornitza Stark Phenotypes for gene: ANKZF1 were changed from Infantile-onset inflammatory bowel disease to Infantile-onset inflammatory bowel disease, MONDO:0005265, ANKZF1-related
Mendeliome v1.1186 ANKRD31 Zornitza Stark Phenotypes for gene: ANKRD31 were changed from Premature ovarian failure to Premature ovarian failure, MONDO:0019852, ANKRD31-related
Mendeliome v1.1185 AMBRA1 Zornitza Stark Phenotypes for gene: AMBRA1 were changed from Neural tube defects to Neural tube defects, susceptibility to, MONDO:0020705, AMBRA1-related
Mendeliome v1.1184 ALPI Zornitza Stark Phenotypes for gene: ALPI were changed from Inflammatory bowel disease to Inflammatory bowel disease, MONDO:0005265, ALPI-related
Mendeliome v1.1183 ALPI Zornitza Stark edited their review of gene: ALPI: Changed phenotypes: Inflammatory bowel disease, MONDO:0005265, ALPI-related
Mendeliome v1.1183 ALG10 Zornitza Stark Phenotypes for gene: ALG10 were changed from Progressive myoclonus epilepsy; CDG to Congenital disorder of glycosylation, MONDO:0015286, ALG10-related
Mendeliome v1.1182 ALG10 Zornitza Stark edited their review of gene: ALG10: Changed phenotypes: Congenital disorder of glycosylation, MONDO:0015286, ALG10-related
Mendeliome v1.1182 AKR1E2 Zornitza Stark Phenotypes for gene: AKR1E2 were changed from congenital cataracts to Cataract, MONDO:0005129, AKR1E2-related
Mendeliome v1.1181 AKR1E2 Zornitza Stark edited their review of gene: AKR1E2: Changed phenotypes: Cataract, MONDO:0005129, AKR1E2-related
Mendeliome v1.1181 AKNA Zornitza Stark Phenotypes for gene: AKNA were changed from Primary ciliary dyskinesia to Primary ciliary dyskinesia, MONDO:0016575, AKNA-related
Mendeliome v1.1180 AKNA Zornitza Stark reviewed gene: AKNA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, AKNA-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1180 AKAP6 Zornitza Stark Phenotypes for gene: AKAP6 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, AKAP6-related
Mendeliome v1.1179 AKAP6 Zornitza Stark edited their review of gene: AKAP6: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, AKAP6-related
Mendeliome v1.1179 AGO3 Zornitza Stark Phenotypes for gene: AGO3 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, AGO3-related
Mendeliome v1.1178 AGMO Zornitza Stark Phenotypes for gene: AGMO were changed from microcephaly; intellectual disability; epilepsy to Neurodevelopmental disorder, MONDO:0700092, AGMO-related
Mendeliome v1.1177 AGMO Zornitza Stark reviewed gene: AGMO: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, AGMO-related; Mode of inheritance: None
Mendeliome v1.1177 ACTL6A Zornitza Stark Phenotypes for gene: ACTL6A were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ACTL6A-related
Mendeliome v1.1176 ACTL6A Zornitza Stark edited their review of gene: ACTL6A: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ACTL6A-related
Mendeliome v1.1176 ACER3 Zornitza Stark Classified gene: ACER3 as Green List (high evidence)
Mendeliome v1.1176 ACER3 Zornitza Stark Gene: acer3 has been classified as Green List (High Evidence).
Mendeliome v1.1175 ACADL Zornitza Stark Phenotypes for gene: ACADL were changed from Pulmonary surfactant dysfunction to Hereditary pulmonary alveoral proteinosis, MONDO:0012580, ACADL-related
Mendeliome v1.1174 ACADL Zornitza Stark edited their review of gene: ACADL: Changed phenotypes: Hereditary pulmonary alveoral proteinosis, MONDO:0012580, ACADL-related
Mendeliome v1.1174 SEMA3E Zornitza Stark Publications for gene: SEMA3E were set to 15235037; 31691538; 31464029
Mendeliome v1.1173 SEMA3E Lucy Spencer reviewed gene: SEMA3E: Rating: AMBER; Mode of pathogenicity: None; Publications: 15235037, 31691538, 31464029, 35628442, 32441320; Phenotypes: CHARGE syndrome MONDO:0008965, SEMA3E-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1173 SCAF4 Zornitza Stark Phenotypes for gene: SCAF4 were changed from Mild intellectual disability; seizures; behavioral abnormalities to Fliedner-Zweier syndrome, MIM#620511
Mendeliome v1.1172 SCAF4 Zornitza Stark reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fliedner-Zweier syndrome, MIM#620511; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1172 NR2F2 Zornitza Stark Phenotypes for gene: NR2F2 were changed from 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 to 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
Mendeliome v1.1171 NR2F2 Zornitza Stark Publications for gene: NR2F2 were set to 24702954; 29478779; 31687637; 27363585; 29222010; 29663647
Mendeliome v1.1170 NR2F2 Zornitza Stark reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37500725; Phenotypes: Syndromic disease, MONDO:0002254, NR2F2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1170 DBR1 Zornitza Stark Phenotypes for gene: DBR1 were changed from {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem; Ichthyosis (MONDO#0019269), DBR1-related to {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem; Xerosis and growth failure with immune and pulmonary dysfunction syndrome, MIM# 620510
Mendeliome v1.1169 TRAC Zornitza Stark Tag technically challenging tag was added to gene: TRAC.
Mendeliome v1.1169 KLK11 Zornitza Stark Marked gene: KLK11 as ready
Mendeliome v1.1169 KLK11 Zornitza Stark Gene: klk11 has been classified as Green List (High Evidence).
Mendeliome v1.1169 KLK11 Zornitza Stark Classified gene: KLK11 as Green List (high evidence)
Mendeliome v1.1169 KLK11 Zornitza Stark Gene: klk11 has been classified as Green List (High Evidence).
Mendeliome v1.1168 KLK11 Zornitza Stark gene: KLK11 was added
gene: KLK11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLK11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLK11 were set to 36689511; 37212630
Phenotypes for gene: KLK11 were set to Ichthyosis with erythrokeratoderma, MIM# 620507
Review for gene: KLK11 was set to GREEN
Added comment: Four families reported: one multiplex with variant segregating with disease in 4 affected and 4 unaffected individuals. Three additional families with de novo variants.
Sources: Literature
Mendeliome v1.1167 GABBR1 Zornitza Stark Phenotypes for gene: GABBR1 were changed from Neurodevelopmental disorder, GABBR1-related, MONDO:0700092 to Neurodevelopmental disorder with language delay and variable cognitive abnormalities, MIM#620502
Mendeliome v1.1166 GABBR1 Zornitza Stark edited their review of gene: GABBR1: Changed phenotypes: Neurodevelopmental disorder with language delay and variable cognitive abnormalities, MIM#620502
Mendeliome v1.1166 FTCD Bryony Thompson Publications for gene: FTCD were set to 27604308; 12815595
Mendeliome v1.1165 FTCD Bryony Thompson edited their review of gene: FTCD: Changed publications: http://iembase.com/disorder/47
Mendeliome v1.1165 FTCD Bryony Thompson changed review comment from: Well-established gene-disease association (see OMIM entry). Glutamate formiminotransferase deficiency is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of amino acid metabolism.
Sources: NHS GMS; to: Glutamate formiminotransferase deficiency is classified as a benign form of folate metabolism disorder and an inborn error of amino acid metabolism without clinically significant phenotype (http://iembase.com/disorder/47).
Mendeliome v1.1165 MAP1B Zornitza Stark Phenotypes for gene: MAP1B were changed from Intellectual disability; seizures; PVNH; dysmorphic features; Periventricular nodular heterotopia 9, MIM# 618918 to Intellectual disability; seizures; PVNH; dysmorphic features; Periventricular nodular heterotopia 9, MIM# 618918; Deafness, autosomal dominant 83, MIM# 619808
Mendeliome v1.1164 MAP1B Zornitza Stark edited their review of gene: MAP1B: Added comment: At least 3 families reported with isolated deafness and mono-allelic variants.; Changed phenotypes: Intellectual disability, seizures, PVNH, dysmorphic features, Periventricular nodular heterotopia 9, MIM# 618918, Deafness, autosomal dominant 83, MIM# 619808
Mendeliome v1.1164 GJA4 Zornitza Stark Marked gene: GJA4 as ready
Mendeliome v1.1164 GJA4 Zornitza Stark Gene: gja4 has been classified as Green List (High Evidence).
Mendeliome v1.1164 GJA4 Zornitza Stark Classified gene: GJA4 as Green List (high evidence)
Mendeliome v1.1164 GJA4 Zornitza Stark Gene: gja4 has been classified as Green List (High Evidence).
Mendeliome v1.1163 GJA4 Zornitza Stark gene: GJA4 was added
gene: GJA4 was added to Mendeliome. Sources: Expert Review
somatic tags were added to gene: GJA4.
Mode of inheritance for gene: GJA4 was set to Other
Publications for gene: GJA4 were set to 33912852
Phenotypes for gene: GJA4 were set to Cavernous hemangioma, MONDO:0003155, GJA4-related
Review for gene: GJA4 was set to GREEN
Added comment: Recurrent somatic GJA4 c.121G>T (p.Gly41Cys) mutation as a driver of hepatic (n=12) and cutaneous (n=3) vascular malformations. Induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation, in lentiviral transduction of primary human endothelial cells.
Sources: Expert Review
Mendeliome v1.1162 COL4A3BP Zornitza Stark Phenotypes for gene: COL4A3BP were changed from Mental retardation, autosomal dominant 34, MIM# 616351 to Intellectual developmental disorder 34 (MIM#616351)
Mendeliome v1.1161 COL4A3BP Zornitza Stark Publications for gene: COL4A3BP were set to 25533962
Mendeliome v1.1160 COL4A3BP Zornitza Stark Mode of pathogenicity for gene: COL4A3BP was changed from to Other
Mendeliome v1.1159 DBR1 Zornitza Stark Phenotypes for gene: DBR1 were changed from {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem to {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem; Ichthyosis (MONDO#0019269), DBR1-related
Mendeliome v1.1158 DBR1 Zornitza Stark edited their review of gene: DBR1: Added comment: PMID: 37656279:
- A homozygous missense as a founder recessive DBR1 variant in four consanguineous families.
- Total of 7 affected children. WES done for one proband from each family.
- Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life.
- RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample.
- Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant.
- Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency.; Changed publications: 29474921, 37656279; Changed phenotypes: {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441, Viral infections of the brainstem, Ichthyosis (MONDO#0019269), DBR1-related
Mendeliome v1.1158 APOO Zornitza Stark Phenotypes for gene: APOO were changed from Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour to Mitochondrial disease, MONDO:0044970, APOO-related; Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour
Mendeliome v1.1157 APOO Zornitza Stark Publications for gene: APOO were set to 32439808
Mendeliome v1.1156 APOO Zornitza Stark edited their review of gene: APOO: Added comment: PMID: 37649161
1 family, 2 individuals (male & female) with same NMD variant c.532G>T (p.E178*), maternally inherited (mother unaffected).

Both died before 18 months of age with partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies.
Other phenotypes included partial syndactyly of the 2nd and 3rd toes, wrinkled palm, and sole skin.

Functional studies included site directed mutagenesis. This mutation resulted in a highly unstable and degradation
prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and
interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells.; Changed publications: 37649161; Changed phenotypes: Mitochondrial disease, MONDO:0044970, APOO-related, Developmental delay, Lactic acidosis, Muscle weakness, Hypotonia, Repetitive infections, Cognitive impairment, Autistic behaviour
Mendeliome v1.1156 RAB5C Rylee Peters changed review comment from: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature; to: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All have mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature
Mendeliome v1.1156 DBR1 Chern Lim reviewed gene: DBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37656279; Phenotypes: Ichthyosis (MONDO#0019269), DBR1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1156 CAP2 Zornitza Stark Phenotypes for gene: CAP2 were changed from Dilated cardiomyopathy to Cardiomyopathy, dilated, 2I (MIM#620462)
Mendeliome v1.1155 COL4A3BP Ee Ming Wong changed review comment from: - Thirty-one unrelated individuals with twenty-two distinct missense variants. The majority of variants were de novo.
- Several variants transfected into HeLa cells demonstrated gain of CERT activity
- CERT gain of function in Drosophila melanogaster led to head and brain size defects and impaired locomotor activity, which was corrected by pharmacological inhibition of CERT; to: - current HGNC symbol: CERT1
- Thirty-one unrelated individuals with twenty-two distinct missense variants. The majority of variants were de novo.
- Several variants transfected into HeLa cells demonstrated gain of CERT activity
- CERT gain of function in Drosophila melanogaster led to head and brain size defects and impaired locomotor activity, which was corrected by pharmacological inhibition of CERT
Mendeliome v1.1155 CAP2 Zornitza Stark Publications for gene: CAP2 were set to 30518548
Mendeliome v1.1154 CAP2 Zornitza Stark Classified gene: CAP2 as Green List (high evidence)
Mendeliome v1.1154 CAP2 Zornitza Stark Gene: cap2 has been classified as Green List (High Evidence).
Mendeliome v1.1153 CAP2 Zornitza Stark reviewed gene: CAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30518548, 33083013, 34862840; Phenotypes: Cardiomyopathy, dilated, 2I (MIM#620462); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1153 COL4A3BP Ee Ming Wong reviewed gene: COL4A3BP: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36976648; Phenotypes: Intellectual developmental disorder 34 (MIM#616351); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1153 RAB5C Ain Roesley Marked gene: RAB5C as ready
Mendeliome v1.1153 RAB5C Ain Roesley Gene: rab5c has been classified as Green List (High Evidence).
Mendeliome v1.1153 RAB5C Ain Roesley Classified gene: RAB5C as Green List (high evidence)
Mendeliome v1.1153 RAB5C Ain Roesley Gene: rab5c has been classified as Green List (High Evidence).
Mendeliome v1.1153 RAB5C Ain Roesley Classified gene: RAB5C as Green List (high evidence)
Mendeliome v1.1153 RAB5C Ain Roesley Gene: rab5c has been classified as Green List (High Evidence).
Mendeliome v1.1152 RAB5C Rylee Peters gene: RAB5C was added
gene: RAB5C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5C were set to PMID: 37552066
Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related
Penetrance for gene: RAB5C were set to Complete
Review for gene: RAB5C was set to GREEN
gene: RAB5C was marked as current diagnostic
Added comment: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature
Mendeliome v1.1152 AXIN1 Elena Savva Phenotypes for gene: AXIN1 were changed from Caudal duplication anomaly, MIM# 607864 to Caudal duplication anomaly, MIM# 607864; Syndromic disease, (MONDO:0002254), AXIN1-related
Mendeliome v1.1152 AXIN1 Elena Savva Publications for gene: AXIN1 were set to 9335612
Mendeliome v1.1151 AXIN1 Elena Savva Classified gene: AXIN1 as Green List (high evidence)
Mendeliome v1.1151 AXIN1 Elena Savva Gene: axin1 has been classified as Green List (High Evidence).
Mendeliome v1.1151 AXIN1 Elena Savva Mode of inheritance for gene: AXIN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1150 AXIN1 Elena Savva Classified gene: AXIN1 as Green List (high evidence)
Mendeliome v1.1150 AXIN1 Elena Savva Gene: axin1 has been classified as Green List (High Evidence).
Mendeliome v1.1149 COL4A3BP Zornitza Stark Tag new gene name tag was added to gene: COL4A3BP.
Mendeliome v1.1149 PPP1R3F Andrew Fennell changed review comment from: Sources: Literature; to: 13 unrelated hemizygous individuals reported with functional evidence
Sources: Literature
Mendeliome v1.1149 PPP1R3F Zornitza Stark Marked gene: PPP1R3F as ready
Mendeliome v1.1149 PPP1R3F Zornitza Stark Gene: ppp1r3f has been classified as Green List (High Evidence).
Mendeliome v1.1149 PPP1R3F Zornitza Stark Classified gene: PPP1R3F as Green List (high evidence)
Mendeliome v1.1149 PPP1R3F Zornitza Stark Gene: ppp1r3f has been classified as Green List (High Evidence).
Mendeliome v1.1148 PPP1R3F Andrew Fennell gene: PPP1R3F was added
gene: PPP1R3F was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP1R3F was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PPP1R3F were set to 37531237
Phenotypes for gene: PPP1R3F were set to Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related
Review for gene: PPP1R3F was set to GREEN
Added comment: Sources: Literature
Mendeliome v1.1148 LAMA3 Bryony Thompson Publications for gene: LAMA3 were set to 7633458; 8530087; 11810295; 10366601
Mendeliome v1.1147 FTH1 Bryony Thompson Publications for gene: FTH1 were set to 11389486; 36778397
Mendeliome v1.1146 FTH1 Bryony Thompson Mode of pathogenicity for gene: FTH1 was changed from None to Other
Mendeliome v1.1145 FTH1 Bryony Thompson Classified gene: FTH1 as Green List (high evidence)
Mendeliome v1.1145 FTH1 Bryony Thompson Added comment: Comment on list classification: Article describing the gene-disease association with neuroferritinopathy now published in HGG advances
Mendeliome v1.1145 FTH1 Bryony Thompson Gene: fth1 has been classified as Green List (High Evidence).
Mendeliome v1.1144 C3 Ain Roesley Phenotypes for gene: C3 were changed from C3 deficiency MIM#613779 to C3 deficiency MIM#613779; C3 deficiency MIM#613779; {Hemolytic uremic syndrome, atypical, susceptibility to, 5}, MIM# 612925
Mendeliome v1.1143 C3 Ain Roesley Publications for gene: C3 were set to 15781264; 1944729; 11813855; 26847111
Mendeliome v1.1143 C3 Ain Roesley Mode of inheritance for gene: C3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1142 C3 Ain Roesley edited their review of gene: C3: Changed phenotypes: C3 deficiency MIM#613779, {Hemolytic uremic syndrome, atypical, susceptibility to, 5}, MIM# 612925
Mendeliome v1.1142 C3 Ain Roesley edited their review of gene: C3: Added comment: Multiple individuals reported with mono-allelic variants and aHUS. At least one report of biallelic variants.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1142 SLC30A7 Zornitza Stark reviewed gene: SLC30A7: Rating: RED; Mode of pathogenicity: None; Publications: 36821639; Phenotypes: Ziegler-Huang syndrome, MIM# 620501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1142 SOX11 Zornitza Stark Phenotypes for gene: SOX11 were changed from Coffin-Siris syndrome 9, MIM# 615866; Congenital abnormalities of the kidneys and urinary tract to Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, MIM# 615866; Congenital abnormalities of the kidneys and urinary tract
Mendeliome v1.1141 SOX11 Zornitza Stark Publications for gene: SOX11 were set to 29459093; 24886874
Mendeliome v1.1140 SOX11 Zornitza Stark edited their review of gene: SOX11: Added comment: Over 40 additional individuals reported, e.g. PMID 35341651. The phenotype that has emerged over time is distinct from patients with mutations in ARID1B (614556) and Coffin-Siris syndrome-1 (135900). Patients with IDDMOH tend to be microcephalic and have ocular motor apraxia, abnormal eye morphology, or hypogonadotropic hypogonadism.; Changed publications: 29459093, 24886874, 33086258, 33785884, 35642566, 35341651
Mendeliome v1.1140 SOX11 Zornitza Stark edited their review of gene: SOX11: Changed phenotypes: Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, MIM# 615866, Congenital abnormalities of the kidneys and urinary tract
Mendeliome v1.1140 RAP1B Zornitza Stark Phenotypes for gene: RAP1B were changed from RAP1B‐associated syndrome; intellectual disability; microcephaly; thrombocytopaenia to Syndromic disease, MONDO:0002254, RAP1B-related; intellectual disability; microcephaly; thrombocytopaenia
Mendeliome v1.1139 PTCD3 Zornitza Stark Publications for gene: PTCD3 were set to 30607703; 19427859
Mendeliome v1.1138 PTCD3 Zornitza Stark Classified gene: PTCD3 as Green List (high evidence)
Mendeliome v1.1138 PTCD3 Zornitza Stark Gene: ptcd3 has been classified as Green List (High Evidence).
Mendeliome v1.1137 PTCD3 Zornitza Stark edited their review of gene: PTCD3: Added comment: Three additional families reported.; Changed rating: GREEN; Changed publications: 30607703, 19427859, 36450274
Mendeliome v1.1137 MRM2 Zornitza Stark Phenotypes for gene: MRM2 were changed from MELAS-like to Mitochondrial DNA depletion syndrome 17, MIM# 618567
Mendeliome v1.1136 MRM2 Zornitza Stark Classified gene: MRM2 as Green List (high evidence)
Mendeliome v1.1136 MRM2 Zornitza Stark Gene: mrm2 has been classified as Green List (High Evidence).
Mendeliome v1.1135 MRM2 Zornitza Stark edited their review of gene: MRM2: Added comment: Two additional families reported.; Changed rating: GREEN; Changed publications: 28973171, 36002240; Changed phenotypes: Mitochondrial DNA depletion syndrome 17, MIM# 618567
Mendeliome v1.1135 COX5A Zornitza Stark Publications for gene: COX5A were set to 2824752
Mendeliome v1.1134 COX5A Zornitza Stark Classified gene: COX5A as Amber List (moderate evidence)
Mendeliome v1.1134 COX5A Zornitza Stark Gene: cox5a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1133 COX5A Zornitza Stark edited their review of gene: COX5A: Added comment: Second family reported, albeit hmz missense.; Changed rating: AMBER; Changed publications: 35246835, 28247525
Mendeliome v1.1133 CRELD1 Zornitza Stark Phenotypes for gene: CRELD1 were changed from Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217 to Developmental and epileptic encephalopathy, MONDO:0100062, CRELD1-related; Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217
Mendeliome v1.1132 CRELD1 Zornitza Stark Mode of inheritance for gene: CRELD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1131 CRELD1 Zornitza Stark Classified gene: CRELD1 as Green List (high evidence)
Mendeliome v1.1131 CRELD1 Zornitza Stark Gene: creld1 has been classified as Green List (High Evidence).
Mendeliome v1.1130 CRELD1 Zornitza Stark edited their review of gene: CRELD1: Added comment: Emerging association between bi-alleic variants in CRELD1 and DEE.; Changed rating: GREEN; Changed phenotypes: Developmental and epileptic encephalopathy, MONDO:0100062, CRELD1-related, Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1130 UBAP2L Zornitza Stark Phenotypes for gene: UBAP2L were changed from Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related to Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies, MIM# 620494
Mendeliome v1.1129 UBAP2L Zornitza Stark edited their review of gene: UBAP2L: Changed phenotypes: Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies, MIM# 620494
Mendeliome v1.1129 NEUROG1 Zornitza Stark Marked gene: NEUROG1 as ready
Mendeliome v1.1129 NEUROG1 Zornitza Stark Gene: neurog1 has been classified as Green List (High Evidence).
Mendeliome v1.1129 NEUROG1 Zornitza Stark Classified gene: NEUROG1 as Green List (high evidence)
Mendeliome v1.1129 NEUROG1 Zornitza Stark Gene: neurog1 has been classified as Green List (High Evidence).
Mendeliome v1.1128 SRSF1 Zornitza Stark Phenotypes for gene: SRSF1 were changed from Neurodevelopmental disorder, SRSF1-related MONDO:0700092 to Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 620489
Mendeliome v1.1127 SRSF1 Zornitza Stark reviewed gene: SRSF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 620489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1127 TPM4 Zornitza Stark Phenotypes for gene: TPM4 were changed from Macrothrombocytopaenia to Bleeding disorder, platelet-type, 25, MIM# 620486
Mendeliome v1.1126 TPM4 Zornitza Stark edited their review of gene: TPM4: Changed phenotypes: Bleeding disorder, platelet-type, 25, MIM# 620486
Mendeliome v1.1126 PTPRJ Zornitza Stark Phenotypes for gene: PTPRJ were changed from Thrombocytopaenia to Thrombocytopenia 10, MIM# 620484
Mendeliome v1.1125 PTPRJ Zornitza Stark edited their review of gene: PTPRJ: Changed phenotypes: Thrombocytopenia 10, MIM# 620484
Mendeliome v1.1125 THPO Zornitza Stark edited their review of gene: THPO: Added comment: 5 families reported with bi-allelic variants and thrombocytopenia with progression to pancytopenia, aplastic anemia, and bone marrow failure.; Changed publications: 9425899, 10583217, 32150607, 28466964, 24085763, 28559357, 29191945, 36226497; Changed phenotypes: Thrombocythemia 1, MIM# 187950, Thrombocytopenia 9, MIM# 620478, Amegakaryocytic thrombocytopenia, congenital, 2, MIM# 620481; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1125 NEUROG1 Achchuthan Shanmugasundram gene: NEUROG1 was added
gene: NEUROG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEUROG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Phenotypes for gene: NEUROG1 were set to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Review for gene: NEUROG1 was set to GREEN
Added comment: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be added with green rating in the intellectual disability panel.

PMID:23419067 - A homozygous micro deletion of NEUROG1 was identified in a six year-old boy presenting with profound sensorineural deafness, balance disorder, severe disorder of oral motor function, and mild global developmental delay. His IQ was normal.

PMID:26077850 - A homozygous NEUROG1 variant (p.Arg116Leu) was identified in a 12 year-old boy presented with syndromic corneal opacity, mild intellectual disability and absent corneal reflex.

PMID:33439489 - A homozygous loss-of-function variant (p.Glu68Ter) was identified in a 12 year-old boy presenting with hypotonia, global developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. This patient had a global IQ of 62 at the age of ten.

PMID:36647078 - A female proband was identified with a novel homozygous truncating frameshift variant (p.Thr78ProfsTer122 and was reported with profound global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her sister also had a similar, but less severe phenotype and also harboured the same variant at homozygous state.

This gene has been associated with relevant phenotypes in OMIM (MIM #620469), but not in Gene2Phenotype.
Sources: Literature
Mendeliome v1.1125 STAT5B Zornitza Stark Tag somatic tag was added to gene: STAT5B.
Mendeliome v1.1125 STAT5B Zornitza Stark changed review comment from: Both bi-allelic and mono allelic (GoF) inheritance reported. AD GoF phenotype: increased IgE, growth failure, eczema but no immune defects compared to AR phenotype (modestly decreased T cells, reduced Tregs and function, hypergammaglobulinaemia, increased IgE).; to: Both bi-allelic and mono allelic (GoF) inheritance reported. AD GoF phenotype: increased IgE, growth failure, eczema but no immune defects compared to AR phenotype (modestly decreased T cells, reduced Tregs and function, hypergammaglobulinaemia, increased IgE).

Somatic variants also reported.
Mendeliome v1.1125 RRM2B Zornitza Stark Mode of inheritance for gene: RRM2B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1124 PPOX Zornitza Stark Phenotypes for gene: PPOX were changed from Porphyria variegata , MIM#176200 to Porphyria variegata , MIM#176200; Variegate porphyria, childhood-onset, MIM# 620483
Mendeliome v1.1123 PPOX Zornitza Stark Publications for gene: PPOX were set to 12357337; 32247286; 23324528; 27982422
Mendeliome v1.1122 PPOX Zornitza Stark Mode of inheritance for gene: PPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1121 PPOX Zornitza Stark edited their review of gene: PPOX: Added comment: Bi-allelic variants cause childhood onset disease.; Changed publications: 12357337, 32247286, 23324528, 27982422, 9811936, 11286631, 33159949; Changed phenotypes: Porphyria variegata , MIM#176200, Variegate porphyria, childhood-onset, MIM# 620483; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1121 THPO Zornitza Stark Phenotypes for gene: THPO were changed from Thrombocythemia 1, MIM# 187950 to Thrombocythemia 1, MIM# 187950; Thrombocytopenia 9, MIM# 620478
Mendeliome v1.1120 THPO Zornitza Stark Publications for gene: THPO were set to 9425899; 10583217
Mendeliome v1.1119 THPO Zornitza Stark edited their review of gene: THPO: Added comment: Thrombocytopenia: 5 unrelated families reported.; Changed publications: 9425899, 10583217, 32150607, 28466964; Changed phenotypes: Thrombocythemia 1, MIM# 187950, Thrombocytopenia 9, MIM# 620478
Mendeliome v1.1119 ACTB Zornitza Stark Phenotypes for gene: ACTB were changed from Baraitser-Winter syndrome 1 243310; ACTB-related neurodevelopment disorder to Baraitser-Winter syndrome 1 243310; Thrombocytopenia 8, with dysmorphic features and developmental delay, MIM# 620475; ACTB-related neurodevelopment disorder
Mendeliome v1.1118 ACTB Zornitza Stark reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thrombocytopenia 8, with dysmorphic features and developmental delay, MIM# 620475; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1118 APOL1 Zornitza Stark Classified gene: APOL1 as Amber List (moderate evidence)
Mendeliome v1.1118 APOL1 Zornitza Stark Gene: apol1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1117 APOL1 Zornitza Stark edited their review of gene: APOL1: Added comment: Assigned Definitive gene-disease validity by the ClinGen Glomerulopathy GCEP - Classification - 09/28/2021
Increased risk of kidney and glomerular diseases in persons carrying two of the risk alleles in this gene: G1/G1, G2/G2 and compound heterozygous G1/G2.
PMID: 20647424 - first study to identify G1 & G2 alleles associated with risk of renal disease. Comparing participants with zero or 1 risk allele of APOL1 to participants with 2 risk alleles provided an odds ratio for FSGS of 10.5 (CI, 6.0-18.4). This analysis supported a completely recessive pattern of inheritance.
PMID: 25993319 - only G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN
rs73885319 (G1) OR 9.66, p=9.97E-25
rs60910145 (G1) OR 9.75, p=9.04E-24
rs71785313 (G2) OR 5.69, p=3.39E-06
2 APOL1 risk alleles OR 18.31, p=3.31E-58
PMID: 34350953 - recessive gain-of-function toxicity mouse model recapitulates human kidney disease
G1:
p.Ser342Gly, AFR/AA gnomAD v2.1 AF 0.2276 (5,671/24,920 alleles, 687 homozygotes)
p.Ile384Met, AFR/AA gnomAD v2.1 AF 0.2278 (5,487/24,082 alleles, 662 homozygotes)
G2:
p.Asn388_Tyr389del, AFR/AA gnomAD v2.1 AF 0.1402(3,402/24,268 alleles, 224 homozygotes

AMBER status due to these being susceptibility alleles, and evidence being limited to these specific variants.; Changed rating: AMBER
Mendeliome v1.1117 GOSR2 Achchuthan Shanmugasundram changed review comment from: Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry.

All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134).; to: This gene should be added in 'Deafness_IsolatedAndComplex' panel with red rating.

Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry.

All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134).
Mendeliome v1.1117 GOSR2 Achchuthan Shanmugasundram reviewed gene: GOSR2: Rating: RED; Mode of pathogenicity: None; Publications: 37074134; Phenotypes: hearing loss, autosomal recessive, MONDO:0019588; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1117 GFI1 Zornitza Stark Tag treatable tag was added to gene: GFI1.
Mendeliome v1.1117 CORO1A Zornitza Stark Tag treatable tag was added to gene: CORO1A.
Mendeliome v1.1117 CD70 Zornitza Stark Tag treatable tag was added to gene: CD70.
Mendeliome v1.1117 CD40 Zornitza Stark Tag treatable tag was added to gene: CD40.
Mendeliome v1.1117 DDRGK1 Ain Roesley Marked gene: DDRGK1 as ready
Mendeliome v1.1117 DDRGK1 Ain Roesley Gene: ddrgk1 has been classified as Green List (High Evidence).
Mendeliome v1.1117 DDRGK1 Ain Roesley Classified gene: DDRGK1 as Green List (high evidence)
Mendeliome v1.1117 DDRGK1 Ain Roesley Gene: ddrgk1 has been classified as Green List (High Evidence).
Mendeliome v1.1116 DDRGK1 Ain Roesley gene: DDRGK1 was added
gene: DDRGK1 was added to Mendeliome. Sources: Literature
founder tags were added to gene: DDRGK1.
Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336
Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type (MIM#602557)
Review for gene: DDRGK1 was set to GREEN
gene: DDRGK1 was marked as current diagnostic
Added comment: RNA and protein studies performed for the splice variant. These two variants likely represents founder variants

PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development.

PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD.

In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455).
Sources: Literature
Mendeliome v1.1115 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, MONDO:0006497, FBXO31-related; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant to Intellectual developmental disorder, autosomal recessive 45 (MIM#615979; Cerebral palsy, MONDO:0006497, FBXO31-related; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant
Mendeliome v1.1114 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant to Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, MONDO:0006497, FBXO31-related; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant
Mendeliome v1.1113 FBXO31 Zornitza Stark Publications for gene: FBXO31 were set to 24623383; 32989326
Mendeliome v1.1112 ATP6V0C Zornitza Stark Phenotypes for gene: ATP6V0C were changed from Epilepsy; Intellectual Disability; microcephaly to Epilepsy, early-onset, with or without developmental delay, MIM#620465; Epilepsy; Intellectual Disability; microcephaly
Mendeliome v1.1111 ATP6V0C Zornitza Stark edited their review of gene: ATP6V0C: Changed phenotypes: Epilepsy, early-onset, with or without developmental delay, MIM#620465, Epilepsy, Intellectual Disability, microcephaly
Mendeliome v1.1111 FBXO31 Ain Roesley reviewed gene: FBXO31: Rating: AMBER; Mode of pathogenicity: None; Publications: 35019165, 24623383; Phenotypes: Intellectual developmental disorder, autosomal recessive 45 (MIM#615979); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1111 TBL1XR1 Achchuthan Shanmugasundram reviewed gene: TBL1XR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28687524, 37010288; Phenotypes: Pierpont syndrome, OMIM:602342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1111 NEB Achchuthan Shanmugasundram reviewed gene: NEB: Rating: AMBER; Mode of pathogenicity: None; Publications: 12207937, 21798101, 33376055, 37010288; Phenotypes: Arthrogryposis multiplex congenita 6, OMIM:619334; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1111 ECEL1 Achchuthan Shanmugasundram reviewed gene: ECEL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30131190, 37010288; Phenotypes: Arthrogryposis, distal, type 5D, OMIM:615065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1111 CCT5 Bryony Thompson edited their review of gene: CCT5: Added comment: Now two families reported with two different missense variants (Leu224Val and His147Arg).; Changed publications: 16399879, 25124038, 25345891, 33076433, 37237456
Mendeliome v1.1111 ZFHX4 Ain Roesley Phenotypes for gene: ZFHX4 were changed from Developmental disorders to neurodevelopmental disorder, ZFHX4-related (MONDO:0700092)
Mendeliome v1.1110 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNH1-related; encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related to Neurodevelopmental disorder, MONDO:0700092, RNH1-related; {Encephalopathy, acute, infection-induced, susceptibiliyt to, 12}, MIM# 620461
Mendeliome v1.1109 HNRNPC Zornitza Stark Marked gene: HNRNPC as ready
Mendeliome v1.1109 HNRNPC Zornitza Stark Gene: hnrnpc has been classified as Green List (High Evidence).
Mendeliome v1.1109 HNRNPC Zornitza Stark Classified gene: HNRNPC as Green List (high evidence)
Mendeliome v1.1109 HNRNPC Zornitza Stark Gene: hnrnpc has been classified as Green List (High Evidence).
Mendeliome v1.1108 HNRNPC Zornitza Stark gene: HNRNPC was added
gene: HNRNPC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPC were set to 37541189
Phenotypes for gene: HNRNPC were set to Neurodevelopmental disorder (MONDO:0700092), HNRNPC-related
Review for gene: HNRNPC was set to GREEN
Added comment: 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five had an identical in-frame deletion of nine amino acids in the extreme C terminus. Supportive functional data; haploinsufficiency is the mechanism.
Sources: Literature
Mendeliome v1.1107 PSMC3 Zornitza Stark Phenotypes for gene: PSMC3 were changed from Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354 to neurodevelopmental disorder, MONDO:0700092, PSMC3-related; Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v1.1106 PSMC3 Zornitza Stark Publications for gene: PSMC3 were set to 32500975
Mendeliome v1.1105 PSMC3 Zornitza Stark Mode of inheritance for gene: PSMC3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1104 PSMC3 Zornitza Stark Classified gene: PSMC3 as Green List (high evidence)
Mendeliome v1.1104 PSMC3 Zornitza Stark Gene: psmc3 has been classified as Green List (High Evidence).
Mendeliome v1.1103 PSMC3 Zornitza Stark edited their review of gene: PSMC3: Added comment: PMID:37256937 - 23 individuals with neurodevelopmental disorder was identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.; Changed rating: GREEN; Changed publications: 32500975, 37256937; Changed phenotypes: neurodevelopmental disorder, MONDO:0700092, PSMC3-related, Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1103 EMC1 Zornitza Stark Publications for gene: EMC1 were set to 26942288; 29271071
Mendeliome v1.1102 EMC1 Zornitza Stark Mode of inheritance for gene: EMC1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1101 EMC1 Chern Lim edited their review of gene: EMC1: Changed rating: GREEN
Mendeliome v1.1101 EMC1 Chern Lim reviewed gene: EMC1: Rating: ; Mode of pathogenicity: None; Publications: 35234901, 26942288; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1101 RELA Zornitza Stark Publications for gene: RELA were set to 28600438; 29305315
Mendeliome v1.1100 RELA Zornitza Stark Classified gene: RELA as Green List (high evidence)
Mendeliome v1.1100 RELA Zornitza Stark Gene: rela has been classified as Green List (High Evidence).
Mendeliome v1.1099 RELA Zornitza Stark changed review comment from: Additional 6 individuals from two families reported.; to: Additional 6 individuals from five families reported.
Mendeliome v1.1099 RELA Zornitza Stark edited their review of gene: RELA: Added comment: Additional 6 individuals from two families reported.; Changed rating: GREEN; Changed publications: 28600438, 29305315, 37273177; Changed phenotypes: Mucocutaneous ulceration, chronic, MIM# 618287, Impaired NFkB activation, reduced production of inflammatory cytokines, autoimmune cytopaenias
Mendeliome v1.1099 DPP9 Zornitza Stark Phenotypes for gene: DPP9 were changed from Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias to Hatipoglu immunodeficiency syndrome MIM#620331; Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias
Mendeliome v1.1098 DPP9 Zornitza Stark Phenotypes for gene: DPP9 were changed from Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias to Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias
Mendeliome v1.1097 DPP9 Zornitza Stark Publications for gene: DPP9 were set to 36112693
Mendeliome v1.1096 DPP9 Zornitza Stark Mode of inheritance for gene: DPP9 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1095 DPP9 Zornitza Stark edited their review of gene: DPP9: Added comment: Amber for mono-allelic association:

de novo monoallelic dominant-negative mutation in DPP9 (c.755G>C, R252P) presenting with HLH at ~2m. Functional data supporting dominant negative mechanism.; Changed publications: 36112693, 37544411; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1095 PDGFD Zornitza Stark Marked gene: PDGFD as ready
Mendeliome v1.1095 PDGFD Zornitza Stark Gene: pdgfd has been classified as Red List (Low Evidence).
Mendeliome v1.1095 PDGFD Zornitza Stark gene: PDGFD was added
gene: PDGFD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PDGFD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFD were set to 33187088; 33971972
Phenotypes for gene: PDGFD were set to Pulmonary arterial hypertension MONDO:0015924, PDGFD-related
Review for gene: PDGFD was set to RED
Added comment: Rated as LIMITED by ClinGen. 10 unique variants (all missense) that have been reported in 10 probands in 2 publications (PMIDs: 33187088, 33971972) are included in this curation. 9 of these variants were observed in a cohort of 1647 idiopathic pulmonary arterial hypertension (IPAH) patients of European Ancestry as part of a case-control study. Variant aggregation analysis revealed a significant burden (p=0.0000172) of likely gene damaging PDGFD variants in the IPAH cohort as compared to a group of 18,819 European controls (PMID:33971972). Gelinas et al. also reported a missense PDGFD variant in a proband with IPAH (PMID:33187088). There is currently no functional evidence demonstrating a damaging effect of any of the reported PDGFD variants in humans.
Sources: Expert list
Mendeliome v1.1094 KLF2 Zornitza Stark Phenotypes for gene: KLF2 were changed from Pulmonary arterial hypertension to Pulmonary arterial hypertension MONDO:0015924, KLF2-related
Mendeliome v1.1093 KLF2 Zornitza Stark edited their review of gene: KLF2: Changed phenotypes: Pulmonary arterial hypertension MONDO:0015924, KLF2-related
Mendeliome v1.1093 FBLN2 Zornitza Stark Marked gene: FBLN2 as ready
Mendeliome v1.1093 FBLN2 Zornitza Stark Gene: fbln2 has been classified as Red List (Low Evidence).
Mendeliome v1.1093 FBLN2 Zornitza Stark gene: FBLN2 was added
gene: FBLN2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FBLN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBLN2 were set to 33971972
Phenotypes for gene: FBLN2 were set to Pulmonary arterial hypertension MONDO:0015924, FBLN2-related
Review for gene: FBLN2 was set to RED
Added comment: LIMITED by ClinGen. Out of a cohort of 1647 idiopathic PAH cases, 3 rare predicted deleterious missense variants were identified in 6 unrelated individuals with one variant recurrent in four individuals. Gene-disease association also supported by tissue expression data.
Sources: Expert list
Mendeliome v1.1092 AQP1 Zornitza Stark Phenotypes for gene: AQP1 were changed from Pulmonary arterial hypertension to Pulmonary arterial hypertension MONDO:0015924, AQP1-related
Mendeliome v1.1091 AQP1 Zornitza Stark Publications for gene: AQP1 were set to PMID:22683574; 29650961
Mendeliome v1.1090 AQP1 Zornitza Stark Classified gene: AQP1 as Amber List (moderate evidence)
Mendeliome v1.1090 AQP1 Zornitza Stark Gene: aqp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1089 AQP1 Zornitza Stark reviewed gene: AQP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37007933, 35627312; Phenotypes: Pulmonary arterial hypertension MONDO:0015924, AQP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1089 TET2 Zornitza Stark Phenotypes for gene: TET2 were changed from Dementia; Lymphoma/myeloid malignancy; Immunodeficiency-75 (IMD75), MIM#619126 to Dementia; Lymphoma/myeloid malignancy; Immunodeficiency-75 (IMD75), MIM#619126; Pulmonary arterial hypertension MONDO:0015924, TET2-related
Mendeliome v1.1088 TET2 Zornitza Stark Publications for gene: TET2 were set to 30890702; 31827242; 32330418
Mendeliome v1.1087 TET2 Zornitza Stark changed review comment from: Association with PAH:
MODERATE by ClinGen. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and knock out TET2 mice exhibiting a PH phenotype.; to: Association with PAH:
MODERATE by ClinGen/Amber rating here. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and knock out TET2 mice exhibiting a PH phenotype.
Mendeliome v1.1087 TET2 Zornitza Stark edited their review of gene: TET2: Added comment: Association with PAH:
MODERATE by ClinGen. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and knock out TET2 mice exhibiting a PH phenotype.; Changed publications: 30890702, 31827242, 32330418, 32518946, 32192357; Changed phenotypes: Dementia, Lymphoma/myeloid malignancy, Immunodeficiency-75 (IMD75), MIM#619126, Pulmonary arterial hypertension MONDO:0015924, TET2-related
Mendeliome v1.1087 HNRNPA2B1 Zornitza Stark Phenotypes for gene: HNRNPA2B1 were changed from oculopharyngeal muscular dystrophy, MONDO:0008116; Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422 to oculopharyngeal muscular dystrophy, MONDO:0008116, OMIM#620460; Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422
Mendeliome v1.1086 AGAP1 Zornitza Stark Phenotypes for gene: AGAP1 were changed from Cerebral palsy to Cerebral palsy, MONDO:0006497, AGAP1-related
Mendeliome v1.1085 AGAP1 Zornitza Stark edited their review of gene: AGAP1: Changed phenotypes: Cerebral palsy, MONDO:0006497, AGAP1-related
Mendeliome v1.1085 PRDM10 Zornitza Stark Phenotypes for gene: PRDM10 were changed from Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086 to Birt-Hogg-Dube syndrome 2, MIM# 620459
Mendeliome v1.1084 PRDM10 Zornitza Stark reviewed gene: PRDM10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Birt-Hogg-Dube syndrome 2, MIM# 620459; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1084 PLCB4 Zornitza Stark Phenotypes for gene: PLCB4 were changed from Auriculocondylar syndrome 2, MIM# 614669 to Auriculocondylar syndrome 2A, MIM# 614669; Auriculocondylar syndrome 2B, MIM# 620458
Mendeliome v1.1083 PLCB4 Zornitza Stark edited their review of gene: PLCB4: Changed phenotypes: Auriculocondylar syndrome 2A, MIM# 614669, Auriculocondylar syndrome 2B, MIM# 620458
Mendeliome v1.1083 IL1R1 Zornitza Stark Marked gene: IL1R1 as ready
Mendeliome v1.1083 IL1R1 Zornitza Stark Gene: il1r1 has been classified as Red List (Low Evidence).
Mendeliome v1.1083 IL1R1 Zornitza Stark gene: IL1R1 was added
gene: IL1R1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL1R1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IL1R1 were set to 37315560
Phenotypes for gene: IL1R1 were set to Chronic recurrent multifocal osteomyelitis 3, MIM# 259680
Review for gene: IL1R1 was set to RED
Added comment: Single individual reported with de novo missense variant in this gene and a phenotype of chronic recurrent multifocal osteomyelitis, auto inflammatory in nature. Some functional data presented.
Sources: Literature
Mendeliome v1.1082 STAB1 Zornitza Stark Marked gene: STAB1 as ready
Mendeliome v1.1082 STAB1 Zornitza Stark Gene: stab1 has been classified as Green List (High Evidence).
Mendeliome v1.1082 STAB1 Zornitza Stark Classified gene: STAB1 as Green List (high evidence)
Mendeliome v1.1082 STAB1 Zornitza Stark Gene: stab1 has been classified as Green List (High Evidence).
Mendeliome v1.1081 RINT1 Zornitza Stark Phenotypes for gene: RINT1 were changed from Recurrent acute liver failure to Infantile liver failure syndrome 3, MIM# 618641
Mendeliome v1.1080 SMARCA4 Zornitza Stark Phenotypes for gene: SMARCA4 were changed from Coffin-Siris syndrome 4, MIM# 614609 to Coffin-Siris syndrome 4, MIM# 614609; Otosclerosis MONDO:0005349, SMARCA4-related
Mendeliome v1.1079 SMARCA4 Zornitza Stark Publications for gene: SMARCA4 were set to 22426308
Mendeliome v1.1078 TBC1D31 Zornitza Stark Marked gene: TBC1D31 as ready
Mendeliome v1.1078 TBC1D31 Zornitza Stark Gene: tbc1d31 has been classified as Red List (Low Evidence).
Mendeliome v1.1078 TBC1D31 Zornitza Stark Classified gene: TBC1D31 as Red List (low evidence)
Mendeliome v1.1078 TBC1D31 Zornitza Stark Gene: tbc1d31 has been classified as Red List (Low Evidence).
Mendeliome v1.1077 AQP4 Zornitza Stark Marked gene: AQP4 as ready
Mendeliome v1.1077 AQP4 Zornitza Stark Gene: aqp4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1077 AQP4 Zornitza Stark Phenotypes for gene: AQP4 were changed from ?Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448 to Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448
Mendeliome v1.1076 AQP4 Zornitza Stark Classified gene: AQP4 as Amber List (moderate evidence)
Mendeliome v1.1076 AQP4 Zornitza Stark Gene: aqp4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1075 EZH1 Zornitza Stark Marked gene: EZH1 as ready
Mendeliome v1.1075 EZH1 Zornitza Stark Gene: ezh1 has been classified as Green List (High Evidence).
Mendeliome v1.1075 EZH1 Zornitza Stark Classified gene: EZH1 as Green List (high evidence)
Mendeliome v1.1075 EZH1 Zornitza Stark Gene: ezh1 has been classified as Green List (High Evidence).
Mendeliome v1.1074 EZH1 Zornitza Stark gene: EZH1 was added
gene: EZH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EZH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EZH1 were set to 37433783
Phenotypes for gene: EZH1 were set to Neurodevelopmental disorder (MONDO:0700092), EZH1-related
Review for gene: EZH1 was set to GREEN
Added comment: PMID: 37433783
Variants were identified 19 individuals from 14 unrelated families, all sharing a clinical phenotype of a neurodevelopmental disorder manifested early in life as global motor, speech and cognitive delay leading to intellectual disability, usually non-progressive and co-occurring with dysmorphic facial features.

Functional studies have shown that some missense EZH1 variants lead to GOF with increased methyltransferase activity and recessive variants impair EZH1 expression causing loss of function effects.
Sources: Literature
Mendeliome v1.1073 GPRC5B Zornitza Stark Marked gene: GPRC5B as ready
Mendeliome v1.1073 GPRC5B Zornitza Stark Gene: gprc5b has been classified as Green List (High Evidence).
Mendeliome v1.1073 GPRC5B Zornitza Stark Classified gene: GPRC5B as Green List (high evidence)
Mendeliome v1.1073 GPRC5B Zornitza Stark Gene: gprc5b has been classified as Green List (High Evidence).
Mendeliome v1.1072 PHF5A Zornitza Stark Marked gene: PHF5A as ready
Mendeliome v1.1072 PHF5A Zornitza Stark Gene: phf5a has been classified as Green List (High Evidence).
Mendeliome v1.1072 PHF5A Zornitza Stark Classified gene: PHF5A as Green List (high evidence)
Mendeliome v1.1072 PHF5A Zornitza Stark Gene: phf5a has been classified as Green List (High Evidence).
Mendeliome v1.1071 SMARCA4 Paul De Fazio changed review comment from: Additional phenotype reported:

A single missense variant E1610K (M_001128849.3) was reported in 7 affected members of a family with progressive hearing loss due to otosclerosis and no other clinical features. Variant is absent from gnomAD. Note that unaffected members of the family were not tested.

A mouse CRISPR model with the orthologous variant had a similar phenotype.; to: Additional phenotype reported:

A single missense variant E1610K (M_001128849.3) was reported in 7 affected members of a family with progressive hearing loss due to otosclerosis and no other clinical features. Variant is absent from gnomAD. Note that unaffected members of the family were not tested - some obligate carriers were apparently unaffected, reflecting incomplete penetrance.

A mouse CRISPR model with the orthologous variant had a similar phenotype.
Mendeliome v1.1071 CANVAS Dean Phelan reviewed STR: CANVAS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37450567; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (MIM:614575); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1071 PHF5A Daniel Flanagan gene: PHF5A was added
gene: PHF5A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PHF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHF5A were set to PMID: 37422718
Phenotypes for gene: PHF5A were set to Neurodevelopmental disorder (MONDO#0700092), PHF5A-related
Review for gene: PHF5A was set to GREEN
Added comment: Nine subjects with congenital malformations, including hypospadias, growth abnormalities, and developmental delay who had de novo PHF5A variants. Prenatally, six subjects had intrauterine growth retardation. All subjects had motor and speech delay and developmental delay. Congenital abnormalities comprised hypospadias in three of four male subjects, and heart defects (3/9), inguinal hernia (3/9), and sacral dimple (3/9). Six of the nine subjects had short stature. Craniofacial dysmorphism is variable in the nine subjects, high forehead and preauricular skin tag(s) in five subjects.
Sources: Expert list
Mendeliome v1.1071 TBC1D31 Lilian Downie gene: TBC1D31 was added
gene: TBC1D31 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TBC1D31 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D31 were set to PMID: 37468454
Phenotypes for gene: TBC1D31 were set to congenital anomaly of kidney and urinary tract MONDO:0019719
Review for gene: TBC1D31 was set to RED
Added comment: Single paper with homozygous mutations in 3 sibs with CAKUT from consanguineous family
Sources: Literature
Mendeliome v1.1071 AQP4 Lucy Spencer gene: AQP4 was added
gene: AQP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AQP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AQP4 were set to 37143309
Phenotypes for gene: AQP4 were set to ?Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448
Review for gene: AQP4 was set to AMBER
Added comment: PMID: 37143309
Cohort of patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). Missense variant in AQP4 seen homozygous in 2 siblings and het in the parents. Patients had macrocephaly, developmental delay, hypotonia, epilepsy, and cognitive deficit.

Western blots on generated MDCK cell lines showed no detectable expression of AQP4 protein from the cells with the patients variant. Immunofluorescence also showed no membrane expression. Overexpression studies in HEK293T cells showed WT was seen as mainly monomers or dimers where as variant protein formed large aggregates- likely due to the saturation of protein degradation pathways because of the overexpression.
Sources: Literature
Mendeliome v1.1071 GPRC5B Lucy Spencer gene: GPRC5B was added
gene: GPRC5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPRC5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPRC5B were set to 37143309
Phenotypes for gene: GPRC5B were set to Megalencephalic leukoencephalopathy with subcortical cysts 3 620447
Review for gene: GPRC5B was set to GREEN
Added comment: PMID: 37143309
Cohort of 5 patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). 3 unrelated patients had variants in GPRC5B, 2 have the same inframe dup Ile175dup and the third has an in frame dup of Ala177. All 3 were de novo and unaffected siblings did not have the variants. All patients have macrocephaly, delayed motor development, seizures, all had varying degrees of cognitive deficits. 2 also had spasticity, ataxia and dystonia. MRI showed MLC, abnormal and swollen cerebral white matter.

Patient cell lines showed reduced regulatory volume decrease, and western blot showed a strong increase in GRPC5B levels in patient lymphoblasts. Together, these findings indicate disturbed volume regulation in lymphoblasts from patients with GPRC5B variants, potentially due to increased GPRC5B levels. Transfected cells caused increased volume-regulated anion channel activity.
Sources: Literature
Mendeliome v1.1071 MAMDC2 Elena Savva Marked gene: MAMDC2 as ready
Mendeliome v1.1071 MAMDC2 Elena Savva Gene: mamdc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1071 MAMDC2 Elena Savva Classified gene: MAMDC2 as Amber List (moderate evidence)
Mendeliome v1.1071 MAMDC2 Elena Savva Gene: mamdc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1070 COX18 Elena Savva Marked gene: COX18 as ready
Mendeliome v1.1070 COX18 Elena Savva Gene: cox18 has been classified as Red List (Low Evidence).
Mendeliome v1.1070 COX18 Elena Savva Classified gene: COX18 as Red List (low evidence)
Mendeliome v1.1070 COX18 Elena Savva Gene: cox18 has been classified as Red List (Low Evidence).
Mendeliome v1.1068 NAA30 Zornitza Stark Marked gene: NAA30 as ready
Mendeliome v1.1068 NAA30 Zornitza Stark Gene: naa30 has been classified as Red List (Low Evidence).
Mendeliome v1.1069 PTPA Zornitza Stark Publications for gene: PTPA were set to 36073231
Mendeliome v1.1068 MAMDC2 Belinda Chong gene: MAMDC2 was added
gene: MAMDC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAMDC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAMDC2 were set to 37503746
Phenotypes for gene: MAMDC2 were set to Muscular Dystrophy MONDO:0020121, MAMDC2-related
Review for gene: MAMDC2 was set to AMBER
Added comment: 17 individuals with an autosomal dominant muscular dystrophy belonging to two unrelated families in which different heterozygous truncating variants in the last exon of MAMDC2 co-segregate correctly with the disease.
Sources: Literature
Mendeliome v1.1068 PTPA Zornitza Stark Mode of inheritance for gene: PTPA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1067 NAA30 Zornitza Stark Phenotypes for gene: NAA30 were changed from to neurodevelopmental disorder, MONDO:0700092, NAA30-related
Mendeliome v1.1066 NAA30 Zornitza Stark Mode of inheritance for gene: NAA30 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1065 NAA30 Zornitza Stark Classified gene: NAA30 as Red List (low evidence)
Mendeliome v1.1065 NAA30 Zornitza Stark Gene: naa30 has been classified as Red List (Low Evidence).
Mendeliome v1.1064 COX18 Naomi Baker gene: COX18 was added
gene: COX18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COX18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX18 were set to PMID:37468577
Phenotypes for gene: COX18 were set to Mitochondrial disease (MONDO:0044970), COX18-related
Review for gene: COX18 was set to RED
Added comment: Paper reports a single patient with a homozygous COX18 missense variant, with a neonatal form of mitochondrial hypertrophic cardiomyopathy, lactic acidosis, failure to thrive and neurological involvement associated with severe skeletal muscle COX deficiency. Functional studies demonstrated COX deficiency which could be partially rescued with over-expression of COX18.
Sources: Literature
Mendeliome v1.1064 TUFM Ain Roesley reviewed gene: TUFM: Rating: RED; Mode of pathogenicity: None; Publications: 37461298; Phenotypes: Inherited primary ovarian failure MONDO:0019852, TUFM-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1064 STAT4 Elena Savva Publications for gene: STAT4 were set to
Mendeliome v1.1064 STAB1 Chern Lim gene: STAB1 was added
gene: STAB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAB1 were set to 37490907; 28052375
Phenotypes for gene: STAB1 were set to Iron metabolism disease (MONDO:0002279), STAB1-related
Review for gene: STAB1 was set to GREEN
gene: STAB1 was marked as current diagnostic
Added comment: PMID: 37490907
- Biallelic variants identified in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies.
- Homozygous/compound heterozygous variants: missense, frameshift, stopgain, inframe del of 3 AAs, one synonymous.
- Samples from three of the patients from two families showed no immunoreactivity with anti-stabilin-1 compared to control liver where high signal was detected in the liver sinusoids (immunohistochemistry analysis).
- Patients’ peripheral monocytes and monocyte-derived macrophages showed very little expression of stabilin-1 on CD14+ monocytes and macrophages compared to control subjects (flow cytometry analysis).
- These families have also been published in PMID: 28052375.
Sources: Literature
Mendeliome v1.1064 STAT4 Elena Savva Phenotypes for gene: STAT4 were changed from to Disabling pansclerotic morphea of childhood MIM#620443
Mendeliome v1.1064 STAT4 Melanie Marty edited their review of gene: STAT4: Changed phenotypes: Disabling pansclerotic morphea of childhood MIM#620443
Mendeliome v1.1064 STAT4 Elena Savva Mode of inheritance for gene: STAT4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.1064 STAT4 Elena Savva Classified gene: STAT4 as Green List (high evidence)
Mendeliome v1.1064 STAT4 Elena Savva Gene: stat4 has been classified as Green List (High Evidence).
Mendeliome v1.1063 PTPA Ee Ming Wong changed review comment from: - Six individuals with later-onset Parkinson disease with no atypical features eg intellectual disability or early cognitive dysfunction
- All were heterozygous for missense variants, a second hit not identified: authors suggests these are monoallelic cases
- Three of the 5 missense variants have multiple heterozygotes in gnomAD, two of the missense variants have homozygotes in gnomAD, including one with 7 homozygotes.; to: - Six individuals with later-onset Parkinson disease with no atypical features eg intellectual disability or early cognitive dysfunction
- All were heterozygous for missense variants, a second hit not identified: authors suggests these are monoallelic cases
- Three of the 5 missense variants have multiple heterozygotes in gnomAD, two of the missense variants have homozygotes in gnomAD, including one with 7 homozygotes.
Mendeliome v1.1063 PTPA Ee Ming Wong reviewed gene: PTPA: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37448355; Phenotypes: Intellectual disability, MONDO: 36073231, PTPA-related, Parkisonism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1063 SLC4A10 Krithika Murali Classified gene: SLC4A10 as Green List (high evidence)
Mendeliome v1.1063 SLC4A10 Krithika Murali Gene: slc4a10 has been classified as Green List (High Evidence).
Mendeliome v1.1062 SLC4A10 Krithika Murali Marked gene: SLC4A10 as ready
Mendeliome v1.1062 SLC4A10 Krithika Murali Gene: slc4a10 has been classified as Red List (Low Evidence).
Mendeliome v1.1062 NAA30 Sarah Pantaleo edited their review of gene: NAA30: Changed phenotypes: neurodevelopmental disorder, MONDO:0700092, NAA30-related
Mendeliome v1.1062 SMARCA4 Paul De Fazio reviewed gene: SMARCA4: Rating: AMBER; Mode of pathogenicity: None; Publications: 37399313; Phenotypes: Otosclerosis MONDO:0005349, SMARCA4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.1062 NAA30 Sarah Pantaleo gene: NAA30 was added
gene: NAA30 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAA30 was set to Unknown
Publications for gene: NAA30 were set to PMID: 37387332
Penetrance for gene: NAA30 were set to unknown
Added comment: Report a de novo heterozygous NAA30 nonsense variant c.244C>T, p.(Gln82*) in a 5yo boy with GDD, ASD, hypotonia, seizures, tracheal cleft and recurrent respiratory infections. Seizures resolved after two weeks of life. Family history of ASD in older sister. Epilepsy in mother, childhood onset.

Biochemical studies performed to assess the functional impact of the premature stop codon on catalytic activity. The variant was found to completely disrupt N-terminal acetyltransferase activity using an in vitro acetylation assay.

Variant de novo, “in a gene sensitive to loss of heterozygosity”. Limitation of study - have not established whether this gene variant acts in a dominant or recessive manner.
Sources: Literature
Mendeliome v1.1062 STAT4 Melanie Marty changed review comment from: Baghdassarian et al (2023) Four patients from three unrelated families with disabling pansclerotic morphea (DPM, a rare inflammatory disorder), 3 x het missense variants identified, AD inheritance. All 4 patients had disease onset before 5 years of age, with signs of mucosal ulcerations and skin sclerosis. All variants occur in the SH2 domain. Functional studies showed a gain of function effect for these variants.; to: Baghdassarian et al (2023) Four patients from three unrelated families with disabling pansclerotic morphea (DPM, a rare inflammatory disorder), 3 x het missense variants identified, AD inheritance. All 4 patients had disease onset before 5 years of age, with signs of mucosal ulcerations and skin sclerosis. These variants occur in the SH2 domain. Functional studies showed a gain of function effect for these variants.
Mendeliome v1.1062 STAT4 Melanie Marty Deleted their comment
Mendeliome v1.1062 STAT4 Melanie Marty commented on gene: STAT4: Baghdassarian et al (2023) Four patients from three unrelated families with disabling pansclerotic morphea (DPM, a rare inflammatory disorder), 3 x het missense variants identified, AD inheritance. All 4 patients had disease onset before 5 years of age, with signs of mucosal ulcerations and skin sclerosis. All variants occur in the SH2 domain. Functional studies showed a gain of function effect for these variants.
Mendeliome v1.1062 STAT4 Melanie Marty edited their review of gene: STAT4: Changed phenotypes: Disabling pansclerotic morphea, inflammatory disorder, poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, squamous-cell carcinoma
Mendeliome v1.1062 PIP5K1C Elena Savva Publications for gene: PIP5K1C were set to 17701898
Mendeliome v1.1061 PEX14 Lilian Downie reviewed gene: PEX14: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37493040; Phenotypes: peroxisome biogenesis disorder due to PEX14 defect MONDO:0100268; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1061 SENP7 Elena Savva Classified gene: SENP7 as Amber List (moderate evidence)
Mendeliome v1.1061 SENP7 Elena Savva Gene: senp7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1060 SENP7 Elena Savva Marked gene: SENP7 as ready
Mendeliome v1.1060 SENP7 Elena Savva Gene: senp7 has been classified as Red List (Low Evidence).
Mendeliome v1.1060 STAT4 Melanie Marty reviewed gene: STAT4: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 37256972; Phenotypes: Disabling pansclerotic morphea, inflammatory disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1060 SENP7 Elena Savva gene: SENP7 was added
gene: SENP7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SENP7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SENP7 were set to PMID: 37460201
Phenotypes for gene: SENP7 were set to Arthrogryposis multiplex congenita, MONDO:0015168, SENP7-related
Review for gene: SENP7 was set to AMBER
Added comment: PMID: 37460201
- 1 family (4 affecteds, sibling pair and 1st cousin) with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia. Fetus could not be tested, so 3 confirmed genetically.
- Homozygous for a PTC, decreased mRNA from one sample supports an NMD outcome.
- Additional studies performed supporting downstream proteins expression being affected
- Neutropenia observed in 2/3 patients
Sources: Literature
Mendeliome v1.1059 STX5 Ain Roesley Marked gene: STX5 as ready
Mendeliome v1.1059 STX5 Ain Roesley Gene: stx5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1059 STX5 Ain Roesley Publications for gene: STX5 were set to
Mendeliome v1.1058 STX5 Ain Roesley Classified gene: STX5 as Amber List (moderate evidence)
Mendeliome v1.1058 STX5 Ain Roesley Gene: stx5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1057 SLC4A10 Krithika Murali gene: SLC4A10 was added
gene: SLC4A10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC4A10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A10 were set to PMID: 37459438
Phenotypes for gene: SLC4A10 were set to Neurodevelopmental disorderMONDO:0700092, SLC4A10-related
Review for gene: SLC4A10 was set to GREEN
Added comment: PMID: 37459438 Fasham et al 2023 (Brain) report 10 affected individuals from 5 unrelated families with biallelic LoF variants in this gene with a novel neurodevelopmental disorder.

Phenotypic features include hypotonia in infancy, delayed psychomotor development, typically severe ID, progressive postnatal microcephaly, ASD traits, corpus callosal abnormalities and 'slit-like' lateral ventricles. These phenotypic features were recapitulated in knockout mice with additional supportive functional studies.

Isolated seizures was reported in 2/10 cases.
Sources: Literature
Mendeliome v1.1056 KDM4B Sarah Pantaleo reviewed gene: KDM4B: Rating: ; Mode of pathogenicity: None; Publications: PMID: 37526414; Phenotypes: Intellectual developmental disorder, autosomal dominant 65, MIM#619320; Mode of inheritance: None
Mendeliome v1.1056 STX5 Ain Roesley edited their review of gene: STX5: Changed publications: 34711829
Mendeliome v1.1056 SHQ1 Zornitza Stark Publications for gene: SHQ1 were set to 34542157; 29178645; 36847845
Mendeliome v1.1055 SHQ1 Zornitza Stark Classified gene: SHQ1 as Green List (high evidence)
Mendeliome v1.1055 SHQ1 Zornitza Stark Gene: shq1 has been classified as Green List (High Evidence).
Mendeliome v1.1054 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Added comment: Additional individual with isolated, early-onset dystonia reported.

It is likely these clinical presentations are part of a spectrum.; Changed rating: GREEN; Changed publications: 34542157, 29178645, 36847845, 37475611
Mendeliome v1.1054 STX5 Ain Roesley gene: STX5 was added
gene: STX5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STX5 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STX5 were set to congenital disorder of glycosylation MONDO#0015286, STX5-related
Review for gene: STX5 was set to AMBER
gene: STX5 was marked as current diagnostic
Added comment: 1x family with 3x deceased shortly after death + 3x spontaneous abortions + 2x abortions due to abnormal fatal ultrasound (US).
Hom for NM_003164.4:c.163 A > G p.(Met55Val), which results in complete loss of short isoform (which uses Met55 as the start)

phenotype: short long bones on US, dysmorphism, skeletal dysplasia, profound hypotonia, hepatomegaly elevated cholesterol.
Post-natally they died of progressive liver failure with cholestasis and hyperinsulinemic hypoglycemias

Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking
Sources: Literature
Mendeliome v1.1053 TEP1 Zornitza Stark Marked gene: TEP1 as ready
Mendeliome v1.1053 TEP1 Zornitza Stark Gene: tep1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1053 TEP1 Zornitza Stark Classified gene: TEP1 as Amber List (moderate evidence)
Mendeliome v1.1053 TEP1 Zornitza Stark Gene: tep1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1052 TEP1 Zornitza Stark gene: TEP1 was added
gene: TEP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TEP1 were set to 34543729
Phenotypes for gene: TEP1 were set to Cerebral palsy, MONDO:0006497, TEP1-related
Review for gene: TEP1 was set to AMBER
Added comment: Wang et al. screened a large cohort of more than 600 CP patients from China and found several variants in TEP1, 11 of which were LoF, while no LoF variant was found in the control cohort. These children all had spastic CP. Among these 11 children, 6 children had birth asphyxia and neonatal encephalopathy. Compared to the total group with birth asphyxia (71/667), 6 patients with TEP1 LOF mutations had a significantly greater risk of birth asphyxia. They confirmed TEP1 as a risk factor for CP by cytological and animal models.

Uncertain if these are risk alleles vs indicative of a monogenic disorder. Note LoF variants in gnomad. As this was a cohort study, inheritance of these variants is unknown.
Sources: Literature
Mendeliome v1.1051 Bryony Thompson removed gene:DUSP7 from the panel
Mendeliome v1.1050 EIF4A2 Zornitza Stark Phenotypes for gene: EIF4A2 were changed from Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related to Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, MIM# 620455
Mendeliome v1.1049 TINF2 Sangavi Sivagnanasundram reviewed gene: TINF2: Rating: AMBER; Mode of pathogenicity: None; Publications: https://doi.org/10.1016/j.xhgg.2023.100225; Phenotypes: Multiple Primary Melanomas (MPM); Mode of inheritance: Unknown
Mendeliome v1.1049 LAMA3 Sangavi Sivagnanasundram changed review comment from: Zhou et al. (2023) - Two heterozygous nonsense variants identified in two individuals of the same family [p.Arg1126Ter and p.Gln1507Ter] that was shown to segregate in the family with reduced penetrance.

The authors hypothesize that function of laminin 𝛼3 is altered as it changes its ability to form heterotrimeric laminins.

In vivo functional study using CRISPR/Cas-9 mediated LAMA3 knockout mice. Results of the functional assay showed development of tricuspid valve and right ventricle abnormalities in the presence of a homozygous LoF variant in LAMA3.; to: Novel gene-disease association
Zhou et al. (2023) - Two heterozygous nonsense variants identified in two individuals of the same family [p.Arg1126Ter and p.Gln1507Ter] that was shown to segregate in the family with reduced penetrance.

The authors hypothesize that function of laminin 𝛼3 is altered as it changes its ability to form heterotrimeric laminins.

In vivo functional study using CRISPR/Cas-9 mediated LAMA3 knockout mice. Results of the functional assay showed development of tricuspid valve and right ventricle abnormalities in the presence of a homozygous LoF variant in LAMA3.
Mendeliome v1.1049 LAMA3 Sangavi Sivagnanasundram reviewed gene: LAMA3: Rating: AMBER; Mode of pathogenicity: None; Publications: https://doi.org/10.1016/j.xhgg.2023.100227; Phenotypes: Ebstein’s anomaly (MIM#224700); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1049 DUSP7 Sangavi Sivagnanasundram gene: DUSP7 was added
gene: DUSP7 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DUSP7 was set to Unknown
Publications for gene: DUSP7 were set to https://doi.org/10.1155/2023/4348290
Phenotypes for gene: DUSP7 were set to Acute Myeloid Leukemia (AML)
Review for gene: DUSP7 was set to RED
Added comment: New gene with an association in AML prognosis.

Gao (2023) - Recruitment from three public AML cohorts - GSE71014, TARGET-AML, and TCGA-AML.
The study results suggest that with an DUSP7 may affect AML progression in individuals by affecting the recruitment of local immune cells.
Sources: Other
Mendeliome v1.1049 PYROXD2 Zornitza Stark Classified gene: PYROXD2 as Red List (low evidence)
Mendeliome v1.1049 PYROXD2 Zornitza Stark Gene: pyroxd2 has been classified as Red List (Low Evidence).
Mendeliome v1.1048 PYROXD2 Zornitza Stark Tag disputed tag was added to gene: PYROXD2.
Mendeliome v1.1048 PYROXD2 Zornitza Stark edited their review of gene: PYROXD2: Added comment: Alternative diagnosis identified in proband, downgrade.; Changed rating: RED
Mendeliome v1.1048 TMEM63B Zornitza Stark Marked gene: TMEM63B as ready
Mendeliome v1.1048 TMEM63B Zornitza Stark Gene: tmem63b has been classified as Green List (High Evidence).
Mendeliome v1.1048 TMEM63B Zornitza Stark Phenotypes for gene: TMEM63B were changed from developmental and epileptic encephalopathy, MONDO:0100062 to developmental and epileptic encephalopathy, MONDO:0100062, TMEM63B-related
Mendeliome v1.1047 TMEM63B Zornitza Stark Classified gene: TMEM63B as Green List (high evidence)
Mendeliome v1.1047 TMEM63B Zornitza Stark Gene: tmem63b has been classified as Green List (High Evidence).
Mendeliome v1.1046 DHX9 Zornitza Stark Marked gene: DHX9 as ready
Mendeliome v1.1046 DHX9 Zornitza Stark Added comment: Comment when marking as ready: LoF variants caused mild NDD phenotypes and nuclear localization signal (NLS) missense variants caused severe NDD. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress.
Mendeliome v1.1046 DHX9 Zornitza Stark Gene: dhx9 has been classified as Green List (High Evidence).
Mendeliome v1.1046 DHX9 Zornitza Stark Marked gene: DHX9 as ready
Mendeliome v1.1046 DHX9 Zornitza Stark Gene: dhx9 has been classified as Green List (High Evidence).
Mendeliome v1.1046 DHX9 Zornitza Stark Classified gene: DHX9 as Green List (high evidence)
Mendeliome v1.1046 DHX9 Zornitza Stark Gene: dhx9 has been classified as Green List (High Evidence).
Mendeliome v1.1045 TMEM63B Achchuthan Shanmugasundram changed review comment from: There is sufficient evidence for this gene to be included with green rating in intellectual disability and epilepsy panels.

17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame.

All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.

All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature; to: There is sufficient evidence for this gene to be included with green rating in 'Intellectual disability syndromic and non-syndromic' and 'Genetic epilepsy' panels.

17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame.

All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.

All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature
Mendeliome v1.1045 TMEM63B Achchuthan Shanmugasundram gene: TMEM63B was added
gene: TMEM63B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63B were set to 37421948
Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: TMEM63B was set to GREEN
Added comment: There is sufficient evidence for this gene to be included with green rating in intellectual disability and epilepsy panels.

17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame.

All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.

All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature
Mendeliome v1.1045 DHX9 Achchuthan Shanmugasundram gene: DHX9 was added
gene: DHX9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX9 were set to 37467750
Phenotypes for gene: DHX9 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; Charcot-Marie-Tooth disease, MONDO:0015626
Review for gene: DHX9 was set to GREEN
Added comment: PMID:37467750 - 17 unrelated individuals were identified with de novo, ultra-rare, heterozygous missense or loss-of-function DHX9 variants, of which 14 individuals were reported with a neurodevelopmental disorder (NDD) and three were reported with Charcot-Marie-Tooth disease (CMT). All 14 cases with NDD had developmental delay, of which eight were reported with intellectual disability (4 severe, 1 moderate, 3 mild). Two cases did not have ID, one had borderline ID and three cases were too young (0-5 years old). The three cases with CMT presented with adult-onset axonal neuropathy.
Sources: Literature
Mendeliome v1.1045 MCOLN1 Achchuthan Shanmugasundram reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17239335, 25156245, 33965501, 35205297; Phenotypes: Mucolipidosis IV, OMIM:252650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1045 KLK1 Zornitza Stark Phenotypes for gene: KLK1 were changed from [Kallikrein, decreased urinary activity of] 615953 to [Kallikrein, decreased urinary activity of] 615953; Pulmonary arterial hypertension MONDO:0015924
Mendeliome v1.1044 KLK1 Zornitza Stark Publications for gene: KLK1 were set to
Mendeliome v1.1043 KLK1 Zornitza Stark Mode of inheritance for gene: KLK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1042 KLK1 Zornitza Stark edited their review of gene: KLK1: Added comment: Association with PAH:

PMID: 31727138
screening of the biobank - 12 individuals with genetic variant in KLK1 relevant to PAH (not all were found to be hereditary). Assay showed that carriers of variants in KLK1 are less clinically severe compared to those who carry variants in BMPR2.

PMID: 17573418
Functional study using sensitive and specific type ELISAs to assay multiple panels of human tissue. KLK1 tissue was abundantly expressed in the pancreas and salivary gland and moderately expressed in the lungs.

Reviewed by ClinGen Pulmonary Hypertension GCEP on 30/8/2022 with LIMITED evidence supporting gene-disease validity; Changed publications: 31727138, 17573418; Changed phenotypes: [Kallikrein, decreased urinary activity of] 615953, Pulmonary arterial hypertension MONDO:0015924; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1042 TBX6 Zornitza Stark Phenotypes for gene: TBX6 were changed from Spondylocostal dysostosis 5, 122600 to Spondylocostal dysostosis 5, 122600; Mayer-Rokitansky-Küster-Hauser syndrome, MONDO:0017771, TBX6-related
Mendeliome v1.1041 WBP4 Zornitza Stark Marked gene: WBP4 as ready
Mendeliome v1.1041 WBP4 Zornitza Stark Gene: wbp4 has been classified as Green List (High Evidence).
Mendeliome v1.1041 WBP4 Zornitza Stark Phenotypes for gene: WBP4 were changed from Neurodevelopmental disorder, MONDO:0700092, WBP4-related to Neurodevelopmental disorder, MONDO:0700092, WBP4-related
Mendeliome v1.1040 WBP4 Zornitza Stark Marked gene: WBP4 as ready
Mendeliome v1.1040 WBP4 Zornitza Stark Gene: wbp4 has been classified as Green List (High Evidence).
Mendeliome v1.1040 WBP4 Zornitza Stark Phenotypes for gene: WBP4 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, WBP4-related
Mendeliome v1.1039 KDM2A Zornitza Stark Marked gene: KDM2A as ready
Mendeliome v1.1039 KDM2A Zornitza Stark Gene: kdm2a has been classified as Green List (High Evidence).
Mendeliome v1.1039 KDM2A Zornitza Stark Phenotypes for gene: KDM2A were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, KDM2A-related
Mendeliome v1.1038 PIP5K1C Zornitza Stark Phenotypes for gene: PIP5K1C were changed from Lethal congenital contractural syndrome 3, MIM# 611369 to Neurodevelopmental disorder and microcephaly, MONDO:0700092, PIP5K1C-related; Lethal congenital contractural syndrome 3, MIM# 611369
Mendeliome v1.1037 PIP5K1C Zornitza Stark Mode of inheritance for gene: PIP5K1C was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1036 PIP5K1C Zornitza Stark Mode of inheritance for gene: PIP5K1C was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1035 INTS13 Zornitza Stark Marked gene: INTS13 as ready
Mendeliome v1.1035 INTS13 Zornitza Stark Gene: ints13 has been classified as Green List (High Evidence).
Mendeliome v1.1035 INTS13 Zornitza Stark Phenotypes for gene: INTS13 were changed from Oral-facial-digital syndrome to Oral-facial-digital syndrome, MONDO:0015375, INTS13-related
Mendeliome v1.1034 TEFM Zornitza Stark Phenotypes for gene: TEFM were changed from Mitochondrial disease (MONDO#0044970), TEFM-related to Combined oxidative phosphorylation deficiency 58, MIM# 620451
Mendeliome v1.1033 MAP3K14 Zornitza Stark Phenotypes for gene: MAP3K14 were changed from NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels to Immunodeficiency 112, MIM# 620449; NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels
Mendeliome v1.1032 MAP3K14 Zornitza Stark edited their review of gene: MAP3K14: Changed phenotypes: Immunodeficiency 112, MIM# 620449, NIK deficiency, Poor T cell proliferation to antigen, Low B-cell numbers, Low NK number and function, recurrent bacterial/viral/ cryptosporidium infections, hypogammaglobulinaemia, decreased immunoglobulin levels
Mendeliome v1.1032 SLC20A1 Zornitza Stark Phenotypes for gene: SLC20A1 were changed from Bladder-Exstrophy-Epispadias Complex (BEEC) to Bladder-Exstrophy-Epispadias Complex (BEEC), MONDO:0017919, SLC20A1-related
Mendeliome v1.1031 TUBB4B Zornitza Stark Phenotypes for gene: TUBB4B were changed from Leber congenital amaurosis with early onset deafness, LCAEOD, OMIM #617879; MONDO:0060650 to Leber congenital amaurosis with early onset deafness, LCAEOD, OMIM #617879; MONDO:0060650; Primary ciliary dyskinesia, MONDO:0016575, TUBB4B-related
Mendeliome v1.1030 CYHR1 Zornitza Stark Marked gene: CYHR1 as ready
Mendeliome v1.1030 CYHR1 Zornitza Stark Gene: cyhr1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1030 CYHR1 Zornitza Stark Phenotypes for gene: CYHR1 were changed from Neurodevelopmental disorder and microcephaly to Neurodevelopmental disorder and microcephaly, MONDO:0700092, CYHR1-related
Mendeliome v1.1029 TSPOAP1 Zornitza Stark Phenotypes for gene: TSPOAP1 were changed from Dystonia, intellectual disability and cerebellar atrophy to Dystonia 22, MIM# 620453
Mendeliome v1.1028 TSPOAP1 Zornitza Stark reviewed gene: TSPOAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia 22, MIM# 620453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1028 TAF4 Zornitza Stark Phenotypes for gene: TAF4 were changed from Neurodevelopmental disorder, MONDO:0700092, TAF4-related to Intellectual developmental disorder, autosomal dominant 73, MIM# 620450
Mendeliome v1.1027 TAF4 Zornitza Stark edited their review of gene: TAF4: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 73, MIM# 620450
Mendeliome v1.1027 NAA60 Zornitza Stark Marked gene: NAA60 as ready
Mendeliome v1.1027 NAA60 Zornitza Stark Gene: naa60 has been classified as Green List (High Evidence).
Mendeliome v1.1027 NAA60 Zornitza Stark Phenotypes for gene: NAA60 were changed from Basal ganglia calcification to Basal ganglia calcification, MONDO:0008947, NAA60-related
Mendeliome v1.1026 POPDC2 Zornitza Stark Marked gene: POPDC2 as ready
Mendeliome v1.1026 POPDC2 Zornitza Stark Gene: popdc2 has been classified as Green List (High Evidence).
Mendeliome v1.1026 POPDC2 Zornitza Stark Phenotypes for gene: POPDC2 were changed from Sinus node dysfunction to Sinoatrial node disorder, MONDO:0000469, POPDC2-related
Mendeliome v1.1025 GPATCH11 Zornitza Stark Marked gene: GPATCH11 as ready
Mendeliome v1.1025 GPATCH11 Zornitza Stark Gene: gpatch11 has been classified as Green List (High Evidence).
Mendeliome v1.1025 GPATCH11 Zornitza Stark Phenotypes for gene: GPATCH11 were changed from Leber congenital amaurosis and developmental delay to Neurodevelopmental disorder, MONDO:0700092, GPATCH11-related; Leber congenital amaurosis and developmental delay
Mendeliome v1.1024 KCNA3 Zornitza Stark Marked gene: KCNA3 as ready
Mendeliome v1.1024 KCNA3 Zornitza Stark Gene: kcna3 has been classified as Green List (High Evidence).
Mendeliome v1.1024 KCNA3 Zornitza Stark Phenotypes for gene: KCNA3 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, KCNA3-related
Mendeliome v1.1023 FSD1L Zornitza Stark Marked gene: FSD1L as ready
Mendeliome v1.1023 FSD1L Zornitza Stark Gene: fsd1l has been classified as Green List (High Evidence).
Mendeliome v1.1023 FSD1L Zornitza Stark Phenotypes for gene: FSD1L were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, FSD1L-related
Mendeliome v1.1022 DENND5B Zornitza Stark Marked gene: DENND5B as ready
Mendeliome v1.1022 DENND5B Zornitza Stark Gene: dennd5b has been classified as Green List (High Evidence).
Mendeliome v1.1022 DENND5B Zornitza Stark Phenotypes for gene: DENND5B were changed from Neurodevelopmental disorder with white matter anomalies to Neurodevelopmental disorder with white matter anomalies, MONDO:0700092, DENND5B-related
Mendeliome v1.1021 DMAP1 Zornitza Stark Marked gene: DMAP1 as ready
Mendeliome v1.1021 DMAP1 Zornitza Stark Gene: dmap1 has been classified as Green List (High Evidence).
Mendeliome v1.1021 DMAP1 Zornitza Stark Phenotypes for gene: DMAP1 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, DMAP1-related
Mendeliome v1.1020 VGLL2 Zornitza Stark Marked gene: VGLL2 as ready
Mendeliome v1.1020 VGLL2 Zornitza Stark Gene: vgll2 has been classified as Green List (High Evidence).
Mendeliome v1.1020 VGLL2 Zornitza Stark Phenotypes for gene: VGLL2 were changed from Syngnathia to Syngnathia, MONDO:0015409, VGLL2-related
Mendeliome v1.1019 COL4A6 Zornitza Stark Publications for gene: COL4A6 were set to 23714752; 12784310
Mendeliome v1.1018 COL4A6 Zornitza Stark Classified gene: COL4A6 as Amber List (moderate evidence)
Mendeliome v1.1018 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1017 HCN2 Zornitza Stark Phenotypes for gene: HCN2 were changed from Febrile seizures, familial, 2, MIM# 602477; Genetic epilepsy with febrile seizures plus; Other seizure disorders to Febrile seizures, familial, 2, MIM# 602477; Genetic epilepsy with febrile seizures plus; Other seizure disorders; Neurodevelopmental disorder (MONDO#0700092), HCN2-related
Mendeliome v1.1016 HCN2 Zornitza Stark edited their review of gene: HCN2: Added comment: ICG congress 2023: cohort presented with ID as key feature.; Changed phenotypes: Febrile seizures, familial, 2, MIM# 602477, Genetic epilepsy with febrile seizures plus, Other seizure disorders, Neurodevelopmental disorder (MONDO#0700092), HCN2-related
Mendeliome v1.1016 SLC4A3 Zornitza Stark Publications for gene: SLC4A3 were set to PMID: 29167417; 34557911
Mendeliome v1.1015 SLC4A3 Zornitza Stark Classified gene: SLC4A3 as Green List (high evidence)
Mendeliome v1.1015 SLC4A3 Zornitza Stark Gene: slc4a3 has been classified as Green List (High Evidence).
Mendeliome v1.1014 PLCG1 Zornitza Stark Marked gene: PLCG1 as ready
Mendeliome v1.1014 PLCG1 Zornitza Stark Gene: plcg1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1014 PLCG1 Zornitza Stark Classified gene: PLCG1 as Amber List (moderate evidence)
Mendeliome v1.1014 PLCG1 Zornitza Stark Gene: plcg1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1013 PLCG1 Zornitza Stark gene: PLCG1 was added
gene: PLCG1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PLCG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLCG1 were set to 37422272
Phenotypes for gene: PLCG1 were set to Autoinflammatory syndrome, MONDO:0019751, PLCG1-related; Immune dysregulation
Mode of pathogenicity for gene: PLCG1 was set to Other
Review for gene: PLCG1 was set to AMBER
Added comment: Single 7yo proband presented with thrombocytopaenia and lymphadenopathy. De Novo , c.3062C>T, p.S1021F with functional testing supportive of GOF mechanism of disease
Sources: Expert Review
Mendeliome v1.1012 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Neurodevelopmental disorder, MONDO:0700092, TTI1-related to Neurodevelopmental disorder with microcephaly and movement abnormalities, MIM# 620445
Mendeliome v1.1011 DCAF15 Zornitza Stark Marked gene: DCAF15 as ready
Mendeliome v1.1011 DCAF15 Zornitza Stark Gene: dcaf15 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1011 DCAF15 Zornitza Stark Phenotypes for gene: DCAF15 were changed from Cornelia de Lange syndrome to Cornelia de Lange syndrome, MONDO:0016033, DCAF15-related
Mendeliome v1.1010 TBX6 Chirag Patel reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36112137, 36161696; Phenotypes: Mayer-Rokitansky-Küster-Hauser syndrome, Combined skeletal-kidney dysplasia syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1010 WBP4 Chirag Patel Classified gene: WBP4 as Green List (high evidence)
Mendeliome v1.1010 WBP4 Chirag Patel Gene: wbp4 has been classified as Green List (High Evidence).
Mendeliome v1.1009 WBP4 Chirag Patel gene: WBP4 was added
gene: WBP4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: WBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WBP4 were set to Neurodevelopmental disorder
Review for gene: WBP4 was set to GREEN
gene: WBP4 was marked as current diagnostic
Added comment: ESHG 2023:
11 individuals from 8 families with homozygous LOF variants in WBP4 gene (4 different variants). Presentation of severe DD and ID, hypotonia, abnormal outer ears, and varying congenital anomalies. WBP4 is spliceosome protein which binds/interacts with SNRNP200. In vivo and in vitro studies previously showed WBP4 enhances splicing and regulates alternative splicing. Patient fibroblasts showed loss of expression of WBP4. RNA sequencing analysis showed abnormal splicing patterns. Proposed spliceosomopathy.
Sources: Other
Mendeliome v1.1008 KDM2A Chirag Patel Classified gene: KDM2A as Green List (high evidence)
Mendeliome v1.1008 KDM2A Chirag Patel Gene: kdm2a has been classified as Green List (High Evidence).
Mendeliome v1.1007 KDM2A Chirag Patel gene: KDM2A was added
gene: KDM2A was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KDM2A were set to Neurodevelopmental disorder
Review for gene: KDM2A was set to GREEN
gene: KDM2A was marked as current diagnostic
Added comment: ESHG 2023:
14 patients with de novo HTZ variants in KDM2A (5 x truncating, 9 x missense)
Presentation with DD, ID (mild), seizures, growth retardation, and dysmorphism.

Functional studies:
-patient blood showed aberrant genome wide methylation profile - potential episignature
-HEK293T cells showed altered subcellular localisation of KDM2A
-Drosophila models showed variants caused neurotoxicity
Sources: Other
Mendeliome v1.1006 PIP5K1C Chirag Patel Classified gene: PIP5K1C as Green List (high evidence)
Mendeliome v1.1006 PIP5K1C Chirag Patel Gene: pip5k1c has been classified as Green List (High Evidence).
Mendeliome v1.1005 PIP5K1C Chirag Patel reviewed gene: PIP5K1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder and microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1005 NSUN6 Chirag Patel changed review comment from: Sufficient evidence for upgrade; to: Drosophila KO showed locomotion defects and reduced learning ability. Sufficient evidence for upgrade
Mendeliome v1.1005 NSUN6 Chirag Patel Classified gene: NSUN6 as Green List (high evidence)
Mendeliome v1.1005 NSUN6 Chirag Patel Gene: nsun6 has been classified as Green List (High Evidence).
Mendeliome v1.1004 NSUN6 Chirag Patel reviewed gene: NSUN6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1004 INTS13 Chirag Patel Classified gene: INTS13 as Green List (high evidence)
Mendeliome v1.1004 INTS13 Chirag Patel Gene: ints13 has been classified as Green List (High Evidence).
Mendeliome v1.1003 INTS13 Chirag Patel gene: INTS13 was added
gene: INTS13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INTS13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS13 were set to PMID: 36229431
Phenotypes for gene: INTS13 were set to Oral-facial-digital syndrome
Review for gene: INTS13 was set to GREEN
gene: INTS13 was marked as current diagnostic
Added comment: 2 families with 4 affected individuals with Oral-facial-digital (OFD) phenotype. Homozygosity mapping and WES found 2 homozygous variants in INTS13 gene. This is a subunit of the Integrator complex, which associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. Variants segregated with disease. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Knockdown in Xenopus embryos leads to motile cilia anomalies.
Sources: Literature
Mendeliome v1.1002 TUBB4B Chirag Patel reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1002 PTCH1 Chirag Patel reviewed gene: PTCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Bladder exstrophy and epispadias complex (BEEC); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1002 DCAF15 Chirag Patel Classified gene: DCAF15 as Amber List (moderate evidence)
Mendeliome v1.1002 DCAF15 Chirag Patel Gene: dcaf15 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1001 DCAF15 Chirag Patel gene: DCAF15 was added
gene: DCAF15 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DCAF15 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DCAF15 were set to Cornelia de Lange syndrome
Review for gene: DCAF15 was set to AMBER
Added comment: ESHG 2023:
3 unrelated cases with CdLS (1 x TOP with MCA, 1 x death @20mths, 1 x living child)
Features suggestive of CdLS - DD, microcephaly, CHD, dysmorphism, visual/hearing impairment.

WES identified recurrent de novo variant (p.Ser470Phe) in DCAF15 gene. This mediates ubiquitination and degradation of target proteins, and interacts with cohesin complex members (SMC1/SMC3).

Protein analysis from individuals showed increased accumulation of ubiquitination-modified proteins and SM3 (GOF mechanism). EpiSign analysis showed same DNA methylation pattern as other CdLS cases/genes. Zebrafish model showed reduced body length, reduced head size, reduced oligodendrocytes, heart defect, aberrant motor neurons, and abnormal response to visual/auditory stimuli.
Sources: Other
Mendeliome v1.1000 PMVK Zornitza Stark Phenotypes for gene: PMVK were changed from Porokeratosis 1, multiple types, MIM# 175800 to Porokeratosis 1, multiple types, MIM# 175800; Autoinflammatory syndrome, MONDO:0019751, PMVK-related
Mendeliome v1.999 PMVK Zornitza Stark Publications for gene: PMVK were set to 26202976
Mendeliome v1.998 PMVK Zornitza Stark Mode of inheritance for gene: PMVK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.997 PMVK Zornitza Stark changed review comment from: Association with auto inflammatory syndrome:

Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; to: Association with auto inflammatory syndrome:

Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.

Amber for bi-allelic disease association.
Mendeliome v1.997 PMVK Zornitza Stark edited their review of gene: PMVK: Added comment: Association with auto inflammatory syndrome:

Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; Changed publications: 26202976, 37364720, 36410683; Changed phenotypes: Porokeratosis 1, multiple types, MIM# 175800, Autoinflammatory syndrome, MONDO:0019751, PMVK-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.997 RIPK3 Zornitza Stark Marked gene: RIPK3 as ready
Mendeliome v1.997 RIPK3 Zornitza Stark Gene: ripk3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.997 RIPK3 Zornitza Stark Classified gene: RIPK3 as Amber List (moderate evidence)
Mendeliome v1.997 RIPK3 Zornitza Stark Gene: ripk3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.996 RIPK3 Zornitza Stark gene: RIPK3 was added
gene: RIPK3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RIPK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIPK3 were set to 37083451
Phenotypes for gene: RIPK3 were set to Hereditary susceptibility to infections, MONDO:0015979, RIPK3-related; Recurrent HSV encephalitis
Review for gene: RIPK3 was set to AMBER
Added comment: Single female patient with independent episodes of HSE at 6 and 17 months of age and with autoimmune encephalitis 1 month after the second episode of HSE with two heterozygous mutations of RIPK3 predicted to be loss of function (pLOF): p. Arg422* (c.1264 C > T, MAF 0.001568, CADD 35) and p. Pro493fs9* (c.1475 C > CC, MAF 0.002611, CADD 24.2). Extensive supportive functional data including RIPK3 knockout human pluripotent stem cell–derived cortical neurons.
Sources: Expert Review
Mendeliome v1.995 SMAD1 Zornitza Stark Tag disputed tag was added to gene: SMAD1.
Mendeliome v1.995 ANO1 Zornitza Stark Phenotypes for gene: ANO1 were changed from Intestinal dysmotility syndrome, MIM# 620045; Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features to Intestinal dysmotility syndrome, MIM# 620045; Moyamoya disease, MONDO:0016820, ANO1 related
Mendeliome v1.994 ANO1 Zornitza Stark Publications for gene: ANO1 were set to 32487539
Mendeliome v1.993 ANO1 Zornitza Stark Mode of inheritance for gene: ANO1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.992 ANO1 Zornitza Stark edited their review of gene: ANO1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.992 ANO1 Zornitza Stark edited their review of gene: ANO1: Added comment: PMID 37253099: screening analysis of Moyamoya disease (MMD) cohort revealed 8 individuals with variants in the ANO1 gene. Two families had the same rare variant p.Met658Val. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harboring these gain-of-function ANO1 variants had classic features of MMD, but also had aneurysm, stenosis, and/or occlusion in the posterior circulation. Amber rating due to somewhat conflicting segregation and functional data presented.; Changed publications: 37253099; Changed phenotypes: Intestinal dysmotility syndrome, MIM# 620045, Moyamoya disease, MONDO:0016820, ANO1 related
Mendeliome v1.992 CYHR1 Chirag Patel Classified gene: CYHR1 as Amber List (moderate evidence)
Mendeliome v1.992 CYHR1 Chirag Patel Gene: cyhr1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.991 CYHR1 Chirag Patel gene: CYHR1 was added
gene: CYHR1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CYHR1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CYHR1 were set to Neurodevelopmental disorder and microcephaly
Review for gene: CYHR1 was set to AMBER
Added comment: ESHG 2023:
5 individuals from 3 families with biallelic LOF variants in CYHR1 (aka ZTRAF1). Presentation with microcephaly, hypotonia, DD, and ID. Expression studies showed mislocalisation of CYHR1. Mutant fibroblasts showed increased lysosomal markers and upregulated lysosomal proteins, leading to impaired autophagy. Zebrafish KO however did not show a phenotype.
Sources: Other
Mendeliome v1.990 NAA60 Chirag Patel Classified gene: NAA60 as Green List (high evidence)
Mendeliome v1.990 NAA60 Chirag Patel Gene: naa60 has been classified as Green List (High Evidence).
Mendeliome v1.989 NAA60 Chirag Patel reviewed gene: NAA60: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary familial brain calcification; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.989 NAA60 Chirag Patel Deleted their review
Mendeliome v1.989 NAA60 Chirag Patel gene: NAA60 was added
gene: NAA60 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NAA60 were set to Basal ganglia calcification
Review for gene: NAA60 was set to GREEN
gene: NAA60 was marked as current diagnostic
Added comment: ESHG 2023:
10 individuals from 7 families with biallelic variants in NAA60 (missense and framshift).
All with primary brain calcification - 4/10 childhood onset (DD, ID), 6/10 adult onset (cerebellar and pyramidal dysfunction, dystonia, parkinsonism, cognitive impairment, psychiatric manifestations).

NAA60 catalyses N-terminal acetylation of transmembrane proteins and localises to Golgi apparatus. In vitro assay of variants showed reduced capacity of Nt acetylation. Fibroblast studies showed significantly reduced levels of phosphate importer (SLC20A2). Loss of function variants in SLC20A2 (~50% of PFBC cases) lead to increased extracellular phosphate (which is thought to lead to calcium deposits in brain).
Sources: Other
Mendeliome v1.988 POPDC2 Chirag Patel Classified gene: POPDC2 as Green List (high evidence)
Mendeliome v1.988 POPDC2 Chirag Patel Gene: popdc2 has been classified as Green List (High Evidence).
Mendeliome v1.987 POPDC2 Chirag Patel gene: POPDC2 was added
gene: POPDC2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: POPDC2 were set to Sinus node dysfunction
Review for gene: POPDC2 was set to GREEN
gene: POPDC2 was marked as current diagnostic
Added comment: ESHG 2023:
3 families with 7 affected with sinus node dysfunction (bradycardia) and AV block (2/7 HCM).

3 x HMZ variants found in POPDC2 (2 x missense, 1 x indel). Variants predicted to diminish cAMP binding of POPDC2, and shown to disrupt regulation of TREK1 channels (lowering of outward K+ current).

POPDC2 is highly expressed in cardiac myocytes, sinoatrial node, and atrioventricular node. Knockdown in zebrafish leads to AV block, and knockout in mice leads to sinus node dysfunction. Sources: Other
Sources: Other
Mendeliome v1.986 GPATCH11 Chirag Patel Classified gene: GPATCH11 as Green List (high evidence)
Mendeliome v1.986 GPATCH11 Chirag Patel Gene: gpatch11 has been classified as Green List (High Evidence).
Mendeliome v1.985 GPATCH11 Chirag Patel gene: GPATCH11 was added
gene: GPATCH11 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: GPATCH11 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GPATCH11 were set to Leber congenital amaurosis and developmental delay
Review for gene: GPATCH11 was set to GREEN
gene: GPATCH11 was marked as current diagnostic
Added comment: ESHG 2023:
3 families with 8 individuals with leber congenital amaurosis, developmental delay, language disorder, and behavioural issues.
GPATCH11 localises to nucleus and basal body of primary cilium (similar to other LCA genes).
Biallelic variants found in GPATCH11 - 1 splice variant common to all 3 families (1 other variant in 3rd family). Splice variant leads to loss of exon 4 (mRNA studies).
Mouse models showed i) abnormal rod/cone responses on ERG; ii) decreased outer nuclear layer in retina, and iii) abnormal associate/episodic memory
Sources: Other
Mendeliome v1.984 KCNA3 Chirag Patel Classified gene: KCNA3 as Green List (high evidence)
Mendeliome v1.984 KCNA3 Chirag Patel Gene: kcna3 has been classified as Green List (High Evidence).
Mendeliome v1.983 KCNA3 Chirag Patel Classified gene: KCNA3 as Green List (high evidence)
Mendeliome v1.983 KCNA3 Chirag Patel Gene: kcna3 has been classified as Green List (High Evidence).
Mendeliome v1.982 KCNA3 Chirag Patel gene: KCNA3 was added
gene: KCNA3 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KCNA3 were set to Neurodevelopmental disorder
Review for gene: KCNA3 was set to GREEN
gene: KCNA3 was marked as current diagnostic
Added comment: ESHG 2023:
10 individuals with de novo missense variants in KCNA3 (K+ channel)
Variable electrophysiology studies of effect of variants (5 x LOF, 4 x GOF, 1 no change)
Presentation: abnormal speech development (8/8), ID (6/8), epilepsy (5/8), and ASD (7/8)
Sources: Other
Mendeliome v1.981 FSD1L Chirag Patel Classified gene: FSD1L as Green List (high evidence)
Mendeliome v1.981 FSD1L Chirag Patel Gene: fsd1l has been classified as Green List (High Evidence).
Mendeliome v1.980 FSD1L Chirag Patel gene: FSD1L was added
gene: FSD1L was added to Mendeliome. Sources: Other
Mode of inheritance for gene: FSD1L was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FSD1L were set to Neurodevelopmental disorder
Review for gene: FSD1L was set to GREEN
gene: FSD1L was marked as current diagnostic
Added comment: ESHG 2023:
8 families with biallelic missense/nonsense variants
Presentation only described 1 family/2 affecteds with DD, ID, spastic paraparesis, epilepsy, corpus callosum hypoplasia, and optic nerve hypoplasia

Functional assays:
-reduced expression of FSD1L in mature neurons (RNA studies)
-very low % mature neurons (neuronal differentiation)
-reduced neuronal migration
Sources: Other
Mendeliome v1.979 DENND5B Chirag Patel Classified gene: DENND5B as Green List (high evidence)
Mendeliome v1.979 DENND5B Chirag Patel Gene: dennd5b has been classified as Green List (High Evidence).
Mendeliome v1.978 DENND5B Chirag Patel gene: DENND5B was added
gene: DENND5B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DENND5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DENND5B were set to Neurodevelopmental disorder with white matter anomalies
Review for gene: DENND5B was set to GREEN
gene: DENND5B was marked as current diagnostic
Added comment: ESHG 2023:
7 patients/7 families with de novo DENND5B variants (6 missense, 1 splice)
DD/ID (mod/profound)(7/7), white matter anomalies (6/7) hypotonia, epilepsy (3/7)

DENND5B acts as:
-GEF for activation of RAB proteins which are involved in membrane trafficking and neurotransmitter release
-regulator of lipid absorption and homeostasis

Functional studies showed loss of expression of DENND5B in fibroblasts, abnormal vesicle trafficking, and impaired lipid uptake and intracellular distribution
Sources: Other
Mendeliome v1.977 DMAP1 Chirag Patel Classified gene: DMAP1 as Green List (high evidence)
Mendeliome v1.977 DMAP1 Chirag Patel Gene: dmap1 has been classified as Green List (High Evidence).
Mendeliome v1.976 DMAP1 Chirag Patel gene: DMAP1 was added
gene: DMAP1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DMAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DMAP1 were set to Neurodevelopmental disorder
Review for gene: DMAP1 was set to GREEN
gene: DMAP1 was marked as current diagnostic
Added comment: ESHG 2023:
9 patients/8 families with bilallelic variants in DMAP1 (3 missense, 7 LOF)
All with DD, speech delay, hypotonia, and ID
Some with epilepsy (4/6), FTT (4/5), and brain malformations (3/5)
Drosophila showed abnormal behaviour pattern and bang sensitivity
Specific methylation episignature also seen
Sources: Other
Mendeliome v1.975 VGLL2 Chirag Patel Classified gene: VGLL2 as Green List (high evidence)
Mendeliome v1.975 VGLL2 Chirag Patel Gene: vgll2 has been classified as Green List (High Evidence).
Mendeliome v1.974 VGLL2 Chirag Patel gene: VGLL2 was added
gene: VGLL2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: VGLL2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VGLL2 were set to Syngnathia
Review for gene: VGLL2 was set to GREEN
gene: VGLL2 was marked as current diagnostic
Added comment: ESHG 2023:
4 families/7 affected individuals with isolated unilateral/bilateral syngnathia
biallelic truncating variants in VGLL2
But not phenotype in KO mouse or zebrafish models
Sources: Other
Mendeliome v1.973 ITFG2 Chirag Patel Classified gene: ITFG2 as Green List (high evidence)
Mendeliome v1.973 ITFG2 Chirag Patel Gene: itfg2 has been classified as Green List (High Evidence).
Mendeliome v1.972 ITFG2 Chirag Patel reviewed gene: ITFG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.972 COL4A6 Ain Roesley reviewed gene: COL4A6: Rating: AMBER; Mode of pathogenicity: None; Publications: 33840813; Phenotypes: Deafness, X-linked 6 MIM#300914; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v1.972 RDH11 Elena Savva reviewed gene: RDH11: Rating: AMBER; Mode of pathogenicity: None; Publications: 24916380, 15634683, 30731079, 18326732, 34988992; Phenotypes: Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.972 SLC4A3 Chern Lim reviewed gene: SLC4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36806574; Phenotypes: Short QT syndrome 7, MIM#620231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.972 C1GALT1C1 Zornitza Stark commented on gene: C1GALT1C1: Two maternal half-brothers with missense variant and aHUS phenotype reported, increasing evidence for association.
Mendeliome v1.972 C1GALT1C1 Zornitza Stark reviewed gene: C1GALT1C1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37216524; Phenotypes: Haemolytic uraemic syndrome, atypical, 8, with rhizomelic short stature, MIM# 301110; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.972 ZMYM3 Zornitza Stark Phenotypes for gene: ZMYM3 were changed from Neurodevelopmental disorder, MONDO:0700092, ZMYM3-related to Intellectual developmental disorder, X-linked 112, MIM# 301111
Mendeliome v1.971 ZMYM3 Zornitza Stark reviewed gene: ZMYM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 112, MIM# 301111; 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 v1.971 ACTN2 Zornitza Stark Classified gene: ACTN2 as Green List (high evidence)
Mendeliome v1.971 ACTN2 Zornitza Stark Gene: actn2 has been classified as Green List (High Evidence).
Mendeliome v1.970 NFE2L2 Zornitza Stark Mode of inheritance for gene: NFE2L2 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.969 NFE2L2 Zornitza Stark edited their review of gene: NFE2L2: Changed phenotypes: Immunodeficiency, developmental delay, and hypohomocysteinemia, MIM# 617744, Recurrent respiratory and skin infection, Growth retardation, Developmental delay, borderline ID, White matter cerebral lesions; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.969 SMAD1 Bryony Thompson Classified gene: SMAD1 as Red List (low evidence)
Mendeliome v1.969 SMAD1 Bryony Thompson Added comment: Comment on list classification: Disputed gene-disease validity curation by ClinGen PH VCEP 21/11/2022 - Only two probands reported to have PAH and SMAD1 variants. The variants are missense variants without functional data at the time of curation. Thus, SMAD1 is classified as disputed for PAH based upon insufficient genetic evidence over multiple years of research.
Mendeliome v1.969 SMAD1 Bryony Thompson Gene: smad1 has been classified as Red List (Low Evidence).
Mendeliome v1.968 DOCK11 Zornitza Stark Phenotypes for gene: DOCK11 were changed from autoimmune disease MONDO:0007179, DOCK11-related to Autoimmune disease with immune dysregulation, X-linked (ADMIDX), MIM#301109
Mendeliome v1.967 ZNF808 Krithika Murali Marked gene: ZNF808 as ready
Mendeliome v1.967 ZNF808 Krithika Murali Gene: znf808 has been classified as Green List (High Evidence).
Mendeliome v1.967 ZNF808 Krithika Murali Classified gene: ZNF808 as Green List (high evidence)
Mendeliome v1.967 ZNF808 Krithika Murali Added comment: Comment on list classification: Green in Genomics England PanelApp neonatal diabetes panel with both of these papers cited in their review. Note that De Franco et al has not been peer-reviewed, however, the evidence provided is strong and from a reputable source.
Mendeliome v1.967 ZNF808 Krithika Murali Gene: znf808 has been classified as Green List (High Evidence).
Mendeliome v1.966 ZNF808 Hazel Phillimore gene: ZNF808 was added
gene: ZNF808 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF808 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF808 were set to PMID: 37308312
Phenotypes for gene: ZNF808 were set to non-syndromic neonatal diabetes; MONDO:0016391
Review for gene: ZNF808 was set to GREEN
Added comment: PMID: 37308312; Alqahtani, MA. et al. (2023) Clin Genet. doi: 10.1111/cge.14389.
Three siblings in one consanguineous Saudi Arabian family with non-syndromic neonatal diabetes, all with a homozygous frameshift variant, NM_001321425.2:c.1448dupA, p.(Tyr483*), in ZNF808. (Same nucleotide and amino acid numbering as for the MANE SELECT transcript, NM_001039886.4).
This variant has been entered as likely pathogenic in ClinVar by this group.
This variant occurs in the last exon of the gene and is therefore not NMD-predicted. Instead it is predicted to cause a truncated protein.
This paper shows a diagram with several other truncating variants in this exon, which were reported in the paper by De Franco, E. et al. (2021).
(These patients also had low vitamin D levels, suggesting an association, and is consistent with other studies looking into loci that are associated with vitamin D).

De Franco, E. et al. (2021) medRxiv 08.23.21262262. (Exeter, UK):
Firstly, this group found a homozygous variant NM_001039886.3:c.637del, p.(Leu213*) that is predicted to cause a truncated protein, and also a homozygous CNV Chr19(GRCh37):g.53057128_53100968del (predicted to cause a deletion of exons 4 and 5) in two unrelated affected individuals. These patients had pancreatic agenesis, defined as insulin-dependent diabetes in the first 6 months of life (neonatal diabetes) and exocrine pancreatic insufficiency. Both were from consanguineous families. Parents were subsequently tested and shown to be heterozygous carriers.
They then investigated 232 additional patients who had been diagnosed with neonatal diabetes before the age of 6 months and found ten more homozygous ZNF808 variants. Six were nonsense: p.(Gln194*), p.(Cys233*), p.(Tyr427*), p.(Lys458*), p.(Tyr528*) and p.(Arg727*), and three were frameshift variants: p.(Ala379Valfs*157), p.(Leu588Profs*118), p.(Asn770Ilefs*98) and one was a whole-gene deletion.
All the frameshift and nonsense variants occurred in the last exon of the gene, which contains all 23 zinc finger domains; and therefore all of these variants are predicted to result in truncated proteins, and removal of some, if not all, those domains.
This group also carried out functional studies using an in vitro model of pancreas development and showed an aberrant activation of many transposable elements (mostly MER11 elements) that would be normally be repressed during early pancreas development.
Sources: Literature
Mendeliome v1.966 SART3 Krithika Murali Classified gene: SART3 as Green List (high evidence)
Mendeliome v1.966 SART3 Krithika Murali Gene: sart3 has been classified as Green List (High Evidence).
Mendeliome v1.965 SART3 Daniel Flanagan gene: SART3 was added
gene: SART3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SART3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SART3 were set to PMID: 37296101
Phenotypes for gene: SART3 were set to Neurodevelopmental disorder (MONDO#0700092), SART3-related; 46,XY disorder of sex development (MONDO:0020040), SART3-related
Review for gene: SART3 was set to GREEN
Added comment: Nine individuals from six families presenting with intellectual disability, global developmental delay, a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Additionally, two individuals had seizures and two had epileptiform activity reported on EEG.

Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro.
Sources: Expert list
Mendeliome v1.965 ARPC5 Elena Savva Classified gene: ARPC5 as Green List (high evidence)
Mendeliome v1.965 ARPC5 Elena Savva Gene: arpc5 has been classified as Green List (High Evidence).
Mendeliome v1.964 ARPC5 Elena Savva Classified gene: ARPC5 as Green List (high evidence)
Mendeliome v1.964 ARPC5 Elena Savva Gene: arpc5 has been classified as Green List (High Evidence).
Mendeliome v1.963 ARPC5 Elena Savva Marked gene: ARPC5 as ready
Mendeliome v1.963 ARPC5 Elena Savva Gene: arpc5 has been removed from the panel.
Mendeliome v1.963 NUDCD2 Krithika Murali Marked gene: NUDCD2 as ready
Mendeliome v1.963 NUDCD2 Krithika Murali Gene: nudcd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.963 NUDCD2 Seb Lunke Marked gene: NUDCD2 as ready
Mendeliome v1.963 NUDCD2 Seb Lunke Gene: nudcd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.963 NUDCD2 Seb Lunke Classified gene: NUDCD2 as Amber List (moderate evidence)
Mendeliome v1.963 NUDCD2 Seb Lunke Gene: nudcd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.962 NUDCD2 Ee Ming Wong gene: NUDCD2 was added
gene: NUDCD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDCD2 were set to 37272762
Phenotypes for gene: NUDCD2 were set to Multiple congenital anomalies (MONDO:0019042), NUDCD2-related
Penetrance for gene: NUDCD2 were set to unknown
Review for gene: NUDCD2 was set to AMBER
gene: NUDCD2 was marked as current diagnostic
Added comment: - Two unrelated probands, each biallelic for two variants in NUDCD2 (total 3x LoF variants, 1x missense variant)
- Immunoblotting of proteins extracted from the primary fibroblasts of one proband with 2x LoF variants demonstrated markedly reduced NUDCD2 levels compared to healthy individuals
Sources: Literature
Mendeliome v1.962 DCAF13 Seb Lunke Marked gene: DCAF13 as ready
Mendeliome v1.962 DCAF13 Seb Lunke Gene: dcaf13 has been classified as Red List (Low Evidence).
Mendeliome v1.962 RAB34 Elena Savva Marked gene: RAB34 as ready
Mendeliome v1.962 RAB34 Elena Savva Gene: rab34 has been classified as Green List (High Evidence).
Mendeliome v1.962 RAB34 Elena Savva Phenotypes for gene: RAB34 were changed from Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies to Multiple congenital anomalies, (MONDO:0019042), RAB34-related
Mendeliome v1.962 DCAF13 Seb Lunke Classified gene: DCAF13 as Red List (low evidence)
Mendeliome v1.962 DCAF13 Seb Lunke Gene: dcaf13 has been classified as Red List (Low Evidence).
Mendeliome v1.962 RAB34 Elena Savva Classified gene: RAB34 as Green List (high evidence)
Mendeliome v1.962 RAB34 Elena Savva Gene: rab34 has been classified as Green List (High Evidence).
Mendeliome v1.961 ARPC5 Paul De Fazio gene: ARPC5 was added
gene: ARPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARPC5 were set to 37349293; 37382373
Phenotypes for gene: ARPC5 were set to Combined immunodeficiency, ARPC5-related MONDO:0015131
Review for gene: ARPC5 was set to GREEN
gene: ARPC5 was marked as current diagnostic
Added comment: 4 individuals from 3 families reported with homozygous LoF variants. All had recurrent and severe infections. Other developmental anomalies were present but seemed variable.

PMID:37349293 reports 2 unrelated patients. Both had scoliosis. One had neurodevelopmental delay and brain atrophy. Patient 1 died at 15yo after a sudden episode of hemoptysis and hematochezia. Patient 2 died at 1yo because of progressive neurologic and respiratory disease; an autopsy was not performed.

PMID:37382373 reports 2 patients from the same family. One had multiple congenital anomalies including a congenital heart defect (CHD) (patent foramen ovale), cleft palate, and hypoplastic corpus callosum. The sibling also had CHD (moderate pulmonary stenosis and atrial septal defect).

Functional studies and a mouse model were supportive of the disease association.
Sources: Literature
Mendeliome v1.961 RPH3A Seb Lunke Marked gene: RPH3A as ready
Mendeliome v1.961 RPH3A Seb Lunke Gene: rph3a has been classified as Green List (High Evidence).
Mendeliome v1.961 DRG1 Krithika Murali Marked gene: DRG1 as ready
Mendeliome v1.961 DRG1 Krithika Murali Gene: drg1 has been classified as Green List (High Evidence).
Mendeliome v1.961 RPH3A Seb Lunke Classified gene: RPH3A as Green List (high evidence)
Mendeliome v1.961 RPH3A Seb Lunke Gene: rph3a has been classified as Green List (High Evidence).
Mendeliome v1.961 DRG1 Krithika Murali Classified gene: DRG1 as Green List (high evidence)
Mendeliome v1.961 DRG1 Krithika Murali Gene: drg1 has been classified as Green List (High Evidence).
Mendeliome v1.960 MIR204 Elena Savva Classified gene: MIR204 as Amber List (moderate evidence)
Mendeliome v1.960 MIR204 Elena Savva Gene: mir204 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.959 MIR204 Elena Savva Classified gene: MIR204 as Amber List (moderate evidence)
Mendeliome v1.959 MIR204 Elena Savva Gene: mir204 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.958 MIR204 Elena Savva Marked gene: MIR204 as ready
Mendeliome v1.958 MIR204 Elena Savva Gene: mir204 has been removed from the panel.
Mendeliome v1.958 DCAF13 Michelle Torres gene: DCAF13 was added
gene: DCAF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DCAF13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCAF13 were set to 36797467
Phenotypes for gene: DCAF13 were set to Neuromuscular disease (MONDO#0019056), DCAF13-related
Review for gene: DCAF13 was set to RED
Added comment: One consanguineous family, 4x individuals homozygous NM_015420.7(DCAF13)c.907 G > A; p.(Asp303Asn) (3x via WES and 1x via Sanger) with a neuromuscular disorder characterized by a waddling gait, limb deformities, muscular weakness and facial palsy.

In silicos analysis of mutant DCAF13 suggests that the amino acid change is deleterious and affects a ß-hairpin turn, within a WD40 domain of the protein which may decrease protein stability. Functional studies were not performed.

Previously, a heterozygous variant in DCAF13 with or without a heterozygous missense variant in CCN3, was suggested to cause inherited cortical myoclonic tremor with epilepsy. In addition, a heterozygous DCAF13 variant has been associated with autism spectrum disorder.
Sources: Literature
Mendeliome v1.958 ERI1 Elena Savva Marked gene: ERI1 as ready
Mendeliome v1.958 ERI1 Elena Savva Gene: eri1 has been classified as Green List (High Evidence).
Mendeliome v1.958 ERI1 Elena Savva Classified gene: ERI1 as Green List (high evidence)
Mendeliome v1.958 ERI1 Elena Savva Gene: eri1 has been classified as Green List (High Evidence).
Mendeliome v1.957 ERI1 Elena Savva gene: ERI1 was added
gene: ERI1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERI1 were set to 37352860
Phenotypes for gene: ERI1 were set to Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related, Intellectual disability (MONDO#0001071), ERI1-related
Review for gene: ERI1 was set to GREEN
Added comment: PMID: 37352860 - 8 individuals from 7 unrelated families
- Patients with biallelic missense show a MORE severe spondyloepimetaphyseal dysplasia, syndactyly, brachydactyly/clinodactyly/camptodactyly
- Patients with biallelic null/whole gene deletion had mild ID and digit anomalies including brachydactyly/clinodactyly/camptodactyly
- Patient chet for a missense and PTC variant has a blended phenotype with short stature, syndactyly, brachydactyly/clinodactyly/camptodactyly, mild ID and failure to thrive

- Missense variants were functionally shown to not be able to rescue 5.8S rRNA processing in KO HeLa cells
- K/O mice had neonatal lethality with growth defects, brachydactyly. Skeletal-specific K/O had mild platyspondyly, had more in keeping with patients with null variants than missense

More severe phenotype hypothesised due to "exonuclease-dead proteins may compete for the target RNA molecules with other exonucleases that have functional redundancy
with ERI1, staying bound to those RNA molecules"
Sources: Literature
Mendeliome v1.956 RAB34 Sarah Pantaleo gene: RAB34 was added
gene: RAB34 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB34 were set to PMID: 37384395
Phenotypes for gene: RAB34 were set to Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies
Penetrance for gene: RAB34 were set to Complete
Review for gene: RAB34 was set to GREEN
Added comment: Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogenous disorders characterised by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in >20 genes encoding ciliary proteins have been found to cause OFDS.

Identified by WES biallelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families (aided by GeneMatcher).

Affected individuals presented a novel form of OFDS accompanied by cardiac, cerebral, skeletal (eg. Shortening of long bones), and anorectal defects.

RAB34 encodes a member of the Lab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Protein products of pathogenic variants clustered near the RAB34 C-terminus exhibit a strong loss of function.

Onset is prenatal (multiple developmental defects including short femur, polydactyly, heart malformations, kidney malformations, brain malformations), resulting in medical termination for three probands.

In the fourth, the only one alive at birth, proband born at 39+5 weeks, normal growth parameters after pregnancy with polyhydramnios, corpus callosum agenesis and polydactyly. Respiratory distress at birth.

All four probands presented typical features of ciliopathy disorders, overlapping with oral, facial and digital abnormalities.

All with homozygous missense variants. All absent in gnomAD (in homozygous state). Sanger sequencing confirmed mode of inheritance.
Sources: Literature
Mendeliome v1.956 DRG1 Dean Phelan gene: DRG1 was added
gene: DRG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DRG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DRG1 were set to PMID: 37179472
Phenotypes for gene: DRG1 were set to Neurodevelopmental disorder (MONDO:0700092), DRG1-related
Review for gene: DRG1 was set to GREEN
Added comment: PMID: 37179472
- Biallelic variants were identified in four affected individuals from three distinct families with neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature and craniofacial anomalies. Functional studies show the variants result in a loss of function.
Sources: Literature
Mendeliome v1.956 RPH3A Lucy Spencer gene: RPH3A was added
gene: RPH3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPH3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPH3A were set to 37403762; 29441694
Phenotypes for gene: RPH3A were set to Neurodevelopmental disorder (MONDO#0700092), RPH3A-related
Review for gene: RPH3A was set to GREEN
Added comment: PMID: 37403762- 6 patients with RPH3A variant. All 6 have ID, 4 have epilepsy, 2 with obesity, 1 with dysmorphic features. All 6 have missense variants, 3 shown to be de novo, the other 3 parents were not available for testing. I patient also had language and motor impairment, breathing issues and mixed hypo/hypertonia- he also had variants in CUL4B, PRKAG2, SCN4A, none of these genes cause seizures (which he had).

Patch clamp studies on 2 of the missense showed they increased either the number of NMDA receptors on neuron membrane surface or increased their conductance. Study suggests that the variants interrupt the normal role of RPH3A activity at the synaptic NMDAR complex which is needed for the induction of synaptic plasticity and NMDAR-dependant behaviours

Previously this gene was reported in PMID: 29441694- 1 girl with learning disabilities, tremors, ataxia, hyperglycemia and muscle fatigability. Chet for 2 RPH3A missense. Functional analysis showed strong and marginal impairment of protein binding for each variant. this is the only biallelic report currently.
Sources: Literature
Mendeliome v1.956 MIR204 Chern Lim gene: MIR204 was added
gene: MIR204 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIR204 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIR204 were set to 26056285; 37321975
Phenotypes for gene: MIR204 were set to Retinal dystrophy and iris coloboma with or without cataract (MIM#616722)
Mode of pathogenicity for gene: MIR204 was set to Other
Review for gene: MIR204 was set to GREEN
gene: MIR204 was marked as current diagnostic
Added comment: PMID: 26056285
- Bilateral coloboma and rod-cone dystrophy with or without cataract in nine individuals of a five-generation family.
- Heterozygous n.37C>T segregates with the disease in all affected individuals.
- Functional analysis including transcriptome analysis showed this variant resulted in significant alterations of miR-204 targeting capabilities. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family.
- Authors suggested gain of function is the likely disease mechanism.

PMID: 37321975
- Four members of a three-generation family with early-onset chorioretinal dystrophy, heterozygous for n.37C>T.
- Additionally, four family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants.
- Haplotype analysis excluded relatedness with the family reported in PMID: 26056285.
- In silico analysis of the MIR204 n.37C>T variant reveals profound changes to its target mRNAs and suggests a gain-of-function mechanism of miR 204 variant.
Sources: Literature
Mendeliome v1.956 CD2AP Bryony Thompson Phenotypes for gene: CD2AP were changed from Glomerulosclerosis, focal segmental, 3, OMIM #607832 to focal segmental glomerulosclerosis 3, susceptibility to MONDO:0011917
Mendeliome v1.955 CD2AP Bryony Thompson Publications for gene: CD2AP were set to 30612599; 17713465; 10997929; 12764198; 15951437
Mendeliome v1.954 CD2AP Bryony Thompson Publications for gene: CD2AP were set to 30612599; 17713465
Mendeliome v1.953 CD2AP Bryony Thompson Mode of inheritance for gene: CD2AP 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 v1.952 CD2AP Bryony Thompson Classified gene: CD2AP as Green List (high evidence)
Mendeliome v1.952 CD2AP Bryony Thompson Added comment: Comment on list classification: Definitive gene-disease assessment by ClinGen Glomerulopathy GCEP - classified 13/12/2021
Mendeliome v1.952 CD2AP Bryony Thompson Gene: cd2ap has been classified as Green List (High Evidence).
Mendeliome v1.951 CBLB Zornitza Stark Phenotypes for gene: CBLB were changed from Autoimmune disease, MONDO:0007179 to Autoimmune disease, multisystem, infantile-onset, 3, MIM# 620430
Mendeliome v1.950 INTS11 Zornitza Stark Phenotypes for gene: INTS11 were changed from intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, MIM# 620428
Mendeliome v1.949 SRRM2 Zornitza Stark Phenotypes for gene: SRRM2 were changed from Neurodevelopmental disorder MONDO:0700092 SRRM2-related to Intellectual developmental disorder, autosomal dominant 72, MIM# 620439
Mendeliome v1.948 NUP54 Zornitza Stark Phenotypes for gene: NUP54 were changed from Striatonigral degeneration, MONDO:0003122, NUP54-related; Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia to Dystonia 37, early-onset, with striatal lesions, MIM# 620427; Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Mendeliome v1.947 BRWD1 Zornitza Stark Phenotypes for gene: BRWD1 were changed from Asthenoteratozoospermia, likely primary ciliary dyskinesia to Ciliary dyskinesia, primary, 51, MIM# 620438
Mendeliome v1.946 UBE3B Achchuthan Shanmugasundram reviewed gene: UBE3B: Rating: AMBER; Mode of pathogenicity: None; Publications: 23200864, 23687348, 37010288; Phenotypes: Kaufman oculocerebrofacial syndrome, OMIM:244450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.946 SMARCB1 Achchuthan Shanmugasundram reviewed gene: SMARCB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: Coffin-Siris syndrome 3, OMIM:614608; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 NOTCH2 Achchuthan Shanmugasundram reviewed gene: NOTCH2: Rating: AMBER; Mode of pathogenicity: None; Publications: 9188663, 30329210, 37010288; Phenotypes: Hajdu-Cheney syndrome, OMIM:102500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 AUTS2 Achchuthan Shanmugasundram reviewed gene: AUTS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31788251, 37010288; Phenotypes: Intellectual developmental disorder, autosomal dominant 26, OMIM:615834; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 ARID1A Achchuthan Shanmugasundram reviewed gene: ARID1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 ZC4H2 Achchuthan Shanmugasundram changed review comment from: There are ten unrelated patients reported with cleft palate. Hence, this gene should be added with green rating to 'clefting disorders' panel.

PMID:31206972 - Of 42 families identified with variants in de novo and inherited heterozygous variants in ZC4H2 gene, eight patients had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with monoallelic sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.; to: There are ten unrelated patients reported with cleft palate. Hence, this gene should be added with green rating to 'clefting disorders' panel.

PMID:31206972 - Of 42 families identified with de novo and inherited variants in ZC4H2 gene, eight patients had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.
Mendeliome v1.946 ZC4H2 Achchuthan Shanmugasundram edited their review of gene: ZC4H2: Changed 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 v1.946 ZC4H2 Achchuthan Shanmugasundram edited their review of gene: ZC4H2: Changed publications: 31206972, 37010288; Changed phenotypes: Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Mendeliome v1.946 ZC4H2 Achchuthan Shanmugasundram reviewed gene: ZC4H2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 GCSH Zornitza Stark Phenotypes for gene: GCSH were changed from Glycine encephalopathy MIM#605899; neurodevelopmental disorder MONDO#0700092, GCHS-related to Multiple mitochondrial dysfunctions syndrome 7, MIM# 620423
Mendeliome v1.945 EWSR1 Bryony Thompson Classified gene: EWSR1 as Red List (low evidence)
Mendeliome v1.945 EWSR1 Bryony Thompson Added comment: Comment on list classification: Disputed gene-disease validity assessment by ClinGen ALS spectrum disorders GCEP - 11/10/2022
Mendeliome v1.945 EWSR1 Bryony Thompson Gene: ewsr1 has been classified as Red List (Low Evidence).
Mendeliome v1.944 STAG2 Achchuthan Shanmugasundram reviewed gene: STAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28296084, 29263825, 30158690, 31334757, 33014403, 37010288; Phenotypes: Holoprosencephaly 13, X-linked, OMIM:301043, Mullegama-Klein-Martinez syndrome, OMIM:301022; 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 v1.944 SMARCA4 Achchuthan Shanmugasundram reviewed gene: SMARCA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: Coffin-Siris syndrome 4, OMIM:614609; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.944 XYLT1 Elena Savva Mode of inheritance for gene: XYLT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.943 POGZ Achchuthan Shanmugasundram changed review comment from: Although there are more than three unrelated cases reported with either cleft palate or bifid uvula in total, this phenotype is not consistently present in patients with monoallelic variants in POGZ gene. Hence, this gene should only be added with amber rating in 'Clefting disorders panel'.

PMID:26739615 - Five unrelated individuals were identified with de novo truncating variants in POGZ gene, of which one individual had cleft palate and another one had bifid uvula.

PMID:31782611 - In this cohort of 22 individuals with 21 different loss of function variants in POGZ, two patients were reported with bifid uvula.

DECIPHER database - Of 42 patients with heterozygous sequence variants, one had cleft palate and another one had bifid uvula (PMID:37010288).

The OMIM entry for White-Sutton syndrome (MIM #616364) does not currently include cleft lip/ palate as one of the clinical manifestations of this syndrome.; to: Although there are more than three unrelated cases reported with either cleft palate or bifid uvula in total, this phenotype is not consistently present in patients with monoallelic variants in POGZ gene. Hence, this gene should only be added with amber rating in 'Clefting disorders' panel.

PMID:26739615 - Five unrelated individuals were identified with de novo truncating variants in POGZ gene, of which one individual had cleft palate and another one had bifid uvula.

PMID:31782611 - In this cohort of 22 individuals with 21 different loss of function variants in POGZ, two patients were reported with bifid uvula.

DECIPHER database - Of 42 patients with heterozygous sequence variants, one had cleft palate and another one had bifid uvula (PMID:37010288).

The OMIM entry for White-Sutton syndrome (MIM #616364) does not currently include cleft lip/ palate as one of the clinical manifestations of this syndrome.
Mendeliome v1.943 POGZ Achchuthan Shanmugasundram reviewed gene: POGZ: Rating: AMBER; Mode of pathogenicity: None; Publications: 26739615, 31782611, 37010288; Phenotypes: White-Sutton syndrome, OMIM:616364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 PGAP3 Achchuthan Shanmugasundram reviewed gene: PGAP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28390064, 37010288; Phenotypes: Hyperphosphatasia with impaired intellectual development syndrome 4, OMIM:615716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.943 KMT2A Achchuthan Shanmugasundram reviewed gene: KMT2A: Rating: AMBER; Mode of pathogenicity: None; Publications: 25929198, 30305169, 31710778, 37010288; Phenotypes: Wiedemann-Steiner syndrome, OMIM:605130; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 GLI2 Achchuthan Shanmugasundram reviewed gene: GLI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24744436, 37010288; Phenotypes: Culler-Jones syndrome, OMIM:615849, Holoprosencephaly 9, OMIM:610829; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 FGFR3 Achchuthan Shanmugasundram reviewed gene: FGFR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 22565872, 29150894, 37010288; Phenotypes: Muenke syndrome, OMIM:602849, Hypochondroplasia, OMIM:146000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 SPTSSA Zornitza Stark Phenotypes for gene: SPTSSA were changed from complex hereditary spastic paraplegia, MONDO:0015150 to Spastic paraplegia 90B, autosomal recessive , MIM# 620417; Spastic paraplegia 90A, autosomal dominant, MIM# 620416
Mendeliome v1.942 SPTSSA Zornitza Stark reviewed gene: SPTSSA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 90B, autosomal recessive , MIM# 620417, Spastic paraplegia 90A, autosomal dominant, MIM# 620416; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.942 VWA8 Zornitza Stark Phenotypes for gene: VWA8 were changed from Retinitis pigmentosa (MONDO:0019200), VWA8-related to Retinitis pigmentosa 97, MIM#620422
Mendeliome v1.941 VWA8 Zornitza Stark reviewed gene: VWA8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 97, MIM#620422; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.941 ARID1B Achchuthan Shanmugasundram changed review comment from: There are at least three unrelated cases with monoallelic variants in ARID1B gene reported with either cleft palate, cleft uvula or bifid uvula. Hence, this gene can be added with green rating in the Clefting disorders panel.

PMID:30349098 - On this web-based survey based on previously reported features of patients with variants in ARID1B gene (143 patients in total), which also included submissions to DECIPHER database, two patients were identified with cleft palate, one with cleft uvula, two with bifid uvula and three with sub mucous cleft. Although variants identified in these patients are reported in this publication, there is no association of individual patients to phenotypes available.

One patient with ARID1B variant (c.3183_3184​insT/ p.Tyr1062LeufsTer10) was reported with submucous cleft soft palate and two patients with ARID1B variants (c.4155_4156​insA/ p.Asn1386LysfsTer18 & c.2620+5G​>A) were reported with bifid uvula in DECIPHER database.; to: Although there are more than three unrelated cases with ARID1B monoallelic variants reported with either cleft palate, cleft uvula or bifid uvula, clefting isn not consistently present in patients with ARID1B variants. Hence, this gene can be added with amber rating in the Clefting disorders panel.

PMID:30349098 - On this web-based survey based on previously reported features of patients with variants in ARID1B gene (143 patients in total), which also included submissions to DECIPHER database, two patients were identified with cleft palate, one with cleft uvula, two with bifid uvula and three with sub mucous cleft. Although variants identified in these patients are reported in this publication, there is no association of individual patients to phenotypes available.

Of >100 patients with ARID1B variants in the DECIPHER database, only one patient (c.3183_3184​insT/ p.Tyr1062LeufsTer10) was reported with submucous cleft soft palate and two patients (c.4155_4156​insA/ p.Asn1386LysfsTer18 & c.2620+5G​>A) were reported with bifid uvula.
Mendeliome v1.941 ARID1B Achchuthan Shanmugasundram edited their review of gene: ARID1B: Changed rating: AMBER
Mendeliome v1.941 CHD4 Achchuthan Shanmugasundram changed review comment from: This gene should be added to the Clefting disorders panel with a green rating as there are four unrelated cases presenting with either cleft palate and/or bifid uvula.

PMID:3138819 reported a patient with heterozygous variant (p.Gln715Ter) in CHD4 that had cleft palate and pierre robin. In addition, another patient identified with heterozygous variant p.Arg1127Gln was reported with bifid uvula.

In addition, DDD study reported two patients with likely pathogenic heterozygous variants who had cleft palate in addition to several other clinical presentations including global developmental delay (PMID:37010288); to: Although there are four unrelated cases presenting with either cleft palate and/or bifid uvula, this phenotype is not consistent among patients identified with monoallelic variants in CHD4 gene. Hence, this gene should be added to the Clefting disorders panel with amber rating.

PMID:31388190 reported 32 patients with heterozygous variants in CHD4 gene, of which one patient (p.Gln715Ter) had cleft palate and pierre robin. In addition, another patient identified with heterozygous variant p.Arg1127Gln was reported with bifid uvula.

In addition, 2 out of 10 patients with pathogenic/ likely pathogenic heterozygous variants from the DDD study were reported with cleft palate in addition to several other clinical presentations including global developmental delay (PMID:37010288).
Mendeliome v1.941 CHD4 Achchuthan Shanmugasundram edited their review of gene: CHD4: Changed rating: AMBER
Mendeliome v1.941 CNTNAP1 Achchuthan Shanmugasundram reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28374019, 29511323, 29882456, 37010288; Phenotypes: Hypomyelinating neuropathy, congenital, 3, OMIM:618186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.941 ARID1B Achchuthan Shanmugasundram reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30349098, 37010288; Phenotypes: Coffin-Siris syndrome 1, OMIM:135900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.941 TUFT1 Zornitza Stark Publications for gene: TUFT1 were set to https://doi.org/10.1093/bjd/ljac026
Mendeliome v1.940 TUFT1 Zornitza Stark edited their review of gene: TUFT1: Changed publications: 36689522
Mendeliome v1.940 TUFT1 Zornitza Stark Phenotypes for gene: TUFT1 were changed from Ectodermal dysplasia, MONDO:0019287, TUFT1-related to Woolly hair-skin fragility syndrome, MIM# 620415
Mendeliome v1.939 TUFT1 Zornitza Stark edited their review of gene: TUFT1: Changed phenotypes: Woolly hair-skin fragility syndrome, MIM# 620415
Mendeliome v1.939 CHD4 Achchuthan Shanmugasundram reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31388190, 37010288; Phenotypes: Sifrim-Hitz-Weiss syndrome, OMIM:617159; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.939 KLHL9 Bryony Thompson Marked gene: KLHL9 as ready
Mendeliome v1.939 KLHL9 Bryony Thompson Gene: klhl9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.939 KLHL9 Bryony Thompson Classified gene: KLHL9 as Amber List (moderate evidence)
Mendeliome v1.939 KLHL9 Bryony Thompson Gene: klhl9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.938 KLHL9 Bryony Thompson changed review comment from: A single German family reported in 2010, segregating a missense variant c.796T>C p.Leu95Phe. In vitro functional assays demonstrated the variant diminishes the binding of KLHL9 to Cul3.
Sources: Literature; to: A single German family reported in 2010, segregating a missense variant c.796T>C p.Leu95Phe. In vitro functional assays demonstrated the variant diminishes the binding of KLHL9 to Cul3.
Ankle flexion contracture is reported in a mouse model, but there are other significant features present in the homozygous animals too - https://www.mousephenotype.org/data/genes/MGI:2180122
Sources: Literature
Mendeliome v1.938 KLHL9 Bryony Thompson gene: KLHL9 was added
gene: KLHL9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLHL9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL9 were set to 20554658
Phenotypes for gene: KLHL9 were set to distal myopathy MONDO:0018949
Review for gene: KLHL9 was set to AMBER
Added comment: A single German family reported in 2010, segregating a missense variant c.796T>C p.Leu95Phe. In vitro functional assays demonstrated the variant diminishes the binding of KLHL9 to Cul3.
Sources: Literature
Mendeliome v1.937 MYMX Bryony Thompson Marked gene: MYMX as ready
Mendeliome v1.937 MYMX Bryony Thompson Gene: mymx has been classified as Amber List (Moderate Evidence).
Mendeliome v1.937 MYMX Bryony Thompson Classified gene: MYMX as Amber List (moderate evidence)
Mendeliome v1.937 MYMX Bryony Thompson Gene: mymx has been classified as Amber List (Moderate Evidence).
Mendeliome v1.936 MYMX Bryony Thompson gene: MYMX was added
gene: MYMX was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYMX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYMX were set to 35642635
Phenotypes for gene: MYMX were set to Carey-Fineman-Ziter syndrome MONDO:0009700
Review for gene: MYMX was set to AMBER
Added comment: Single family, two siblings with weakness of the facial musculature, hypomimic face, increased overbite, micrognathia, and facial dysmorphism with homozygous p.Arg46*. The phenotype resembles CFZ syndrome. The variant prevents fusion of myoblasts from patient-derived iPSCs. Mouse model recapitulates a lethal CFZS-like phenotype.
Sources: Literature
Mendeliome v1.935 NOP10 Zornitza Stark Phenotypes for gene: NOP10 were changed from Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Telomere syndrome MONDO:0100137 to Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9, MIM# 620400
Mendeliome v1.934 NOP10 Zornitza Stark Publications for gene: NOP10 were set to 17507419; 32554502
Mendeliome v1.933 NOP10 Zornitza Stark Mode of inheritance for gene: NOP10 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.932 NOP10 Zornitza Stark edited their review of gene: NOP10: Added comment: PMID 32139460: large multiplex family with 4 affected individuals segregating a heterozygous variant.; Changed rating: AMBER; Changed publications: 17507419, 32139460; Changed phenotypes: Dyskeratosis congenita, autosomal recessive 1, MIM#224230, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9, MIM# 620400; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.932 MFN2 Zornitza Stark Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM #609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM #617087; Hereditary motor and sensory neuropathy VIA, OMIM #601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A 609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, MIM# 617087; Hereditary motor and sensory neuropathy VIA, MIM# 601152; Lipomatosis, multiple symmetric, with or without peripheral neuropathy, MIM# 151800
Mendeliome v1.931 MFN2 Zornitza Stark edited their review of gene: MFN2: Changed phenotypes: Charcot-Marie-Tooth disease, axonal, type 2A2A 609260, Charcot-Marie-Tooth disease, axonal, type 2A2B, MIM# 617087, Hereditary motor and sensory neuropathy VIA, MIM# 601152, Lipomatosis, multiple symmetric, with or without peripheral neuropathy, MIM# 151800
Mendeliome v1.931 RHOBTB2 Zornitza Stark Publications for gene: RHOBTB2 were set to 29276004; 29768694
Mendeliome v1.930 RHOBTB2 Zornitza Stark Mode of pathogenicity for gene: RHOBTB2 was changed from Other to None
Mendeliome v1.929 RHOBTB2 Zornitza Stark Mode of inheritance for gene: RHOBTB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.928 RHOBTB2 Zornitza Stark reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37165955; Phenotypes: Epileptic encephalopathy, early infantile, 64, MIM#618004; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.928 NFATC1 Zornitza Stark Marked gene: NFATC1 as ready
Mendeliome v1.928 NFATC1 Zornitza Stark Gene: nfatc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.928 NFATC1 Zornitza Stark Classified gene: NFATC1 as Amber List (moderate evidence)
Mendeliome v1.928 NFATC1 Zornitza Stark Gene: nfatc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.927 NFATC1 Zornitza Stark gene: NFATC1 was added
gene: NFATC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NFATC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC1 were set to 37249233
Phenotypes for gene: NFATC1 were set to Inborn error of immunity, MONDO:0003778, NFATC1-related; Combined Immune deficiency
Review for gene: NFATC1 was set to AMBER
Added comment: 3 individuals from a multigenerational consanguineous pedigree with early-onset sinopulmonary infections and bronchiectasis, recurrent viral (warts) and bacterial (folliculitis and abscesses) skin infections, hypogammaglobulinemia, lower CD4+/CD8+ T-cell ratio and lower recent thymic emigrants compared with the age-matched controls. Lymphocyte proliferation responses to PHA and CD3/CD28 stimulations were defective.

Single pedigree with supportive functional studies.
Sources: Literature
Mendeliome v1.926 CNTN1 Bryony Thompson Phenotypes for gene: CNTN1 were changed from Myopathy, congenital, Compton-North 612540 to Compton-North congenital myopathy MONDO:0012929; fetal akinesia deformation sequence MONDO:0008824
Mendeliome v1.925 CNTN1 Bryony Thompson Publications for gene: CNTN1 were set to 19026398
Mendeliome v1.924 CNTN1 Bryony Thompson Classified gene: CNTN1 as Green List (high evidence)
Mendeliome v1.924 CNTN1 Bryony Thompson Gene: cntn1 has been classified as Green List (High Evidence).
Mendeliome v1.923 CNTN1 Bryony Thompson reviewed gene: CNTN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19026398, 10595523, 22242131, 32779773; Phenotypes: Compton-North congenital myopathy MONDO:0012929, fetal akinesia deformation sequence MONDO:0008824; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.923 TNNT1 Zornitza Stark Phenotypes for gene: TNNT1 were changed from Nemaline myopathy 5, Amish type, MIM# 605355; nemaline myopathy MONDO:0018958 to Nemaline myopathy 5, Amish type, MIM# 605355; Nemaline myopathy-5B with rigid spine and respiratory insufficiency (NEM5B), MIM#620386; nemaline myopathy-5C (NEM5C), autosomal dominant, MIMD620389
Mendeliome v1.922 TNNT1 Zornitza Stark edited their review of gene: TNNT1: Changed phenotypes: Nemaline myopathy 5, Amish type, MIM# 605355, Nemaline myopathy-5B with rigid spine and respiratory insufficiency (NEM5B), MIM#620386, nemaline myopathy-5C (NEM5C), autosomal dominant, MIMD620389
Mendeliome v1.922 CHRM5 Zornitza Stark Marked gene: CHRM5 as ready
Mendeliome v1.922 CHRM5 Zornitza Stark Gene: chrm5 has been classified as Red List (Low Evidence).
Mendeliome v1.922 MRPL50 Zornitza Stark Marked gene: MRPL50 as ready
Mendeliome v1.922 MRPL50 Zornitza Stark Gene: mrpl50 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.922 MRPL50 Zornitza Stark Classified gene: MRPL50 as Amber List (moderate evidence)
Mendeliome v1.922 MRPL50 Zornitza Stark Gene: mrpl50 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.921 MRPL50 Zornitza Stark reviewed gene: MRPL50: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial disease, MONDO: 004470, MRPL50-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.921 MOS Zornitza Stark Marked gene: MOS as ready
Mendeliome v1.921 MOS Zornitza Stark Gene: mos has been classified as Green List (High Evidence).
Mendeliome v1.921 MOS Zornitza Stark Phenotypes for gene: MOS were changed from Early embryonic arrest and fragmentation; infertility to Infertility disorder, MONDO:0005047, MOS-related; Early embryonic arrest and fragmentation
Mendeliome v1.920 MOS Zornitza Stark Classified gene: MOS as Green List (high evidence)
Mendeliome v1.920 MOS Zornitza Stark Gene: mos has been classified as Green List (High Evidence).
Mendeliome v1.919 HMGCR Zornitza Stark Phenotypes for gene: HMGCR were changed from [Low density lipoprotein cholesterol level QTL 3] to autosomal recessive limb-girdle muscular dystrophy (MONDO: 0015152), HMGCR-related
Mendeliome v1.918 HMGCR Zornitza Stark Publications for gene: HMGCR were set to 18354102; 29480216
Mendeliome v1.917 HMGCR Zornitza Stark Mode of inheritance for gene: HMGCR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.916 HMGCR Zornitza Stark Classified gene: HMGCR as Green List (high evidence)
Mendeliome v1.916 HMGCR Zornitza Stark Gene: hmgcr has been classified as Green List (High Evidence).
Mendeliome v1.915 MOS Melanie Marty gene: MOS was added
gene: MOS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MOS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MOS were set to PMID: 34779126; PMID: 34997960; PMID: 36403623; PMID: 35670744
Phenotypes for gene: MOS were set to Early embryonic arrest and fragmentation; infertility
Review for gene: MOS was set to GREEN
Added comment: PMID: 34779126: 3 x females with infertility with biallelic MOS variants identified. Using oocyte-specific Erk1/2 knockout mice, they verified that MOS-ERK signal pathway inactivation in oocytes caused early embryonic arrest and fragmentation.

PMID: 34997960: 2 x females with biallelic MOS variants. Functional studies showed a reduction of protein for two of these variants (missense and frameshift). Functional studies also showed these variants reduced the ability of MOS to phosphorylate its downstream target, extracellular signal-regulated kinase 1/2.

PMID: 35670744 1 x additional family (twins) with infertility and abnormal oocyte morphology with large first polar body. Functional studies showed the MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells. In addition, functional studies also showed when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1.

PMID: 36403623 1 x female with primary infertility, patient’s oocytes had a large polar body and poor embryonic development, hom missense variant in MOS identified.
Sources: Literature
Mendeliome v1.915 TAPT1 Elena Savva Publications for gene: TAPT1 were set to 26365339
Mendeliome v1.914 UNC79 Zornitza Stark Phenotypes for gene: UNC79 were changed from Neurodevelopmental disorder (MONDO:0700092), UNC70-related to Neurodevelopmental disorder (MONDO:0700092), UNC79-related
Mendeliome v1.913 NSUN6 Elena Savva Classified gene: NSUN6 as Amber List (moderate evidence)
Mendeliome v1.913 NSUN6 Elena Savva Gene: nsun6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.912 NSUN6 Elena Savva Classified gene: NSUN6 as Amber List (moderate evidence)
Mendeliome v1.912 NSUN6 Elena Savva Gene: nsun6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.911 NSUN6 Elena Savva Marked gene: NSUN6 as ready
Mendeliome v1.911 NSUN6 Elena Savva Gene: nsun6 has been removed from the panel.
Mendeliome v1.911 TAPT1 Paul De Fazio reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36697720, 36652330; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.911 PRSS8 Elena Savva Classified gene: PRSS8 as Amber List (moderate evidence)
Mendeliome v1.911 PRSS8 Elena Savva Gene: prss8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.910 PRSS8 Elena Savva Marked gene: PRSS8 as ready
Mendeliome v1.910 PRSS8 Elena Savva Gene: prss8 has been removed from the panel.
Mendeliome v1.910 RNH1 Ain Roesley Phenotypes for gene: RNH1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNH1-related to Neurodevelopmental disorder, MONDO:0700092, RNH1-related; encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related
Mendeliome v1.909 RNH1 Ain Roesley Publications for gene: RNH1 were set to PMID: 36935417
Mendeliome v1.909 RNH1 Ain Roesley Classified gene: RNH1 as Green List (high evidence)
Mendeliome v1.909 RNH1 Ain Roesley Gene: rnh1 has been classified as Green List (High Evidence).
Mendeliome v1.908 PRSS8 Lucy Spencer gene: PRSS8 was added
gene: PRSS8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRSS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRSS8 were set to 36715754
Phenotypes for gene: PRSS8 were set to ichthyosis MONDO:0019269, PRSS8-related
Review for gene: PRSS8 was set to AMBER
Added comment: PMID: 36715754
1 family with 3 affected sons with congenital ichthyosis, consanguineous parents. All 3 affected members are homozygous for a canonical splice in PRSS8, quantitative RT-PCR showed a significant reduction in normal PRSS8 transcript.

A second family with 4 affected members (proband and 3 cousins) with ichthyosis (3 also had autism), also consanguineous. Only the proband was tested who is homozygous for a missense in PTSS8. However this patient also had a TAAR1 missense (no disease association, but the paper suggests this could be responsible for the autism phenotype- KO mice have abnormal learning behaviour).
Sources: Literature
Mendeliome v1.908 RNH1 Dean Phelan reviewed gene: RNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37191094; Phenotypes: encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.908 UNC79 Elena Savva Marked gene: UNC79 as ready
Mendeliome v1.908 UNC79 Elena Savva Gene: unc79 has been classified as Green List (High Evidence).
Mendeliome v1.908 UNC79 Elena Savva Phenotypes for gene: UNC79 were changed from Neurodevelopmental disorderMONDO:0700092 to Neurodevelopmental disorder (MONDO:0700092), UNC70-related
Mendeliome v1.907 UNC79 Elena Savva Classified gene: UNC79 as Green List (high evidence)
Mendeliome v1.907 UNC79 Elena Savva Gene: unc79 has been classified as Green List (High Evidence).
Mendeliome v1.906 NSUN6 Michelle Torres gene: NSUN6 was added
gene: NSUN6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NSUN6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSUN6 were set to 37226891
Phenotypes for gene: NSUN6 were set to neurodevelopmental disorder MONDO:0700092, NSUN6-related
Review for gene: NSUN6 was set to AMBER
Added comment: Three unrelated consanguineous families with developmental delay, intellectual disability, motor delay, and behavioral anomalies. WES detected homozygous variants:
- p.(Leu9Glufs*3): even though authors say is is predicted to cause NMD, it actually is NMD escape. No further studies were performed. A deceased affected sibling and parents were NOT tested.
- p.(Asp323Asn): Shown to result in a misfolded protein. Methylation assay showed mutant could not catalyze m5C deposition in transcribed tRNACys and tRNAThr substrates in vitro. One of the parents and both unaffected siblings were shown to be carriers.
- p.(Glu441Profs*15): truncation (full protein is 470aa) which would result in loss of residues involved in recognition and methylation. Shown to result in a misfolded protein. Parents were shown carriers.
Sources: Literature
Mendeliome v1.906 HMGCR Naomi Baker reviewed gene: HMGCR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37167966, 36745799; Phenotypes: autosomal recessive limb-girdle muscular dystrophy (MONDO: 0015152), HMGCR-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.906 UNC79 Krithika Murali gene: UNC79 was added
gene: UNC79 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC79 were set to PMID:37183800
Phenotypes for gene: UNC79 were set to Neurodevelopmental disorderMONDO:0700092
Review for gene: UNC79 was set to AMBER
Added comment: PMID:37183800 Bayat et al 2023 report 6 unrelated patients with heterozygous NMD-predicted LoF variants in UNC79 - x1 canonical splice site variant, x5 nonsense/frameshift. 5 were confirmed de novo, 1 not identified in mother - father unavailable for testing. All variants absent in gnomAD and v2 pLI score for UNC79 is 1.

Patients with UNC79 variants were identified through GeneMatcher or an international network of Epilepsy and Genetics departments. x1 patient underwent duo exome sequencing, remaining had trio exome sequencing - no other causative variants identified.

Phenotypic features included:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal to bilateral tonic-clonic seizures)
- 5/6 hypotonia

unc79 knockdown drosophila flies exhibited significantly higher rate of seizure-like behaviour than controls. unc79 haploinsufficiency shown to lead to significant reduction in protein levels of both unc79 and unc80 in mouse brains. Unc79 haploinsufficiency associated with deficiency in hippocampal-dependent learning and memory in mice.

Authors have reviewed their own evidence in relation to the gene-disease criteria detailed by Strande et al 2017 and note that their clinical and experimental data provides moderate-level evidence supporting the association between UNC79 and a neurodevelopment disorder including ASD.

Amber association favoured due to clinical phenotypic range reported between affected individuals and their lack of specificity.
Sources: Literature
Mendeliome v1.906 U2AF2 Elena Savva Publications for gene: U2AF2 were set to 34112922; 37092751; 36747105; 37134193
Mendeliome v1.905 U2AF2 Elena Savva Publications for gene: U2AF2 were set to 33057194
Mendeliome v1.905 U2AF2 Elena Savva Classified gene: U2AF2 as Green List (high evidence)
Mendeliome v1.905 U2AF2 Elena Savva Gene: u2af2 has been classified as Green List (High Evidence).
Mendeliome v1.904 NPR1 Zornitza Stark Marked gene: NPR1 as ready
Mendeliome v1.904 NPR1 Zornitza Stark Gene: npr1 has been classified as Green List (High Evidence).
Mendeliome v1.904 NPR1 Zornitza Stark Classified gene: NPR1 as Green List (high evidence)
Mendeliome v1.904 NPR1 Zornitza Stark Gene: npr1 has been classified as Green List (High Evidence).
Mendeliome v1.903 MRPL50 Anna Ritchie gene: MRPL50 was added
gene: MRPL50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL50 were set to PMID: 37148394
Phenotypes for gene: MRPL50 were set to Mitochondrial disease, MONDO: 004470, MRPL50-related
Added comment: A homozygous missense variant (c.335T>A; p.Val112Asp) shared by twin sisters presenting with premature ovarian insufficiency, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction.
Quantitative proteomics data demonstrated a significant reduction in abundance of MRPL50 protein when compared with controls.
Patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. This data supports a biochemical phenotype associated with MRPL50 variants.
Knockdown/knockout of mRpL50 in Drosophila, resulted abnormal ovarian development.
Sources: Literature
Mendeliome v1.903 POU3F2 Ain Roesley Marked gene: POU3F2 as ready
Mendeliome v1.903 POU3F2 Ain Roesley Gene: pou3f2 has been classified as Green List (High Evidence).
Mendeliome v1.903 ACBD6 Elena Savva Marked gene: ACBD6 as ready
Mendeliome v1.903 ACBD6 Elena Savva Gene: acbd6 has been classified as Green List (High Evidence).
Mendeliome v1.903 ACBD6 Elena Savva Marked gene: ACBD6 as ready
Mendeliome v1.903 ACBD6 Elena Savva Gene: acbd6 has been classified as Green List (High Evidence).
Mendeliome v1.903 POU3F2 Ain Roesley Classified gene: POU3F2 as Green List (high evidence)
Mendeliome v1.903 POU3F2 Ain Roesley Gene: pou3f2 has been classified as Green List (High Evidence).
Mendeliome v1.902 ACBD6 Elena Savva Classified gene: ACBD6 as Green List (high evidence)
Mendeliome v1.902 ACBD6 Elena Savva Gene: acbd6 has been classified as Green List (High Evidence).
Mendeliome v1.902 ACBD6 Elena Savva Classified gene: ACBD6 as Green List (high evidence)
Mendeliome v1.902 ACBD6 Elena Savva Gene: acbd6 has been classified as Green List (High Evidence).
Mendeliome v1.901 ACBD6 Elena Savva Marked gene: ACBD6 as ready
Mendeliome v1.901 ACBD6 Elena Savva Gene: acbd6 has been classified as Green List (High Evidence).
Mendeliome v1.901 POU3F2 Ain Roesley Phenotypes for gene: POU3F2 were changed from Autism spectrum disorder, NDD, and adolescent-onset obesity to Autism spectrum disorder, NDD, and adolescent-onset obesity; neurodevelopmental disorder MONDO:0700092, POU3F2-related
Mendeliome v1.901 ACBD6 Elena Savva Classified gene: ACBD6 as Green List (high evidence)
Mendeliome v1.901 ACBD6 Elena Savva Gene: acbd6 has been classified as Green List (High Evidence).
Mendeliome v1.901 MCM6 Zornitza Stark Publications for gene: MCM6 were set to
Mendeliome v1.900 MCM6 Zornitza Stark Phenotypes for gene: MCM6 were changed from Lactase persistence/nonpersistence 223100 to Neurodevelopmental disorder, MONDO:0700092, MCM6-related; Lactase persistence/nonpersistence 223100
Mendeliome v1.899 MCM6 Zornitza Stark Classified gene: MCM6 as Green List (high evidence)
Mendeliome v1.899 MCM6 Zornitza Stark Gene: mcm6 has been classified as Green List (High Evidence).
Mendeliome v1.898 NPR1 Lilian Downie gene: NPR1 was added
gene: NPR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPR1 were set to PMID: 37080586
Phenotypes for gene: NPR1 were set to Genetic hypertension MONDO:0015512
Review for gene: NPR1 was set to GREEN
Added comment: 4 sibs with systemic hypertension in the neonatal period - presenting with cardiogenic shock, with homozygous variants (consanguineous parents), parents confirmed heterozygotes. 3/4 infants had increased NT (>3.5) in utero
RT-PCR shows dramatic reduction of RNA levels
2 sibs in a second family, normal NT and pregnancy, neonatal systematic hypertension presenting with cardiogenic shock,
Sources: Literature
Mendeliome v1.898 POU3F2 Sarah Pantaleo gene: POU3F2 was added
gene: POU3F2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POU3F2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU3F2 were set to PMID: 37207645
Phenotypes for gene: POU3F2 were set to Autism spectrum disorder, NDD, and adolescent-onset obesity
Penetrance for gene: POU3F2 were set to unknown
Mode of pathogenicity for gene: POU3F2 was set to Other
Review for gene: POU3F2 was set to GREEN
Added comment: We associate ultra-rare variants in POU3F2, encoding a central nervous system transcription factor, with syndromic obesity and neurodevelopment delay in 12 individuals. Demonstrate variant pathogenicity through in vitro analysis. Used exome sequencing, GeneMatcher and Genomics England 100,000 Genomes Project rare disease database.

Both truncating and missense variants in over 10 individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity (may have had other features eg. CAKUT in 2 individuals, diabetes in two) . Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperplasia during childhood. With the exception of an early truncating variant, the variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promoter activation.

Variants absent from population and clinical databases. Almost all constituted putatively non-inherited de novo variants (8/10).

Functional studies provide evidence for loss of function in eight and gain of function in one obesity-associated POU3F2 variant. One variant did not impact POU3F2-promoter activation, leaving the possibility for further path-mechanisms.
Sources: Literature
Mendeliome v1.898 MAP4K4 Zornitza Stark Mode of inheritance for gene: MAP4K4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.897 ACBD6 Lucy Spencer gene: ACBD6 was added
gene: ACBD6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 36457943; 21937992; 35446914
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder (MONDO#0700092), ACBD6-related
Review for gene: ACBD6 was set to GREEN
Added comment: PMID: 36457943
2 siblings with a neurodevelopmental disorder: severely delayed development, obesity, pancytopenia, diabetes, liver cirrhosis, intravertebral disc herniation, mild brain atrophy. Consanguineous family both siblings found to have a homozygous frameshift.

This paper also mentioned 3 other reported variants in 6 individuals (only 3 unrelated) all homozygous, 2 frameshift, 1 canonical splice. All reported to have a neurodevelopmental disorder, some with limited information but one family also has obesity, spasticity, and dysmorphism. PMIDs: 21937992, 35446914
Sources: Literature
Mendeliome v1.897 MAP4K4 Zornitza Stark Classified gene: MAP4K4 as Green List (high evidence)
Mendeliome v1.897 MAP4K4 Zornitza Stark Gene: map4k4 has been classified as Green List (High Evidence).
Mendeliome v1.896 U2AF2 Paul De Fazio reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34112922, 37092751, 36747105, 37134193; Phenotypes: Neurodevelopmental disorder, U2AF2-related (MONDO:0700092); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.896 MAP4K4 Zornitza Stark edited their review of gene: MAP4K4: Added comment: 26 individuals from 21 families reported with Rasopathy-like phenotype, comprising ID/DD, dysmorphic features and congenital anomalies.; Changed rating: GREEN; Changed publications: 37126546; Changed phenotypes: RASopathy, MONDO:0021060, MAP4K4-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.896 CHRM5 Elena Savva gene: CHRM5 was added
gene: CHRM5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHRM5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRM5 were set to 37213061
Phenotypes for gene: CHRM5 were set to Congenital anomaly of kidney and urinary tract, (MONDO:0019719), CHRM5-related
Review for gene: CHRM5 was set to RED
Added comment: PMID: 37213061
- homozygous missense p.(Q184R) in a proband with neurogenic bladder and CAKUT. Additional features were small trabeculated urinary bladder, bilateral severe hydronephrosis, grade V VUR right, chronic kidney disease (stage 4).
- Radioligand binding experiments were inconclusive - the missense variant had no effect on receptor expression or binding affinity.
- ACh binding assay did show a 2-fold increase (borderline significant), but no effect in secondary messenger accumulation.
- Transfected CHO line showed no effect on receptor expression
- Described a mouse K/O as having a bladder overactivity

No hom PTCs in gnomAD
Sources: Literature
Mendeliome v1.895 SLC26A1 Ain Roesley reviewed gene: SLC26A1: Rating: RED; Mode of pathogenicity: None; Publications: 36719378; Phenotypes: perichondritis, hyposulphatemia, renal sulphate wasting; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.895 MCM6 Suliman Khan reviewed gene: MCM6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37198333; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, MCM6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.895 TPR Zornitza Stark Phenotypes for gene: TPR were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, TPR-related to Intellectual developmental disorder, autosomal recessive 79, MIM# 620393
Mendeliome v1.894 TPR Zornitza Stark edited their review of gene: TPR: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 79, MIM# 620393
Mendeliome v1.894 AMFR Zornitza Stark Marked gene: AMFR as ready
Mendeliome v1.894 AMFR Zornitza Stark Gene: amfr has been classified as Green List (High Evidence).
Mendeliome v1.894 AMFR Zornitza Stark Phenotypes for gene: AMFR were changed from Hereditary spastic paraplegia, MONDO:0019064 to Spastic paraplegia 89, autosomal recessive, MIM# 620379
Mendeliome v1.893 AMFR Zornitza Stark Classified gene: AMFR as Green List (high evidence)
Mendeliome v1.893 AMFR Zornitza Stark Gene: amfr has been classified as Green List (High Evidence).
Mendeliome v1.892 AMFR Zornitza Stark reviewed gene: AMFR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 89, autosomal recessive, MIM# 620379; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.892 ATP11A Zornitza Stark Classified gene: ATP11A as Green List (high evidence)
Mendeliome v1.892 ATP11A Zornitza Stark Gene: atp11a has been classified as Green List (High Evidence).
Mendeliome v1.891 ATP11A Zornitza Stark edited their review of gene: ATP11A: Added comment: PMID 35278131 reports three additional families with deafness, including segregation in a large pedigree.; Changed rating: GREEN; Changed publications: 35278131
Mendeliome v1.891 SCN4A Zornitza Stark Phenotypes for gene: SCN4A were changed from Hyperkalemic periodic paralysis, type 2, MIM# 170500; Hypokalemic periodic paralysis, type 2, MIM# 613345; Myasthenic syndrome, congenital, 16, MIM# 614198; Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390; Paramyotonia congenita , MIM#168300 to Congenital myopathy 22A, classic, MIM# 620351; Congenital myopathy 22B, severe fetal, MIM# 620369; Hyperkalemic periodic paralysis, type 2, MIM# 170500; Hypokalemic periodic paralysis, type 2, MIM# 613345; Myasthenic syndrome, congenital, 16, MIM# 614198; Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390; Paramyotonia congenita , MIM#168300
Mendeliome v1.890 SCN4A Zornitza Stark edited their review of gene: SCN4A: Changed phenotypes: Congenital myopathy 22A, classic, MIM# 620351, Congenital myopathy 22B, severe fetal, MIM# 620369, Hyperkalemic periodic paralysis, type 2, MIM# 170500, Hypokalemic periodic paralysis, type 2, MIM# 613345, Myasthenic syndrome, congenital, 16, MIM# 614198, Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390, Paramyotonia congenita , MIM#168300
Mendeliome v1.890 OXGR1 Zornitza Stark Phenotypes for gene: OXGR1 were changed from Nephrolithiasis/nephrocalcinosis MONDO:0008171, OXGR1-related to Nephrolithiasis, calcium oxalate, 2, with nephrocalcinosis, MIM# 620374
Mendeliome v1.889 OXGR1 Zornitza Stark reviewed gene: OXGR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephrolithiasis, calcium oxalate, 2, with nephrocalcinosis, MIM# 620374; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.889 LYN Zornitza Stark Phenotypes for gene: LYN were changed from Vasculitis, MONDO:0018882, LYN-related to Autoinflammatory disease, systemic, with vasculitis, MIM# 620376
Mendeliome v1.888 LYN Zornitza Stark edited their review of gene: LYN: Changed phenotypes: Autoinflammatory disease, systemic, with vasculitis, MIM# 620376
Mendeliome v1.888 NDUFA13 Zornitza Stark Classified gene: NDUFA13 as Green List (high evidence)
Mendeliome v1.888 NDUFA13 Zornitza Stark Gene: ndufa13 has been classified as Green List (High Evidence).
Mendeliome v1.887 GIGYF2 Bryony Thompson Publications for gene: GIGYF2 were set to PMID: 18358451, 19449032
Mendeliome v1.886 GIGYF2 Bryony Thompson Classified gene: GIGYF2 as Red List (low evidence)
Mendeliome v1.886 GIGYF2 Bryony Thompson Gene: gigyf2 has been classified as Red List (Low Evidence).
Mendeliome v1.885 GIGYF2 Bryony Thompson reviewed gene: GIGYF2: Rating: RED; Mode of pathogenicity: None; Publications: 18358451, 33239198, 25279164, 20060621, 19250854, 26152800; Phenotypes: {Parkinson disease 11} , OMIM # 607688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.885 NDUFA13 Lucy Spencer reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.885 UNC13A Ain Roesley Phenotypes for gene: UNC13A were changed from Congenital myasthenia; dyskinesia; autism; developmental delay to Congenital myasthenia; dyskinesia; autism; developmental delay; neurodevelopmental disorder MONDO#0700092, UNC13A-related
Mendeliome v1.884 UNC13A Ain Roesley Classified gene: UNC13A as Green List (high evidence)
Mendeliome v1.884 UNC13A Ain Roesley Gene: unc13a has been classified as Green List (High Evidence).
Mendeliome v1.883 UNC13A Ain Roesley reviewed gene: UNC13A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO#0700092, UNC13A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.883 RANBP2 Bryony Thompson Phenotypes for gene: RANBP2 were changed from to familial acute necrotizing encephalopathy MONDO:0011953
Mendeliome v1.882 RANBP2 Bryony Thompson Mode of inheritance for gene: RANBP2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.881 RANBP2 Bryony Thompson Publications for gene: RANBP2 were set to
Mendeliome v1.880 GATAD2A Bryony Thompson Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Mendeliome v1.879 GATAD2A Bryony Thompson changed review comment from: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature; to: PMID: 37181331 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Mendeliome v1.879 GATAD2A Bryony Thompson edited their review of gene: GATAD2A: Changed publications: 37181331, 17565372
Mendeliome v1.879 NAF1 Zornitza Stark Phenotypes for gene: NAF1 were changed from Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148 to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365
Mendeliome v1.878 NAF1 Zornitza Stark reviewed gene: NAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.878 ZNF292 Michelle Torres reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 64, MIM#619188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.878 ESAM Zornitza Stark Phenotypes for gene: ESAM were changed from Neurodevelopmental disorder (MONDO#0700092), ESAM-related to Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371
Mendeliome v1.877 ESAM Zornitza Stark reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.877 ARFGEF3 Ain Roesley reviewed gene: ARFGEF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.877 RRAGC Zornitza Stark Phenotypes for gene: RRAGC were changed from Dilated cardiomyopathy; cataract to Dilated cardiomyopathy (MONDO:0005021), RRAGC-related
Mendeliome v1.876 RRAGC Zornitza Stark Classified gene: RRAGC as Green List (high evidence)
Mendeliome v1.876 RRAGC Zornitza Stark Gene: rragc has been classified as Green List (High Evidence).
Mendeliome v1.875 RECQL4 Zornitza Stark Phenotypes for gene: RECQL4 were changed from Baller-Gerold syndrome, MIM# 218600; RAPADILINO syndrome, MIM# 266280; Rothmund-Thomson syndrome, type 2,MIM# 268400 to Baller-Gerold syndrome, MIM# 218600; RAPADILINO syndrome, MIM# 266280; Rothmund-Thomson syndrome, type 2,MIM# 268400; RECON progeroid syndrome, MIM# 620370
Mendeliome v1.874 RECQL4 Zornitza Stark Publications for gene: RECQL4 were set to
Mendeliome v1.873 RECQL4 Zornitza Stark reviewed gene: RECQL4: Rating: RED; Mode of pathogenicity: None; Publications: 35025765; Phenotypes: RECON progeroid syndrome, MIM# 620370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.873 ATP5O Zornitza Stark Phenotypes for gene: ATP5O were changed from mitochondrial disease, ATP5F1E-related MONDO:0044970 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359
Mendeliome v1.872 ATP5O Zornitza Stark Publications for gene: ATP5O were set to 34954817
Mendeliome v1.871 ATP5O Zornitza Stark Classified gene: ATP5O as Green List (high evidence)
Mendeliome v1.871 ATP5O Zornitza Stark Gene: atp5o has been classified as Green List (High Evidence).
Mendeliome v1.870 ATP5O Zornitza Stark reviewed gene: ATP5O: Rating: GREEN; Mode of pathogenicity: None; Publications: 35621276; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.870 SLITRK2 Zornitza Stark Phenotypes for gene: SLITRK2 were changed from Neurodevelopmental disorder, SLITRK2-related MONDO:0700092 to Intellectual developmental disorder, X-linked 111, MIM# 301107
Mendeliome v1.869 SLITRK2 Zornitza Stark reviewed gene: SLITRK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 111, MIM# 301107; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.869 AMFR Yetong Chen gene: AMFR was added
gene: AMFR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AMFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMFR were set to 37119330
Phenotypes for gene: AMFR were set to Hereditary spastic paraplegia, MONDO:0019064
Review for gene: AMFR was set to GREEN
Added comment: PMID 37119330 reports 20 individuals harbouring AMFR variants from 8 unrelated, consanguineous families. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature
Mendeliome v1.869 POLD3 Bryony Thompson Classified gene: POLD3 as Amber List (moderate evidence)
Mendeliome v1.869 POLD3 Bryony Thompson Gene: pold3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.868 POLD3 Bryony Thompson Marked gene: POLD3 as ready
Mendeliome v1.868 POLD3 Bryony Thompson Gene: pold3 has been classified as Red List (Low Evidence).
Mendeliome v1.868 POLD3 Bryony Thompson gene: POLD3 was added
gene: POLD3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLD3 were set to 37030525; 36395985; 27524497
Phenotypes for gene: POLD3 were set to Severe combined immunodeficiency MONDO:0015974
Review for gene: POLD3 was set to AMBER
Added comment: Homozygous missense variant (NM_006591.3; p.Ile10Thr) identified in a single Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency with neurodevelopmental delay and hearing loss. POLD3 as well as POLD1 and POLD2 expression was abolished in the patient's cells. Null mouse models are embryonic lethal and demonstrate Pold3 is essential for DNA replication in murine B cells.
Sources: Literature
Mendeliome v1.867 POLD2 Bryony Thompson edited their review of gene: POLD2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.867 POLD2 Bryony Thompson Phenotypes for gene: POLD2 were changed from Intellectual disability; immunodeficiency to Non-severe combined immunodeficiency due to polymerase delta deficiency MONDO:0800145
Mendeliome v1.866 POLD2 Bryony Thompson Publications for gene: POLD2 were set to 31449058
Mendeliome v1.865 POLD2 Bryony Thompson Classified gene: POLD2 as Amber List (moderate evidence)
Mendeliome v1.865 POLD2 Bryony Thompson Gene: pold2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.864 POLD2 Bryony Thompson reviewed gene: POLD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31449058, 36528861; Phenotypes: Non-severe combined immunodeficiency due to polymerase delta deficiency MONDO:0800145; Mode of inheritance: None
Mendeliome v1.864 SLC4A2 Zornitza Stark Marked gene: SLC4A2 as ready
Mendeliome v1.864 SLC4A2 Zornitza Stark Gene: slc4a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.864 SLC4A2 Zornitza Stark Classified gene: SLC4A2 as Amber List (moderate evidence)
Mendeliome v1.864 SLC4A2 Zornitza Stark Gene: slc4a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.863 SLC4A2 Zornitza Stark gene: SLC4A2 was added
gene: SLC4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC4A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A2 were set to 34668226; 20507629
Phenotypes for gene: SLC4A2 were set to Osteopetrosis, autosomal recessive 9, MIM# 620366
Review for gene: SLC4A2 was set to AMBER
Added comment: Single individual reported with homozygous missense variant. However, cattle and mouse models support gene-disease association.
Sources: Literature
Mendeliome v1.862 ZCCHC8 Bryony Thompson Phenotypes for gene: ZCCHC8 were changed from Pulmonary fibrosis to pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Mendeliome v1.861 ZCCHC8 Bryony Thompson edited their review of gene: ZCCHC8: Changed phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Mendeliome v1.861 NOP10 Bryony Thompson Phenotypes for gene: NOP10 were changed from Dyskeratosis congenita, autosomal recessive 1, MIM#224230 to Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Telomere syndrome MONDO:0100137
Mendeliome v1.860 NOP10 Bryony Thompson Publications for gene: NOP10 were set to 17507419
Mendeliome v1.859 NOP10 Bryony Thompson Classified gene: NOP10 as Amber List (moderate evidence)
Mendeliome v1.859 NOP10 Bryony Thompson Gene: nop10 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.858 NOP10 Bryony Thompson reviewed gene: NOP10: Rating: AMBER; Mode of pathogenicity: None; Publications: 17507419, 32554502; Phenotypes: Telomere syndrome MONDO:0100137; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.858 ACD Bryony Thompson Phenotypes for gene: ACD were changed from Dyskeratosis congenita, MIM# 616553 to telomere syndrome MONDO:0100137; dyskeratosis congenita, autosomal dominant 6 MONDO:0014690; Hoyeraal-Hreidarsson syndrome MONDO:0018045
Mendeliome v1.857 ACD Bryony Thompson Publications for gene: ACD were set to 25205116; 25233904
Mendeliome v1.856 ACD Bryony Thompson Classified gene: ACD as Green List (high evidence)
Mendeliome v1.856 ACD Bryony Thompson Gene: acd has been classified as Green List (High Evidence).
Mendeliome v1.855 ACD Bryony Thompson reviewed gene: ACD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27807141, 31515401, 30995915, 27528712, 25205116, 24316971, 30064976, 33446513, 25233904; Phenotypes: telomere syndrome MONDO:0100137, dyskeratosis congenita, autosomal dominant 6 MONDO:0014690, Hoyeraal-Hreidarsson syndrome MONDO:0018045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.855 RRAGC Naomi Baker reviewed gene: RRAGC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:37057673, 27234373, 33057194; Phenotypes: Dilated cardiomyopathy (MONDO:0005021), RRAGC-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.855 MCAT Zornitza Stark reviewed gene: MCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.855 MCAT Zornitza Stark Phenotypes for gene: MCAT were changed from progressive autosomal recessive optic neuropathy to Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309
Mendeliome v1.854 DNAH7 Zornitza Stark Phenotypes for gene: DNAH7 were changed from non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related to Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related
Mendeliome v1.853 DNAH7 Zornitza Stark reviewed gene: DNAH7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.853 RARA Zornitza Stark commented on gene: RARA: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER).

Both individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs)
- Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic
nasal bones, and oligodontia)
- Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency.

The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.
Mendeliome v1.853 RARA Zornitza Stark Phenotypes for gene: RARA were changed from Syndromic chorioretinal coloboma to Craniosynostosis - MONDO:0015469; Syndromic chorioretinal coloboma
Mendeliome v1.852 RARA Zornitza Stark Publications for gene: RARA were set to 31343737
Mendeliome v1.851 RARA Zornitza Stark Classified gene: RARA as Amber List (moderate evidence)
Mendeliome v1.851 RARA Zornitza Stark Gene: rara has been classified as Amber List (Moderate Evidence).
Mendeliome v1.850 RARA Zornitza Stark edited their review of gene: RARA: Added comment: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER).

Both individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs)
- Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic
nasal bones, and oligodontia)
- Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency.

The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.; Changed rating: AMBER; Changed publications: 31343737, 37086723; Changed phenotypes: Craniosynostosis - MONDO:0015469, Syndromic chorioretinal coloboma; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.850 PMEPA1 Zornitza Stark Phenotypes for gene: PMEPA1 were changed from Familial thoracic aortic aneurysm disease (FTAAD); Loeys-Dietz syndrome to Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related
Mendeliome v1.849 PMEPA1 Zornitza Stark reviewed gene: PMEPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.849 NAF1 Bryony Thompson Marked gene: NAF1 as ready
Mendeliome v1.849 NAF1 Bryony Thompson Gene: naf1 has been classified as Green List (High Evidence).
Mendeliome v1.849 NAF1 Bryony Thompson Classified gene: NAF1 as Green List (high evidence)
Mendeliome v1.849 NAF1 Bryony Thompson Gene: naf1 has been classified as Green List (High Evidence).
Mendeliome v1.848 NAF1 Bryony Thompson gene: NAF1 was added
gene: NAF1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NAF1 were set to 27510903
Phenotypes for gene: NAF1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Review for gene: NAF1 was set to GREEN
Added comment: At least 3 probands/families with telomere-related pulmonary fibrosis and a supporting mouse model
PMID: 27510903 - 5 individuals from 2 unrelated families with pulmonary fibrosis-emphysema and extrapulmonary manifestations including myelodysplastic syndrome and liver disease, with LoF variants. Truncated NAF1 was detected in cells derived from patients, and, in cells in which a frameshift mutation was introduced by genome editing telomerase RNA levels were reduced. Shortened telomere length also segregated with the variants. A Naf1+/- mouse model had reduced telomerase RNA levels

ClinVar - 1 nonsense and 2 splice site variants (ID: 2443185, 1338525, 2443184) called LP by the Genetic Services Laboratory, University of Chicago but no clinical details were provided
- SCV002547372.1 - Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center - at least one individual with pulmonary fibrosis and leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
Sources: Expert list
Mendeliome v1.847 PMEPA1 Hazel Phillimore changed review comment from: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature; to: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
(Note: the variant is present in gnomAD v2.1.1 in 22 heterozygotes as a filtered out variant.).

Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Mendeliome v1.847 PMEPA1 Seb Lunke Marked gene: PMEPA1 as ready
Mendeliome v1.847 PMEPA1 Seb Lunke Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.847 PMEPA1 Seb Lunke Classified gene: PMEPA1 as Amber List (moderate evidence)
Mendeliome v1.847 PMEPA1 Seb Lunke Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.846 LHX2 Zornitza Stark Marked gene: LHX2 as ready
Mendeliome v1.846 LHX2 Zornitza Stark Gene: lhx2 has been classified as Green List (High Evidence).
Mendeliome v1.846 LHX2 Zornitza Stark Classified gene: LHX2 as Green List (high evidence)
Mendeliome v1.846 LHX2 Zornitza Stark Gene: lhx2 has been classified as Green List (High Evidence).
Mendeliome v1.845 CNOT9 Karina Sandoval edited their review of gene: CNOT9: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.845 CNOT9 Zornitza Stark Marked gene: CNOT9 as ready
Mendeliome v1.845 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Mendeliome v1.845 CBX1 Seb Lunke Marked gene: CBX1 as ready
Mendeliome v1.845 CBX1 Seb Lunke Gene: cbx1 has been classified as Green List (High Evidence).
Mendeliome v1.845 CNOT9 Zornitza Stark Mode of inheritance for gene: CNOT9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.844 CBX1 Seb Lunke Classified gene: CBX1 as Green List (high evidence)
Mendeliome v1.844 CBX1 Seb Lunke Gene: cbx1 has been classified as Green List (High Evidence).
Mendeliome v1.843 CNOT9 Zornitza Stark Classified gene: CNOT9 as Green List (high evidence)
Mendeliome v1.843 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Mendeliome v1.842 LHX2 Manny Jacobs gene: LHX2 was added
gene: LHX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LHX2 were set to PMID: 37057675
Phenotypes for gene: LHX2 were set to Neurodevelopmental disorder (MONDO: 0700092)
Review for gene: LHX2 was set to GREEN
Added comment: PMID: 37057675

Case series of 19 individuals across 18 families.
1 whole gene deletion, 7 missense, 10 predicted LoF variants.
Proposed loss-of-function mechanism.
Variable phenotype, with variable intellectual disability and behavioural (ASD/ADHD) features.
Microcephaly in 7 individuals.
1 variant inherited from a mildly affected parent, all other variants with parental genotype available shown to be de novo.
Sources: Literature
Mendeliome v1.842 DNAH7 Seb Lunke Marked gene: DNAH7 as ready
Mendeliome v1.842 DNAH7 Seb Lunke Gene: dnah7 has been classified as Green List (High Evidence).
Mendeliome v1.842 DNAH7 Seb Lunke Classified gene: DNAH7 as Green List (high evidence)
Mendeliome v1.842 DNAH7 Seb Lunke Gene: dnah7 has been classified as Green List (High Evidence).
Mendeliome v1.842 MRPL39 Zornitza Stark Phenotypes for gene: MRPL39 were changed from Leigh syndrome MONDO:0009723 to Mitochondrial disease MONDO:0044970
Mendeliome v1.841 PMEPA1 Hazel Phillimore gene: PMEPA1 was added
gene: PMEPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMEPA1 were set to PMID: 36928819
Phenotypes for gene: PMEPA1 were set to Familial thoracic aortic aneurysm disease (FTAAD); Loeys-Dietz syndrome
Mode of pathogenicity for gene: PMEPA1 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: PMEPA1 was set to AMBER
Added comment: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Mendeliome v1.841 GPR156 Zornitza Stark Marked gene: GPR156 as ready
Mendeliome v1.841 GPR156 Zornitza Stark Gene: gpr156 has been classified as Green List (High Evidence).
Mendeliome v1.841 GPR156 Zornitza Stark Classified gene: GPR156 as Green List (high evidence)
Mendeliome v1.841 GPR156 Zornitza Stark Gene: gpr156 has been classified as Green List (High Evidence).
Mendeliome v1.840 MRPL39 Zornitza Stark Classified gene: MRPL39 as Green List (high evidence)
Mendeliome v1.840 MRPL39 Zornitza Stark Gene: mrpl39 has been classified as Green List (High Evidence).
Mendeliome v1.839 CBX1 Daniel Flanagan gene: CBX1 was added
gene: CBX1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CBX1 were set to PMID: 37087635
Phenotypes for gene: CBX1 were set to Neurodevelopmental disorder (MONDO#0700092), CBX1-related
Review for gene: CBX1 was set to GREEN
Added comment: Three different de novo missense variants identified in three unrelated individuals with developmental delay, hypotonia, autistic features, and variable dysmorphic features such as broad forehead and head circumference above average. Mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Functional studies confirmed the reduction of mutant HP1β binding to heterochromatin.
Sources: Expert list
Mendeliome v1.839 MCAT Seb Lunke Classified gene: MCAT as Amber List (moderate evidence)
Mendeliome v1.839 MCAT Seb Lunke Gene: mcat has been classified as Amber List (Moderate Evidence).
Mendeliome v1.838 SRSF1 Zornitza Stark Marked gene: SRSF1 as ready
Mendeliome v1.838 SRSF1 Zornitza Stark Gene: srsf1 has been classified as Green List (High Evidence).
Mendeliome v1.838 CNOT9 Karina Sandoval gene: CNOT9 was added
gene: CNOT9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CNOT9 were set to PMID: 37092538
Phenotypes for gene: CNOT9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CNOT9 was set to GREEN
Added comment: 7 individuals with de novo variants. In silico predictions of functional relevance. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include.

Symptoms: Neuro dev disorder. ID, Epilepsy. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities.
Sources: Literature
Mendeliome v1.838 SRSF1 Zornitza Stark Classified gene: SRSF1 as Green List (high evidence)
Mendeliome v1.838 SRSF1 Zornitza Stark Gene: srsf1 has been classified as Green List (High Evidence).
Mendeliome v1.837 DNAH7 Chern Lim gene: DNAH7 was added
gene: DNAH7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH7 were set to 34476482; 35543642
Phenotypes for gene: DNAH7 were set to non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related
Review for gene: DNAH7 was set to GREEN
gene: DNAH7 was marked as current diagnostic
Added comment: PMID: 34476482 (Wei et al 2021):
- Hom/chet missense DNAH7 variants in three unrelated infertile patients with idiopathic asthenozoospermia, presented with primary ciliary dyskinesia (PCD)-associated symptoms.
- Functional studies showed expression of DNAH7 in the spermatozoa from the DNAH7-defective patients was significantly decreased.

PMID: 35543642 (Gao et al 2022):
- One proband with idiopathic asthenozoospermia, presented a history of PCD-like symptoms. Hom frameshift variant predicted to cause NMD, both parents are heterozygous.
- Immunofluorescent staining showed DNAH7 signal significantly decreased or was even completely absent in the sperm from the investigated patient.
Sources: Literature
Mendeliome v1.837 MRPL39 Lilian Downie edited their review of gene: MRPL39: Changed rating: GREEN; Changed phenotypes: Mitochondrial disease MONDO:0044970
Mendeliome v1.837 INTS11 Seb Lunke Marked gene: INTS11 as ready
Mendeliome v1.837 INTS11 Seb Lunke Gene: ints11 has been classified as Green List (High Evidence).
Mendeliome v1.837 MRPL39 Lilian Downie changed review comment from: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature; to: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.837 INTS11 Seb Lunke Phenotypes for gene: INTS11 were changed from to intellectual disability, MONDO:0001071
Mendeliome v1.836 INTS11 Melanie Marty changed review comment from: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.; to: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages.
Mendeliome v1.836 SRSF1 Paul De Fazio gene: SRSF1 was added
gene: SRSF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SRSF1 were set to 37071997
Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder, SRSF1-related MONDO:0700092
Review for gene: SRSF1 was set to GREEN
gene: SRSF1 was marked as current diagnostic
Added comment: 17 individuals from 16 families reported with mostly de novo variants. Variants were a mixture of missense, nonsense/frameshift (both NMD-predicted and not NMD-predicted) and microdeletions. In one family, only one parent was available for testing. In another family, 2 affected siblings had the variant but the variant was not identified in either parent suggesting germline mosaicism.

Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. Episignature analysis (EpiSign) on patient DNA from blood showed a specific DNA methylation signature in patients with the variants classified pathogenic but not those classified VUS.

Phenotypes included mainly neurological abnormalities (mild to moderate ID/dev delay, motor delay, speech delay, and behavioural disorders) and facial dysmorphisms.

Other features included hypotonia (11/16), variable brain abnormalities on MRI (6/12), variable cardiac malformations (6/14). urogenital malformations e.g. hypospadias, cryptorchidism (6/13), scoliosis (5/17) and/or variable other skeletal abnormalities (10/17).
Sources: Literature
Mendeliome v1.836 INTS11 Seb Lunke Classified gene: INTS11 as Green List (high evidence)
Mendeliome v1.836 INTS11 Seb Lunke Gene: ints11 has been classified as Green List (High Evidence).
Mendeliome v1.835 SLC30A9 Zornitza Stark Marked gene: SLC30A9 as ready
Mendeliome v1.835 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Mendeliome v1.835 SLC30A9 Zornitza Stark Classified gene: SLC30A9 as Green List (high evidence)
Mendeliome v1.835 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Mendeliome v1.834 SLC30A9 Lucy Spencer gene: SLC30A9 was added
gene: SLC30A9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A9 were set to 37041080
Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome (MIM#617595)
Review for gene: SLC30A9 was set to GREEN
Added comment: PMID:37041080 - 2 families previously reported and this paper describes 4 more with biallelic SLC30A9 variants. Original 2 families: 6 affected members all hom for Ala350del, and 1 affected member chet for 2 frameshifts. 4 families from this paper: 2 families have the same homozygous missense (Gly418Val), family 3 has 4 affected sibs hom for Ala350del, family 4 1 affected chet for a frameshift and a synonymous. So 2 fams homs for Ala350del and 2 fams hom for Gly418Val.
All have Brik-Landau-Perez syndrome: all with ID, movement disorder and dystonia, and many with oculomotor apraxia, renal abnormalitie, ptosis, some had hearing impairment.
Sources: Literature
Mendeliome v1.834 GPR156 Anna Ritchie gene: GPR156 was added
gene: GPR156 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPR156 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPR156 were set to PMID: 36928819
Phenotypes for gene: GPR156 were set to Sensorineural hearing loss, MONDO:60700002, GPR156-related
Review for gene: GPR156 was set to GREEN
Added comment: Eight affected individuals from three unrelated families with congenital nonsyndromic bilateral sensorineural hearing loss. Homozygous or compound heterozygous loss of function variants were reported in these families.
Sources: Literature
Mendeliome v1.834 MRPL39 Lilian Downie changed review comment from: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (MIM 256000)
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature; to: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.834 DPP9 Sarah Pantaleo reviewed gene: DPP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 36112693; Phenotypes: Hatipoglu immunodeficiency syndrome MIM#620331; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.834 MRPL39 Lilian Downie gene: MRPL39 was added
gene: MRPL39 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL39 were set to PMID: 37133451
Phenotypes for gene: MRPL39 were set to Leigh syndrome MONDO:0009723
Added comment: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (MIM 256000)
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.834 INTS11 Melanie Marty reviewed gene: INTS11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37054711; Phenotypes: Global developmental delay, launguage delay, intellectual disability, impaired motor development, brain atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.834 ERG Ain Roesley Publications for gene: ERG were set to
Mendeliome v1.833 ERG Ain Roesley Phenotypes for gene: ERG were changed from to primary lymphoedema MONDO#0019175, ERG-related
Mendeliome v1.832 ERG Ain Roesley Mode of inheritance for gene: ERG was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.832 ERG Ain Roesley Classified gene: ERG as Green List (high evidence)
Mendeliome v1.832 ERG Ain Roesley Gene: erg has been classified as Green List (High Evidence).
Mendeliome v1.831 ERG Ain Roesley reviewed gene: ERG: Rating: GREEN; Mode of pathogenicity: None; Publications: 36928819; Phenotypes: primary lymphoedema MONDO#0019175, ERG-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.831 GATAD2A Bryony Thompson Marked gene: GATAD2A as ready
Mendeliome v1.831 GATAD2A Bryony Thompson Gene: gatad2a has been classified as Green List (High Evidence).
Mendeliome v1.831 GATAD2A Bryony Thompson Classified gene: GATAD2A as Green List (high evidence)
Mendeliome v1.831 GATAD2A Bryony Thompson Gene: gatad2a has been classified as Green List (High Evidence).
Mendeliome v1.830 GATAD2A Bryony Thompson gene: GATAD2A was added
gene: GATAD2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related
Review for gene: GATAD2A was set to GREEN
Added comment: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Mendeliome v1.829 RNF212B Bryony Thompson Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189
Mendeliome v1.828 KDM5A Zornitza Stark Marked gene: KDM5A as ready
Mendeliome v1.828 KDM5A Zornitza Stark Gene: kdm5a has been classified as Green List (High Evidence).
Mendeliome v1.828 KDM5A Zornitza Stark Classified gene: KDM5A as Green List (high evidence)
Mendeliome v1.828 KDM5A Zornitza Stark Gene: kdm5a has been classified as Green List (High Evidence).
Mendeliome v1.827 YWHAE Zornitza Stark Marked gene: YWHAE as ready
Mendeliome v1.827 YWHAE Zornitza Stark Gene: ywhae has been classified as Green List (High Evidence).
Mendeliome v1.827 YWHAE Zornitza Stark Classified gene: YWHAE as Green List (high evidence)
Mendeliome v1.827 YWHAE Zornitza Stark Gene: ywhae has been classified as Green List (High Evidence).
Mendeliome v1.826 YWHAE Zornitza Stark gene: YWHAE was added
gene: YWHAE was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: YWHAE.
Mode of inheritance for gene: YWHAE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAE were set to 36999555
Phenotypes for gene: YWHAE were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: YWHAE was set to GREEN
Added comment: PMID 36999555 reports 10 patients with YWHAE variants (1 intragenic deletion and 5 large deletions encompassing YWHEA but not PAFAH1B1) who have mild to severe intellectual disability. 3 individuals with SNVs. Mouse model supports gene-disease association.
Sources: Literature
Mendeliome v1.825 OXGR1 Bryony Thompson Publications for gene: OXGR1 were set to PMID:35671463
Mendeliome v1.824 KPNA7 Zornitza Stark Phenotypes for gene: KPNA7 were changed from Epilepsy; intellectual disability to Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Neurodevelopmental disorder
Mendeliome v1.823 KPNA7 Zornitza Stark Publications for gene: KPNA7 were set to 24045845; 32179771
Mendeliome v1.822 KPNA7 Zornitza Stark Classified gene: KPNA7 as Amber List (moderate evidence)
Mendeliome v1.822 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.821 KPNA7 Zornitza Stark reviewed gene: KPNA7: Rating: AMBER; Mode of pathogenicity: None; Publications: 36647821; Phenotypes: Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.821 ACSL5 Zornitza Stark Phenotypes for gene: ACSL5 were changed from severe FTT (no OMIM #) to Diarrhoea 13, MIM# 620357
Mendeliome v1.820 DNM1 Zornitza Stark Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346; Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Mendeliome v1.819 DNM1 Zornitza Stark edited their review of gene: DNM1: Changed phenotypes: Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346, Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Mendeliome v1.819 INTS11 Achchuthan Shanmugasundram edited their review of gene: INTS11: Changed phenotypes: intellectual disability, MONDO:0001071
Mendeliome v1.819 INTS11 Achchuthan Shanmugasundram gene: INTS11 was added
gene: INTS11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS11 were set to 37054711
Review for gene: INTS11 was set to GREEN
Added comment: Comment on gene rating: This gene should be rated GREEN in Intellectual disability panel as it has 10 unrelated cases and functional evidence in support of this association.

PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants.
Sources: Literature
Mendeliome v1.819 DNAH14 Zornitza Stark Tag disputed tag was added to gene: DNAH14.
Mendeliome v1.819 DNAH14 Elena Savva commented on gene: DNAH14
Mendeliome v1.819 DNAH14 Elena Savva Classified gene: DNAH14 as Red List (low evidence)
Mendeliome v1.819 DNAH14 Elena Savva Gene: dnah14 has been classified as Red List (Low Evidence).
Mendeliome v1.818 RFX7 Zornitza Stark Phenotypes for gene: RFX7 were changed from ID, ASD, ADHD to Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, MIM# 620330
Mendeliome v1.817 RFX7 Zornitza Stark edited their review of gene: RFX7: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, MIM# 620330
Mendeliome v1.817 MED11 Zornitza Stark Phenotypes for gene: MED11 were changed from neurodevelopmental disorder MONDO#0700092, MED11-related to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327
Mendeliome v1.816 MED11 Zornitza Stark reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.816 MARS Zornitza Stark Phenotypes for gene: MARS were changed from Interstitial lung and liver disease, MIM#615486; Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280; Trichothiodystrophy 9, nonphotosensitive, MIM# 619692 to Interstitial lung and liver disease, MIM#615486; Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280; Trichothiodystrophy 9, nonphotosensitive, MIM# 619692; Spastic paraplegia 70, autosomal recessive, MIM# 620323
Mendeliome v1.815 MARS Zornitza Stark Publications for gene: MARS were set to 23729695; 24354524; 29655802; 24103465; 25913036; 33909043
Mendeliome v1.814 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Six individuals from two unrelated families reported with SPG.; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036, 24482476, 34585293; Changed phenotypes: Interstitial lung and liver disease, MIM#615486, Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280, Spastic paraplegia 70, autosomal recessive, MIM# 620323
Mendeliome v1.814 WARS Zornitza Stark Phenotypes for gene: WARS were changed from Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); Neurodevelopmental disorder (MONDO:0700092), WARS-related to Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities, MIM# 620317
Mendeliome v1.813 UNC119 Zornitza Stark Phenotypes for gene: UNC119 were changed from Cone-rod dystrophy, MONDO:0015993; Immunodeficiency 13 MIM#615518 to Cone-rod dystrophy 24, MIM# 620342; Immunodeficiency 13 MIM#615518
Mendeliome v1.812 UNC119 Zornitza Stark edited their review of gene: UNC119: Changed phenotypes: Cone-rod dystrophy 24, MIM# 620342, Immunodeficiency 13 MIM#615518
Mendeliome v1.812 DNAJB4 Zornitza Stark Phenotypes for gene: DNAJB4 were changed from Congenital myopathy 21 with early respiratory failure, MIM# 620326 to Congenital myopathy 21 with early respiratory failure, MIM# 620326; distal myopathy MONDO:0018949
Mendeliome v1.811 DNAJB4 Zornitza Stark Publications for gene: DNAJB4 were set to PMID: 36264506
Mendeliome v1.810 DNAJB4 Zornitza Stark Mode of inheritance for gene: DNAJB4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.809 DNAJB4 Zornitza Stark Phenotypes for gene: DNAJB4 were changed from Myopathy, MONDO:0005336, DNAJB4-related to Congenital myopathy 21 with early respiratory failure, MIM# 620326
Mendeliome v1.808 DNAJB4 Zornitza Stark reviewed gene: DNAJB4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 21 with early respiratory failure, MIM# 620326; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.808 C16orf62 Chirag Patel Classified gene: C16orf62 as Green List (high evidence)
Mendeliome v1.808 C16orf62 Chirag Patel Gene: c16orf62 has been classified as Green List (High Evidence).
Mendeliome v1.808 C16orf62 Chirag Patel Classified gene: C16orf62 as Green List (high evidence)
Mendeliome v1.808 C16orf62 Chirag Patel Gene: c16orf62 has been classified as Green List (High Evidence).
Mendeliome v1.807 C16orf62 Chirag Patel reviewed gene: C16orf62: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36113987; Phenotypes: Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.807 DNAJB4 Bryony Thompson reviewed gene: DNAJB4: Rating: AMBER; Mode of pathogenicity: Other; Publications: 36512060; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.807 TSPAN7 Ain Roesley reviewed gene: TSPAN7: Rating: AMBER; Mode of pathogenicity: None; Publications: 26350204, 36625203; Phenotypes: Intellectual developmental disorder, X-linked 58, MIM #300210, MONDO:0010266; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v1.807 KDM5A Achchuthan Shanmugasundram gene: KDM5A was added
gene: KDM5A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM5A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KDM5A were set to 21937992; 33350388
Phenotypes for gene: KDM5A were set to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Review for gene: KDM5A was set to GREEN
Added comment: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.

This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM.
Sources: Literature
Mendeliome v1.807 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Congenital heart disease; Pituitary anomalies; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; intellectual disability, MONDO:0001071 to Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.806 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303, Nystagmus 8, congenital, autosomal recessive, MIM# 257400, Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.806 ROBO1 Zornitza Stark Publications for gene: ROBO1 were set to 28592524; 30530901; 30692597; 33270637; 28402530; 33270637; 28402530; 35348658
Mendeliome v1.805 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed publications: 28286008, 30692597, 35227688, 35348658, 28592524, 30530901, 33270637, 28402530
Mendeliome v1.805 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Congenital heart disease; Pituitary anomalies to Congenital heart disease; Pituitary anomalies; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; intellectual disability, MONDO:0001071
Mendeliome v1.804 ROBO1 Zornitza Stark Publications for gene: ROBO1 were set to 28592524; 30530901; 30692597; 33270637; 28402530
Mendeliome v1.803 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Added comment: Association with ID: GREEN for bi-allelic variants:

PMID:28286008 reported a boy with compound heterozygous variants that was presented with developmental delay in 13 months and had severe intellectual disability and hyperactivity at nine years of age. He was nonverbal and wheelchair dependent because of spastic diplegia and ataxia.

PMID:30692597 reported a five year old boy identified with a homozygous ROBO1 variant who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus and characteristic facial features.

PMID:35227688 reported eight patients including the boy reported in PMID:30692597. Of the other seven patients, three were presented with intellectual disability. Of these three patients, two harboured compound heterozygous and one harboured homozygous variants.

PMID:35348658 reported a patient identified with monoallelic de novo variant (p.D422G) who presented with early-onset epileptic encephalopathy and had severe developmental delay.; Changed phenotypes: Congenital heart disease, Pituitary anomalies, Nystagmus 8, congenital, autosomal recessive, MIM# 257400, intellectual disability, MONDO:0001071
Mendeliome v1.803 ROBO1 Zornitza Stark changed review comment from: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu.; to: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu. This association is RED.
Mendeliome v1.803 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Added comment: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu.; Changed publications: 28592524, 30530901, 30692597, 33270637, 28402530, 35348658; Changed phenotypes: Congenital heart disease, Pituitary anomalies, Nystagmus 8, congenital, autosomal recessive, MIM# 257400
Mendeliome v1.803 CAMSAP1 Zornitza Stark Phenotypes for gene: CAMSAP1 were changed from lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related to Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316
Mendeliome v1.802 CAMSAP1 Zornitza Stark reviewed gene: CAMSAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.802 RYR3 Zornitza Stark Phenotypes for gene: RYR3 were changed from Congenital myopathy 20, MIM# 620310 to Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062)
Mendeliome v1.801 RYR3 Zornitza Stark Publications for gene: RYR3 were set to 29498452; 32451403; 31230720
Mendeliome v1.800 RYR3 Zornitza Stark Mode of inheritance for gene: RYR3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.799 RYR3 Zornitza Stark Phenotypes for gene: RYR3 were changed from Nemaline myopathy; fetal akinesia; arthrogryposis to Congenital myopathy 20, MIM# 620310
Mendeliome v1.798 RYR3 Zornitza Stark edited their review of gene: RYR3: Changed phenotypes: Congenital myopathy 20, MIM# 620310
Mendeliome v1.798 LYN Zornitza Stark Phenotypes for gene: LYN were changed from to Vasculitis, MONDO:0018882, LYN-related
Mendeliome v1.797 LYN Zornitza Stark Publications for gene: LYN were set to
Mendeliome v1.796 LYN Zornitza Stark Mode of inheritance for gene: LYN was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.795 LYN Zornitza Stark Classified gene: LYN as Green List (high evidence)
Mendeliome v1.795 LYN Zornitza Stark Gene: lyn has been classified as Green List (High Evidence).
Mendeliome v1.794 LYN Zornitza Stark reviewed gene: LYN: Rating: GREEN; Mode of pathogenicity: None; Publications: 36932076, 36122175; Phenotypes: Vasculitis, MONDO:0018882, LYN-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.794 MAP3K3 Zornitza Stark Marked gene: MAP3K3 as ready
Mendeliome v1.794 MAP3K3 Zornitza Stark Gene: map3k3 has been classified as Green List (High Evidence).
Mendeliome v1.794 MAP3K3 Zornitza Stark Classified gene: MAP3K3 as Green List (high evidence)
Mendeliome v1.794 MAP3K3 Zornitza Stark Gene: map3k3 has been classified as Green List (High Evidence).
Mendeliome v1.793 MAP3K3 Zornitza Stark gene: MAP3K3 was added
gene: MAP3K3 was added to Mendeliome. Sources: Literature
somatic tags were added to gene: MAP3K3.
Mode of inheritance for gene: MAP3K3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K3 were set to 33729480; 35355835; 33891857; 36995941; 10700190; 25728774
Phenotypes for gene: MAP3K3 were set to Cerebral malformation, MONDO:0016054, MAP3K3-related
Mode of pathogenicity for gene: MAP3K3 was set to Other
Review for gene: MAP3K3 was set to GREEN
Added comment: Recurrent somatic missense variant (p.I441M) identified in sporadic cases of cerebral and spinal cavernous malformation. Recent publication demonstrates that this missense variant can drive CCM formation (in vitro and in vivo studies).
Sources: Literature
Mendeliome v1.792 VWA8 Zornitza Stark Marked gene: VWA8 as ready
Mendeliome v1.792 VWA8 Zornitza Stark Gene: vwa8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.792 VWA8 Zornitza Stark Classified gene: VWA8 as Amber List (moderate evidence)
Mendeliome v1.792 VWA8 Zornitza Stark Gene: vwa8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.791 MKL2 Zornitza Stark Marked gene: MKL2 as ready
Mendeliome v1.791 MKL2 Zornitza Stark Gene: mkl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.791 MKL2 Zornitza Stark Classified gene: MKL2 as Amber List (moderate evidence)
Mendeliome v1.791 MKL2 Zornitza Stark Gene: mkl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.790 ACTC1 Zornitza Stark Marked gene: ACTC1 as ready
Mendeliome v1.790 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Mendeliome v1.790 ACTC1 Zornitza Stark Classified gene: ACTC1 as Green List (high evidence)
Mendeliome v1.790 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Mendeliome v1.789 ACTC1 Zornitza Stark reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 5 MIM#612794, Cardiomyopathy, dilated, 1R MIM#613424, Cardiomyopathy, hypertrophic, 11 MIM#612098, ACTC1 related distal arthrogryposis MONDO:0019942; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.789 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from RNH1-related disorder to Neurodevelopmental disorder, MONDO:0700092, RNH1-related
Mendeliome v1.788 RNH1 Zornitza Stark reviewed gene: RNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.788 POLR1A Zornitza Stark Phenotypes for gene: POLR1A were changed from Acrofacial dysostosis, Cincinnati type, (MIM#616462); Leukodystrophy to Acrofacial dysostosis, Cincinnati type, (MIM#616462); Leukodystrophy MONDO:0019046, POLR1A-related
Mendeliome v1.787 POLR1A Zornitza Stark Publications for gene: POLR1A were set to 25913037; 28051070
Mendeliome v1.786 POLR1A Zornitza Stark Mode of inheritance for gene: POLR1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.785 POLR1A Zornitza Stark commented on gene: POLR1A: Evidence for association of bi-allelic variants with leukodystrophy is moderate.
Mendeliome v1.785 POLR1A Zornitza Stark edited their review of gene: POLR1A: Changed rating: GREEN; Changed phenotypes: Leukodystrophy MONDO:0019046, POLR1A-related, Acrofacial dysostosis, Cincinnati type, (MIM#616462); Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.785 FILIP1 Zornitza Stark Marked gene: FILIP1 as ready
Mendeliome v1.785 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Mendeliome v1.785 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Mendeliome v1.784 FILIP1 Zornitza Stark Classified gene: FILIP1 as Green List (high evidence)
Mendeliome v1.784 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Mendeliome v1.783 BIN1 Bryony Thompson Publications for gene: BIN1 were set to 17676042
Mendeliome v1.782 BIN1 Bryony Thompson Added comment: Comment on mode of inheritance: ClinGen Definititive for semidominant for centronuclear myopathy by the Congenital myopathy GCEP - Classification - 04/27/2020
Mendeliome v1.782 BIN1 Bryony Thompson Mode of inheritance for gene: BIN1 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 v1.781 VWA8 Dean Phelan gene: VWA8 was added
gene: VWA8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VWA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VWA8 were set to PMID: 37012052
Phenotypes for gene: VWA8 were set to Retinitis pigmentosa (MONDO:0019200), VWA8-related
Review for gene: VWA8 was set to AMBER
Added comment: PMID: 37012052
- Single family with 11 affected patients, 9 - 87y, all presented initial symptoms of night blindness, visual field defects and reduced visual acuity later, macular changes, including macular degeneration and dystrophy. A heterozygous two-loci variant in VWA8 c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter) was identified and segregated with disease. Expression studies showed reduced protein expression. Zebrafish knockout model displayed an RP phenotype.
Sources: Literature
Mendeliome v1.781 MKL2 Dean Phelan gene: MKL2 was added
gene: MKL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID: 37013900
Phenotypes for gene: MKL2 were set to Neurodevelopmental disorder (MONDO:0700092), MKL2-related
Mode of pathogenicity for gene: MKL2 was set to Other
Review for gene: MKL2 was set to AMBER
Added comment: PMID: 37013900
- de novo missense variants in MKL2 (now known as MRTFB) were identified in two patients with mild dysmorphic features, intellectual disability, global developmental delay, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Sources: Literature
Mendeliome v1.781 RNH1 Seb Lunke Marked gene: RNH1 as ready
Mendeliome v1.781 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Mendeliome v1.781 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Mendeliome v1.781 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Mendeliome v1.780 ESAM Seb Lunke Marked gene: ESAM as ready
Mendeliome v1.780 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Mendeliome v1.780 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Mendeliome v1.780 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Mendeliome v1.779 CRIPT Zornitza Stark Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies (MIM#615789) to Short stature with microcephaly and distinctive facies (MIM#615789); Rothmund-Thomson syndrome MONDO:0010002
Mendeliome v1.778 CRIPT Zornitza Stark Classified gene: CRIPT as Green List (high evidence)
Mendeliome v1.778 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Mendeliome v1.777 CEP162 Zornitza Stark Marked gene: CEP162 as ready
Mendeliome v1.777 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.777 CEP162 Zornitza Stark Classified gene: CEP162 as Amber List (moderate evidence)
Mendeliome v1.777 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.776 CRIPT Karina Sandoval changed review comment from: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome, two new identified and 4 were already published. 5 were hom, 1 was chet, all with different variants. Additionally all presented with neuro dev delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom; to: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome characterised by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. Two new variants identified and 4 were already published. 5 were hom, 1 was chet, all with different variants.
All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom
Mendeliome v1.776 CEP162 Paul De Fazio gene: CEP162 was added
gene: CEP162 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP162 were set to 36862503
Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related
Penetrance for gene: CEP162 were set to unknown
Review for gene: CEP162 was set to AMBER
gene: CEP162 was marked as current diagnostic
Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior.

Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation.

Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients.

Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background).
Sources: Literature
Mendeliome v1.776 ACTC1 Lilian Downie gene: ACTC1 was added
gene: ACTC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to PMID: 36945405
Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 MIM#612794; Cardiomyopathy, dilated, 1R MIM#613424; Cardiomyopathy, hypertrophic, 11 MIM#612098; ACTC1 related distal arthrogryposis MONDO:0019942
Review for gene: ACTC1 was set to GREEN
Added comment: ClinGen definitive association with HCM, moderate for DCM
5 new families (8 individuals) with a distral arthrogryposis phenotype (PMID: 36945405)
multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy
facial features: microretrognathia, ptosis, downslanting palpebral fissures, low-set ears, and a long nasal bridge
All missense variants
Sources: Literature
Mendeliome v1.776 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.776 DOCK11 Seb Lunke Marked gene: DOCK11 as ready
Mendeliome v1.776 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Mendeliome v1.776 DOCK11 Seb Lunke Classified gene: DOCK11 as Green List (high evidence)
Mendeliome v1.776 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Mendeliome v1.775 POLR1A Lucy Spencer reviewed gene: POLR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 28051070, 36917474; Phenotypes: Leukodystrophy MONDO:0019046, POLR1A-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.775 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Mendeliome v1.775 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Mendeliome v1.775 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.775 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Mendeliome v1.775 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.774 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.774 DOCK11 Lucy Spencer gene: DOCK11 was added
gene: DOCK11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to autoimmune disease MONDO:0007179, DOCK11-related
Review for gene: DOCK11 was set to GREEN
Added comment: 8 male patients from 7 unrelated families all with hemizygous DOCK11 missense variants. 6 mothers were tested and found to carry the same missense. Early onset autoimmuniy with cytopenia, systemic lupus erythematosus, and skin and digestive manifestations. Patients platelets had abnormal morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls.

6 of the variants are either absent or have only 1 het in gnomad v2, but one of them has 2 hemis and 1 het. The patient with this variant R1885C does seem to be more mild.
Sources: Literature
Mendeliome v1.774 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Mendeliome v1.774 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Mendeliome v1.774 RNH1 Krithika Murali changed review comment from: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature; to: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis. No antenatal features reported.
Sources: Literature
Mendeliome v1.774 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.774 DAAM2 Zornitza Stark Phenotypes for gene: DAAM2 were changed from Nephrotic syndrome, type 24, MIM# 619263; steroid-resistant nephrotic syndrome (SRNS) to Nephrotic syndrome, type 24, MIM# 619263; steroid-resistant nephrotic syndrome (SRNS); Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related
Mendeliome v1.773 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.773 DAAM2 Zornitza Stark Publications for gene: DAAM2 were set to 33232676
Mendeliome v1.772 DAAM2 Zornitza Stark Mode of inheritance for gene: DAAM2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.771 DAAM2 Zornitza Stark edited their review of gene: DAAM2: Added comment: AIS: 6 unrelated individuals with extensive functional data.; Changed publications: 33232676, 36972684; Changed phenotypes: Nephrotic syndrome, type 24, MIM# 619263, Steroid-resistant nephrotic syndrome (SRNS), Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.771 MB Elena Savva Classified gene: MB as Green List (high evidence)
Mendeliome v1.771 MB Elena Savva Gene: mb has been classified as Green List (High Evidence).
Mendeliome v1.770 MB Elena Savva Classified gene: MB as Green List (high evidence)
Mendeliome v1.770 MB Elena Savva Gene: mb has been classified as Green List (High Evidence).
Mendeliome v1.769 MB Elena Savva Marked gene: MB as ready
Mendeliome v1.769 MB Elena Savva Gene: mb has been classified as Red List (Low Evidence).
Mendeliome v1.769 MB Elena Savva gene: MB was added
gene: MB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MB were set to 35527200; 30918256
Phenotypes for gene: MB were set to Myopathy, sarcoplasmic body MIM#620286
Mode of pathogenicity for gene: MB was set to Other
Review for gene: MB was set to GREEN
Added comment: PMID: 30918256:
- Recurrent c.292C>T (p.His98Tyr) in fourteen members of six European families with AD progressive myopathy.
- Mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin.
- GOF hypothesised
- 2/3 of myoglobin knockout mice die in utero, 1/3 live to adulthood with little sign of functional effects, likely due to multiple compensatory mechanisms.

PMID: 35527200:
- single adult patient with myoglobinopathy
- same recurring p.His98Tyr variant
Sources: Literature
Mendeliome v1.768 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Mendeliome v1.768 PKDCC Zornitza Stark Phenotypes for gene: PKDCC were changed from Dysmorphism; shortening of extremities to Rhizomelic limb shortening with dysmorphic features, MIM# 618821
Mendeliome v1.767 PKDCC Zornitza Stark Publications for gene: PKDCC were set to PMID:30478137; 19097194
Mendeliome v1.766 PKDCC Zornitza Stark Classified gene: PKDCC as Green List (high evidence)
Mendeliome v1.766 PKDCC Zornitza Stark Gene: pkdcc has been classified as Green List (High Evidence).
Mendeliome v1.765 PKDCC Zornitza Stark reviewed gene: PKDCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 36896672; Phenotypes: Rhizomelic limb shortening with dysmorphic features 618821; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.765 NPPA Chern Lim changed review comment from: PMID: 36303204:
- 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP.

PMID: 19646991:
- NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has 195 hets in gnomADv3.

PMID: 23275345:
- Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD.

ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).; to: PMID: 36303204:
- 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP.

PMID: 19646991:
- NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has >200 hets in gnomADv3.

PMID: 23275345:
- Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD.

ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).
Mendeliome v1.765 PPCS Bryony Thompson Publications for gene: PPCS were set to 29754768
Mendeliome v1.764 PPCS Bryony Thompson Classified gene: PPCS as Green List (high evidence)
Mendeliome v1.764 PPCS Bryony Thompson Gene: ppcs has been classified as Green List (High Evidence).
Mendeliome v1.763 PPCS Bryony Thompson reviewed gene: PPCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35616428, 29754768; Phenotypes: Cardiomyopathy, dilated, 2C, MIM# 618189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.763 PPCDC Bryony Thompson Marked gene: PPCDC as ready
Mendeliome v1.763 PPCDC Bryony Thompson Gene: ppcdc has been classified as Red List (Low Evidence).
Mendeliome v1.763 PPCDC Bryony Thompson gene: PPCDC was added
gene: PPCDC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPCDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPCDC were set to 36564894
Phenotypes for gene: PPCDC were set to dilated cardiomyopathy MONDO:0005021
Review for gene: PPCDC was set to RED
Added comment: Single family reported with two siblings with a fatal cardiac phenotype including dilated cardiomyopathy with biallelic variants p.Thr53Pro and p.Ala95Val. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant.
Sources: Literature
Mendeliome v1.762 ELOC Bryony Thompson Marked gene: ELOC as ready
Mendeliome v1.762 ELOC Bryony Thompson Gene: eloc has been classified as Red List (Low Evidence).
Mendeliome v1.762 ELOC Bryony Thompson Classified gene: ELOC as Red List (low evidence)
Mendeliome v1.762 ELOC Bryony Thompson Gene: eloc has been classified as Red List (Low Evidence).
Mendeliome v1.761 EPHA10 Bryony Thompson Marked gene: EPHA10 as ready
Mendeliome v1.761 EPHA10 Bryony Thompson Gene: epha10 has been classified as Red List (Low Evidence).
Mendeliome v1.761 EPHA10 Bryony Thompson Classified gene: EPHA10 as Red List (low evidence)
Mendeliome v1.761 EPHA10 Bryony Thompson Gene: epha10 has been classified as Red List (Low Evidence).
Mendeliome v1.760 RNF212B Bryony Thompson Marked gene: RNF212B as ready
Mendeliome v1.760 RNF212B Bryony Thompson Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.760 RNF212B Bryony Thompson Classified gene: RNF212B as Amber List (moderate evidence)
Mendeliome v1.760 RNF212B Bryony Thompson Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.759 SLC25A36 Bryony Thompson Marked gene: SLC25A36 as ready
Mendeliome v1.759 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Mendeliome v1.759 SLC25A36 Bryony Thompson Classified gene: SLC25A36 as Green List (high evidence)
Mendeliome v1.759 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Mendeliome v1.758 NCAPG2 Zornitza Stark Classified gene: NCAPG2 as Amber List (moderate evidence)
Mendeliome v1.758 NCAPG2 Zornitza Stark Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.757 NCAPG2 Zornitza Stark changed review comment from: Two families and functional evidence (zebrafish model).
Sources: Literature; to: Two families and functional evidence (zebrafish model). Rated as LIMITED by ClinGen; one of the families had a homozygous missense variant. Internal case identified by VCGS but dual diagnosis.
Sources: Literature
Mendeliome v1.757 NCAPG2 Zornitza Stark edited their review of gene: NCAPG2: Changed rating: AMBER; Changed phenotypes: Khan-Khan-Katsanis syndrome, MIM# 618460
Mendeliome v1.757 NPPA Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.757 RNF212B Sangavi Sivagnanasundram gene: RNF212B was added
gene: RNF212B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: RNF212B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189
Phenotypes for gene: RNF212B were set to Infertility disorder, MONDO:0005047
Review for gene: RNF212B was set to AMBER
Added comment: Homozygous nonsense mutation (R150X) causative of oligoasthenotheratozoospermia (OAT) identified in three unrelated individuals (two of Jewish decent from the same consanguineous family).

Drosophila ZIP3/RNF212 related gene paralogs (vilya, narya, nenya) showed loss of function in the RNF212B protein and promoted formation of DNA double-stand breaks. The mutant was shown to result in a reduction in fertility in the Drosophila paralogs.

Note: RNF212B is reported to be exclusively expressed in the testes only compared to RNF212 which is reported in both the testes and ovaries.
Sources: Other
Mendeliome v1.757 RYR3 Chern Lim reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25262651; Phenotypes: developmental and epileptic encephalopathy (MONDO:0100062); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.757 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Mendeliome v1.756 SLC31A1 Zornitza Stark edited their review of gene: SLC31A1: Changed phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Mendeliome v1.756 HCK Zornitza Stark Phenotypes for gene: HCK were changed from Autoinflammatory syndrome, MONDO:0019751, HCK-related to Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Mendeliome v1.755 HCK Zornitza Stark edited their review of gene: HCK: Changed phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Mendeliome v1.755 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Möbius syndrome, MONDO:0008006; Congenital heart disease, MONDO:0005453, PLXND1-related to Möbius syndrome, MONDO:0008006; Congenital heart defects, multiple types, 9, MIM# 620294
Mendeliome v1.754 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Möbius syndrome, Congenital heart defects, multiple types, 9, MIM# 620294
Mendeliome v1.754 AGO1 Zornitza Stark Phenotypes for gene: AGO1 were changed from Neurodevelopmental disorder MONDO:0700092, AGO1-related; non-syndromic ID and seizures to Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Mendeliome v1.753 AGO1 Zornitza Stark edited their review of gene: AGO1: Changed phenotypes: Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Mendeliome v1.753 PRDM10 Zornitza Stark Marked gene: PRDM10 as ready
Mendeliome v1.753 PRDM10 Zornitza Stark Gene: prdm10 has been classified as Red List (Low Evidence).
Mendeliome v1.753 PRDM10 Zornitza Stark Classified gene: PRDM10 as Red List (low evidence)
Mendeliome v1.753 PRDM10 Zornitza Stark Gene: prdm10 has been classified as Red List (Low Evidence).
Mendeliome v1.752 PRDM10 Achchuthan Shanmugasundram gene: PRDM10 was added
gene: PRDM10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRDM10 were set to 36440963
Phenotypes for gene: PRDM10 were set to Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086
Review for gene: PRDM10 was set to RED
Added comment: PMID:36440963 reported a family presenting with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with Birt-Hogg-Dubé syndrome (BHD, MIM #135150) based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. A heterozygous missense variant (p.Cys677Tyr) was identified, which co-segregated with the phenotype in the family.

Functional studies show that Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN.

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.752 COL12A1 Elena Savva commented on gene: COL12A1
Mendeliome v1.752 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
Mendeliome v1.752 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Mendeliome v1.752 SLC26A7 Zornitza Stark Classified gene: SLC26A7 as Green List (high evidence)
Mendeliome v1.752 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Mendeliome v1.751 SLC26A7 Zornitza Stark gene: SLC26A7 was added
gene: SLC26A7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321
Phenotypes for gene: SLC26A7 were set to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related
Review for gene: SLC26A7 was set to GREEN
Added comment: More than 10 unrelated families reported.
Sources: Expert list
Mendeliome v1.750 LCP2 Zornitza Stark Publications for gene: LCP2 were set to 33231617
Mendeliome v1.749 LCP2 Zornitza Stark Classified gene: LCP2 as Green List (high evidence)
Mendeliome v1.749 LCP2 Zornitza Stark Gene: lcp2 has been classified as Green List (High Evidence).
Mendeliome v1.748 LCP2 Zornitza Stark edited their review of gene: LCP2: Added comment: PMID 36474126: second individual reported. Functional data.; Changed rating: GREEN; Changed publications: 33231617, 36474126
Mendeliome v1.748 STX4 Zornitza Stark Phenotypes for gene: STX4 were changed from to Non-syndromic genetic hearing loss, MONDO:0019497, STX4-related.
Mendeliome v1.747 STX4 Zornitza Stark Publications for gene: STX4 were set to
Mendeliome v1.746 STX4 Zornitza Stark Mode of inheritance for gene: STX4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.745 STX4 Zornitza Stark Classified gene: STX4 as Amber List (moderate evidence)
Mendeliome v1.745 STX4 Zornitza Stark Gene: stx4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.744 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862
Mendeliome v1.743 STX4 Achchuthan Shanmugasundram reviewed gene: STX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 36355422; Phenotypes: Hearing impairment, HP:0000365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram edited their review of gene: ARF1: Changed publications: 36345169
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram reviewed gene: ARF1: Rating: ; Mode of pathogenicity: None; Publications: 3634516; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.743 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Mendeliome v1.743 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Mendeliome v1.743 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
Mendeliome v1.742 RNPC3 Zornitza Stark Phenotypes for gene: RNPC3 were changed from Growth hormone deficiency; Intellectual disability to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Mendeliome v1.741 RNPC3 Zornitza Stark edited their review of gene: RNPC3: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Mendeliome v1.741 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.740 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.740 MS4A1 Zornitza Stark Publications for gene: MS4A1 were set to 20038800
Mendeliome v1.739 MS4A1 Zornitza Stark Classified gene: MS4A1 as Amber List (moderate evidence)
Mendeliome v1.739 MS4A1 Zornitza Stark Gene: ms4a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.738 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from Currarino syndrome, MIM# 176450 to Currarino syndrome, MIM# 176450; Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Mendeliome v1.737 MNX1 Zornitza Stark Mode of inheritance for gene: MNX1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.736 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.736 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Mendeliome v1.736 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Mendeliome v1.736 IRS4 Zornitza Stark Classified gene: IRS4 as Green List (high evidence)
Mendeliome v1.736 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Mendeliome v1.735 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.
Sources: Expert Review
Mendeliome v1.734 HECTD4 Zornitza Stark Marked gene: HECTD4 as ready
Mendeliome v1.734 HECTD4 Zornitza Stark Gene: hectd4 has been classified as Green List (High Evidence).
Mendeliome v1.734 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM# to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Mendeliome v1.733 HECTD4 Zornitza Stark reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.733 TNFRSF9 Zornitza Stark Phenotypes for gene: TNFRSF9 were changed from EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection to Immunodeficiency 109 with lymphoproliferation, MIM# 620282; EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection
Mendeliome v1.732 TNFRSF9 Zornitza Stark edited their review of gene: TNFRSF9: Changed phenotypes: Immunodeficiency 109 with lymphoproliferation, MIM# 620282, EBV lymphoproliferation, B-cell lymphoma, Chronic active EBV infection
Mendeliome v1.732 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) to Juvenile amyotrophic lateral sclerosis-27, MIM#620285; Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v1.731 SPTLC1 Zornitza Stark edited their review of gene: SPTLC1: Changed phenotypes: Juvenile amyotrophic lateral sclerosis-27, MIM#620285, Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400, Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v1.731 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.730 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.730 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.730 NLGN4X Zornitza Stark Classified gene: NLGN4X as Green List (high evidence)
Mendeliome v1.730 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Green List (High Evidence).
Mendeliome v1.729 Zornitza Stark removed gene:MTSS1 from the panel
Mendeliome v1.728 TAB2 Achchuthan Shanmugasundram reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35971781; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.728 ACTA1 Zornitza Stark Phenotypes for gene: ACTA1 were changed from Myopathy, actin, congenital, with cores, MIM#161800; Myopathy, actin, congenital, with excess of thin myofilaments, MIM#161800; Myopathy, congenital, with fiber-type disproportion 1, MIM#255310; Nemaline myopathy 3, MIM#161800; ?Myopathy, scapulohumeroperoneal to Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Myopathy, actin, congenital, with cores, MIM#161800; Myopathy, actin, congenital, with excess of thin myofilaments, MIM#161800; Myopathy, congenital, with fiber-type disproportion 1, MIM#255310; Nemaline myopathy 3, MIM#161800; ?Myopathy, scapulohumeroperoneal
Mendeliome v1.727 ACTA1 Zornitza Stark reviewed gene: ACTA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.727 REPS1 Zornitza Stark Marked gene: REPS1 as ready
Mendeliome v1.727 REPS1 Zornitza Stark Gene: reps1 has been classified as Red List (Low Evidence).
Mendeliome v1.727 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Mendeliome v1.726 MCF2L Zornitza Stark Mode of inheritance for gene: MCF2L was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.725 FTH1 Zornitza Stark Phenotypes for gene: FTH1 were changed from Hemochromatosis, type 5, MIM# 615517 to Hemochromatosis, type 5, MIM# 615517; Neuroferritinopathy (MONDO:0011638)
Mendeliome v1.724 FTH1 Zornitza Stark Publications for gene: FTH1 were set to 11389486
Mendeliome v1.723 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)
Mendeliome v1.723 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.722 TLN1 Zornitza Stark Phenotypes for gene: TLN1 were changed from idiopathic spontaneous coronary artery dissection MONDO:0007385 to idiopathic spontaneous coronary artery dissection MONDO:0007385; thrombocytopenia, MONDO:0002049, TLN1-related
Mendeliome v1.721 TLN1 Zornitza Stark Publications for gene: TLN1 were set to 30888838
Mendeliome v1.720 DPYSL2 Zornitza Stark Marked gene: DPYSL2 as ready
Mendeliome v1.720 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.720 DPYSL2 Zornitza Stark Classified gene: DPYSL2 as Amber List (moderate evidence)
Mendeliome v1.720 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.719 DPYSL2 Zornitza Stark gene: DPYSL2 was added
gene: DPYSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071, DPYSL2-related
Review for gene: DPYSL2 was set to AMBER
Added comment: Two unrelated cases with monoallelic variants in DPYSL2/ CRMP2, supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature
Mendeliome v1.718 RBSN Zornitza Stark Marked gene: RBSN as ready
Mendeliome v1.718 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Mendeliome v1.718 RBSN Zornitza Stark Classified gene: RBSN as Green List (high evidence)
Mendeliome v1.718 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Mendeliome v1.717 RBSN Zornitza Stark gene: RBSN was added
gene: RBSN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 25233840; 29784638; 35652444
Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071, RBSN-related
Review for gene: RBSN was set to GREEN
Added comment: Four unrelated families reported, consistent feature is ID.

PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis.

PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal.

PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism.
Sources: Literature
Mendeliome v1.716 SRPRA Zornitza Stark Marked gene: SRPRA as ready
Mendeliome v1.716 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Mendeliome v1.716 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Mendeliome v1.716 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Mendeliome v1.715 SRPRA Zornitza Stark gene: SRPRA was added
gene: SRPRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to 36223592
Phenotypes for gene: SRPRA were set to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Review for gene: SRPRA was set to AMBER
Added comment: De novo variant; zebrafish model. Schwachman-Diamond like.
Sources: Literature
Mendeliome v1.714 SRP19 Zornitza Stark Marked gene: SRP19 as ready
Mendeliome v1.714 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.714 SRP19 Zornitza Stark Classified gene: SRP19 as Amber List (moderate evidence)
Mendeliome v1.714 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.713 SRP19 Zornitza Stark gene: SRP19 was added
gene: SRP19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP19 were set to 36223592
Phenotypes for gene: SRP19 were set to Neutropenia, MONDO:0001475, SRP19-related
Review for gene: SRP19 was set to AMBER
Added comment: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.
Sources: Literature
Mendeliome v1.712 ATP5B Zornitza Stark Publications for gene: ATP5B were set to 36860166
Mendeliome v1.711 ATP5B Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature; to: PMID 36860166: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mendeliome v1.711 ATP5B Zornitza Stark edited their review of gene: ATP5B: Changed publications: 36860166, 36239646
Mendeliome v1.711 ATP5B Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.
Sources: Literature; to: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. Particularly, Eph overexpressed flies had a poorer performance compared to controls in negative geotaxis assay. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram changed review comment from: Comment on gene rating: This gene should be rated AMBER as there is one case and supportive functional data to associate OXR1 with hearing loss.

A four years old girl was identified with a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in OXR1 gene and was reported with sensorineural hearing loss.

Functional studies in zebrafish model showed that the ortholog orx1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL). In addition, knockdown of oxr1b resulted in a significant developmental defect of SAG and pLL and this phenotype was rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs.; to: Comment on gene rating: This gene should be rated AMBER as there is one case and supportive functional data to associate OXR1 with hearing loss.

A four years old girl was identified with a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in OXR1 gene and was reported with sensorineural hearing loss.

Functional studies in zebrafish model showed that the ortholog orx1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL). In addition, knockdown of oxr1b resulted in a significant developmental defect of SAG and pLL and this phenotype was rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs.

This gene has not yet been associated with hearing loss either in OMIM or in Gene2Phenotype.
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram reviewed gene: OXR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36130215; Phenotypes: sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram gene: EPHA10 was added
gene: EPHA10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EPHA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPHA10 were set to 36048850
Phenotypes for gene: EPHA10 were set to postlingual non-syndromic genetic hearing loss, MONDO:0016298
Mode of pathogenicity for gene: EPHA10 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: EPHA10 was set to RED
Added comment: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 ATP5B Zornitza Stark Marked gene: ATP5B as ready
Mendeliome v1.711 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.711 ATP5B Zornitza Stark Classified gene: ATP5B as Amber List (moderate evidence)
Mendeliome v1.711 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.710 ATP5B Zornitza Stark gene: ATP5B was added
gene: ATP5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5B were set to 36860166
Phenotypes for gene: ATP5B were set to Inherited dystonia, MONDO:0044807, ATP5B-related
Review for gene: ATP5B was set to AMBER
Added comment: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.
Sources: Literature
Mendeliome v1.709 SHQ1 Zornitza Stark Publications for gene: SHQ1 were set to 34542157; 29178645
Mendeliome v1.708 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Added comment: Fourth family reported in PMID 36847845 with hypotonia and paroxysmal dyskinesia.; Changed publications: 34542157, 29178645, 36847845
Mendeliome v1.708 YWHAZ Zornitza Stark Marked gene: YWHAZ as ready
Mendeliome v1.708 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Red List (Low Evidence).
Mendeliome v1.708 YWHAZ Zornitza Stark gene: YWHAZ was added
gene: YWHAZ was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YWHAZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAZ were set to 36001342
Phenotypes for gene: YWHAZ were set to Intellectual disability, MONDO:0001071
Review for gene: YWHAZ was set to RED
Added comment: PMID:36001342 reported one large three-generation family with intellectual disability and global developmental delay, where all affected members were identified with a heterozygous missense variant (c.147A>T/ p.Lys49Asn) in YWHAZ gene. Although there were 10 other rare variants located in 10 genes (ARHGAP4, AGPS, APOL3, CES3, DACT2, ECH1, FAM71E2, KREMEN1, YWHAZ, ZFYVE26) that co-segregated with the ID/GDD phenotype were identified in the family, they were either not present in all affected members or present in unaffected members. In addition, computational modeling and knockdown/ knockin studies with Drosophila also confirmed the role of this YWHAZ variant in intellectual disability.
Sources: Literature
Mendeliome v1.707 KIF5B Zornitza Stark Publications for gene: KIF5B were set to PMID: 35342932
Mendeliome v1.706 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Möbius syndrome to Möbius syndrome, MONDO:0008006; Congenital heart disease, MONDO:0005453, PLXND1-related
Mendeliome v1.705 PLXND1 Zornitza Stark Publications for gene: PLXND1 were set to 26068067
Mendeliome v1.704 PLXND1 Zornitza Stark Mode of inheritance for gene: PLXND1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.703 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Möbius syndrome, Congenital heart disease, MONDO:0005453, PLXND1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.703 ZNF143 Zornitza Stark Marked gene: ZNF143 as ready
Mendeliome v1.703 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
Mendeliome v1.703 ZNF143 Zornitza Stark gene: ZNF143 was added
gene: ZNF143 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related
Review for gene: ZNF143 was set to RED
Added comment: Single individual reported with compound heterozygous variants.
Sources: Literature
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram edited their review of gene: PLXND1: Changed phenotypes: Truncus arteriosus, HP:0001660
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram reviewed gene: PLXND1: Rating: ; Mode of pathogenicity: None; Publications: 35396997; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.702 KIF5B Achchuthan Shanmugasundram reviewed gene: KIF5B: Rating: ; Mode of pathogenicity: None; Publications: 36018820; Phenotypes: dilated cardiomyopathy, MONDO:0005021, ophthalmoplegia, MONDO:0003425, myopathy, MONDO:0005336, Hypotonia, HP:0001252, Seizure, HP:0001250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.702 CYB561 Zornitza Stark Marked gene: CYB561 as ready
Mendeliome v1.702 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
Mendeliome v1.702 CYB561 Zornitza Stark Classified gene: CYB561 as Green List (high evidence)
Mendeliome v1.702 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
Mendeliome v1.701 CYB561 Zornitza Stark gene: CYB561 was added
gene: CYB561 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYB561 were set to 29343526; 31822578
Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182
Review for gene: CYB561 was set to GREEN
Added comment: Three families reported.

Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood.

Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa)
Sources: Expert Review
Mendeliome v1.700 TLN1 Achchuthan Shanmugasundram reviewed gene: TLN1: Rating: RED; Mode of pathogenicity: None; Publications: 35861643; Phenotypes: thrombocytopenia, MONDO:0002049, lymphopenia, MONDO:0003783; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.700 PCK2 Bryony Thompson Classified gene: PCK2 as Amber List (moderate evidence)
Mendeliome v1.700 PCK2 Bryony Thompson Gene: pck2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.699 PCK2 Bryony Thompson reviewed gene: PCK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36845668; Phenotypes: Peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.699 FTH1 Paul De Fazio reviewed gene: FTH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36778397; Phenotypes: Neuroferritinopathy (MONDO:0011638); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.699 MCF2L Zornitza Stark Marked gene: MCF2L as ready
Mendeliome v1.699 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Mendeliome v1.699 MCF2L Zornitza Stark Classified gene: MCF2L as Red List (low evidence)
Mendeliome v1.699 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Mendeliome v1.698 MCF2L Michelle Torres gene: MCF2L was added
gene: MCF2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCF2L was set to Unknown
Publications for gene: MCF2L were set to 36760094
Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related
Review for gene: MCF2L was set to RED
Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7).
Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery).
Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery).
Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested.
Sources: Literature
Mendeliome v1.698 TRPV1 Krithika Murali reviewed gene: TRPV1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 36454632, PMID: 36472910; Phenotypes: Channelopathy-associated congenital insensitivity to pain, autosomal recessive - MONDO:0009459; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.698 TEFM Zornitza Stark Marked gene: TEFM as ready
Mendeliome v1.698 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Mendeliome v1.698 TEFM Zornitza Stark Classified gene: TEFM as Green List (high evidence)
Mendeliome v1.698 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Mendeliome v1.697 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Mendeliome v1.697 AMOTL1 Seb Lunke Phenotypes for gene: AMOTL1 were changed from Cleft lip and palate; imperforate anus; dysmorphism to Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related
Mendeliome v1.696 AMOTL1 Seb Lunke Publications for gene: AMOTL1 were set to 33026150
Mendeliome v1.695 TEFM Ee Ming Wong gene: TEFM was added
gene: TEFM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Mitochondrial disease (MONDO#0044970), TEFM-related
Review for gene: TEFM was set to GREEN
gene: TEFM was marked as current diagnostic
Added comment: - Seven TEFM variants (4 missense, 2 fs, 1 in-frame del) in seven individuals across five unrelated families
- Muscle and primary fibroblast from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts
- TEFM knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function
Sources: Literature
Mendeliome v1.695 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Mendeliome v1.695 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Mendeliome v1.694 AMOTL1 Lucy Spencer reviewed gene: AMOTL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36751037; Phenotypes: Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.694 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from Mirror image foot polydactyly; Neurodevelopmental disorder MONDO:0700092, HMGB1-related to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Neurodevelopmental disorder MONDO:0700092, HMGB1-related
Mendeliome v1.694 HMGB1 Ain Roesley Publications for gene: HMGB1 were set to 34159400; 34164801
Mendeliome v1.693 LGR4 Elena Savva Phenotypes for gene: LGR4 were changed from {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254) to {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254)
Mendeliome v1.692 LGR4 Elena Savva Phenotypes for gene: LGR4 were changed from Delayed puberty to {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254)
Mendeliome v1.691 HMGB1 Ain Roesley edited their review of gene: HMGB1: Added comment: PMID:36755093
4 new families with de novo protein truncating variants.

In addition with PMID 34159400 ( all de novos)

c.556_559delGAAG;p.(Glu186Argfs*42) - 1 family
c.551_554delAGAA;p.(Lys184Argfs*44) - 4 families; Changed rating: GREEN; Changed publications: 34159400, 36755093; Changed phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Set current diagnostic: yes
Mendeliome v1.691 LGR4 Elena Savva Publications for gene: LGR4 were set to 32493844
Mendeliome v1.690 LGR4 Elena Savva Mode of inheritance for gene: LGR4 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 v1.689 LGR4 Elena Savva changed review comment from: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; to: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).
Mendeliome v1.689 LGR4 Elena Savva edited their review of gene: LGR4: Added comment: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; Changed publications: PMID: 32493844, 36538378; Changed phenotypes: {Bone mineral density, low, susceptibility to} MIM#615311; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.689 USMG5 Bryony Thompson Marked gene: USMG5 as ready
Mendeliome v1.689 USMG5 Bryony Thompson Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.689 USMG5 Bryony Thompson Classified gene: USMG5 as Amber List (moderate evidence)
Mendeliome v1.689 USMG5 Bryony Thompson Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.688 USMG5 Bryony Thompson gene: USMG5 was added
gene: USMG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USMG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USMG5 were set to 29917077; 30240627
Phenotypes for gene: USMG5 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6 MIM#618683
Review for gene: USMG5 was set to AMBER
Added comment: A homozygous splice site mutation in 4 patients from 3 unrelated families of Ashkenazi Jewish descent. Experimental analyses demonstrated that the splice variant leads to loss of protein expression and haplotype analysis suggested a founder effect. In situ cryo-ET analysis of the mitochondria of a homozygous affected case showed profound disturbances of mitochondrial crista ultrastructure.
Sources: Literature
Mendeliome v1.687 SLC35B2 Zornitza Stark Phenotypes for gene: SLC35B2 were changed from Leukodystrophy, MONDO:0019046, SLC35B2-related to Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269
Mendeliome v1.686 SLC35B2 Zornitza Stark reviewed gene: SLC35B2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.686 ATG4D Zornitza Stark Marked gene: ATG4D as ready
Mendeliome v1.686 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Mendeliome v1.686 ATG4D Zornitza Stark Phenotypes for gene: ATG4D were changed from neurodevelopmental disorder; Abnormal facial shape to Neurodevelopmental disorder, MONDO:0700092, ATG4D-related
Mendeliome v1.685 ATG4D Zornitza Stark Classified gene: ATG4D as Green List (high evidence)
Mendeliome v1.685 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Mendeliome v1.684 ATG4D Zornitza Stark reviewed gene: ATG4D: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, ATG4D-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.684 NLGN4X Elena Savva reviewed gene: NLGN4X: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36747195; Phenotypes: Intellectual developmental disorder, X-linked MIM#300495; 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 v1.684 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.684 ELOC Achchuthan Shanmugasundram gene: ELOC was added
gene: ELOC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELOC was set to Unknown
Publications for gene: ELOC were set to 35323939
Phenotypes for gene: ELOC were set to von Hippel-Lindau disease, MONDO:0008667; renal cell carcinoma, MONDO:0005086; retinal hemangioblastoma, MONDO:0003343
Review for gene: ELOC was set to RED
Added comment: Comment on gene classification: This gene should be rated red as there is only one case with germline variant found so far.

A female patient was identified with a germline de novo missense variant in ELOC gene (c.236A>G/ p.Tyr79Cys) and satisfied the clinical diagnostic criteria for von Hippel-Lindau (VHL) disease. The patient had left retinal haemangioblastomas, renal cell carcinomas, cyst of the right kidney, spinal haemangioblastoma, a haemangioblastoma at the cervicomedullary junction and Henoch-Schonlein purpura (PMID:35323939).

This is the only germline variant detected in ELOC gene and was associated with VHL so far. However, ~20 somatic ELOC variants have been reported to be associated with renal cell carcinomas so far.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.684 ATG4D Suliman Khan gene: ATG4D was added
gene: ATG4D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG4D were set to PMID: 36765070
Phenotypes for gene: ATG4D were set to neurodevelopmental disorder; Abnormal facial shape
Penetrance for gene: ATG4D were set to unknown
Review for gene: ATG4D was set to GREEN
Added comment: PMID: 36765070 reported three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment with a similar facial gestalt comprising almond-shaped eyes, depressed nasal bridge, and a prominent Cupid’s bow with variable disease severity and progression. NGS analysis revealed bi-allelic loss-of-function variants in ATG4D gene. Based on the clinical, bioinformatic, and functional data, the author concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.
Sources: Literature
Mendeliome v1.684 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224 to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224; Cataract 50 with or without glaucoma, MIM#620253
Mendeliome v1.683 TRPM3 Zornitza Stark Publications for gene: TRPM3 were set to 31278393
Mendeliome v1.682 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Added comment: Publications 25090642; 33484482: Single multi-generational family reported with a missense variant in this gene and cataract. Mouse model of same variant supports association. Amber for this association.; Changed publications: 31278393, 25090642, 33484482; Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224, Cataract 50 with or without glaucoma, MIM#620253
Mendeliome v1.682 PPM1K Zornitza Stark Publications for gene: PPM1K were set to 23086801
Mendeliome v1.681 PPM1K Zornitza Stark Classified gene: PPM1K as Amber List (moderate evidence)
Mendeliome v1.681 PPM1K Zornitza Stark Gene: ppm1k has been classified as Amber List (Moderate Evidence).
Mendeliome v1.680 PPM1K Zornitza Stark edited their review of gene: PPM1K: Added comment: PMID: 36706222 reported a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K; Changed rating: AMBER; Changed publications: 23086801, 36706222
Mendeliome v1.680 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related to Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Mendeliome v1.679 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194; 36450800
Mendeliome v1.678 ARHGAP35 Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: 36178483; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.678 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Mendeliome v1.678 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Mendeliome v1.678 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia and heterotaxy, no OMIM # to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Mendeliome v1.677 EFCAB1 Zornitza Stark reviewed gene: EFCAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.677 CST6 Zornitza Stark Marked gene: CST6 as ready
Mendeliome v1.677 CST6 Zornitza Stark Gene: cst6 has been classified as Green List (High Evidence).
Mendeliome v1.677 CST6 Zornitza Stark Classified gene: CST6 as Green List (high evidence)
Mendeliome v1.677 CST6 Zornitza Stark Gene: cst6 has been classified as Green List (High Evidence).
Mendeliome v1.676 CST6 Zornitza Stark gene: CST6 was added
gene: CST6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CST6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CST6 were set to 30425301; 36371786
Phenotypes for gene: CST6 were set to Ectodermal dysplasia 15, hypohidrotic/hair type MIM#618535
Review for gene: CST6 was set to GREEN
Added comment: Two families reported and functional data.
Sources: Literature
Mendeliome v1.675 JPH3 Zornitza Stark Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Intellectual disability; dystonia
Mendeliome v1.674 JPH3 Zornitza Stark Publications for gene: JPH3 were set to 33824468
Mendeliome v1.673 JPH3 Zornitza Stark Mode of inheritance for gene: JPH3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.672 JPH3 Zornitza Stark Classified gene: JPH3 as Amber List (moderate evidence)
Mendeliome v1.672 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.671 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.671 WNT11 Zornitza Stark Marked gene: WNT11 as ready
Mendeliome v1.671 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Mendeliome v1.671 WNT11 Zornitza Stark Classified gene: WNT11 as Green List (high evidence)
Mendeliome v1.671 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Mendeliome v1.670 MRPS7 Zornitza Stark Publications for gene: MRPS7 were set to 25556185
Mendeliome v1.669 MRPS7 Zornitza Stark Classified gene: MRPS7 as Amber List (moderate evidence)
Mendeliome v1.669 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.668 MRPS7 Zornitza Stark edited their review of gene: MRPS7: Added comment: Now second publication (PMID: 36421788) describes sisters with an overlapping phenotype including sensorineural deafness and premature ovarian insufficiency. They both had compound heterozygous (one missense, one nonsense) MRPS7 variants.; Changed rating: AMBER; Changed publications: 25556185, 36421788
Mendeliome v1.668 STAT6 Zornitza Stark Marked gene: STAT6 as ready
Mendeliome v1.668 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Mendeliome v1.668 STAT6 Zornitza Stark Classified gene: STAT6 as Green List (high evidence)
Mendeliome v1.668 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Mendeliome v1.667 STAT6 Zornitza Stark gene: STAT6 was added
gene: STAT6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT6 were set to 36216080; 36758835
Phenotypes for gene: STAT6 were set to Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies
Review for gene: STAT6 was set to GREEN
Added comment: Two families reported with GoF variants and extensive functional data.
Sources: Literature
Mendeliome v1.666 LTV1 Zornitza Stark Marked gene: LTV1 as ready
Mendeliome v1.666 LTV1 Zornitza Stark Gene: ltv1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.666 LTV1 Zornitza Stark Classified gene: LTV1 as Amber List (moderate evidence)
Mendeliome v1.666 LTV1 Zornitza Stark Gene: ltv1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.665 LTV1 Achchuthan Shanmugasundram gene: LTV1 was added
gene: LTV1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LTV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTV1 were set to 34999892
Phenotypes for gene: LTV1 were set to Inflammatory poikiloderma with hair abnormalities and acral keratoses, OMIM:620199
Review for gene: LTV1 was set to AMBER
Added comment: Comment on classification of gene: This gene should be rated amber as it has been implicated in inflammatory poikiloderma with hair abnormalities and acral keratoses as identified from two unrelated families harbouring the same biallelic variant and supported by functional studies.

PMID:34999892 reported four UK women of South Asian origin (three Pakistani sisters and an unrelated Indian woman) identified with homozygous variant c.503A>G, (p.Asn168Ser) and presented with poikiloderma, hair abnormalities, and acral keratoses, which the authors named as inflammatory poikiloderma with hair abnormalities and acral keratoses (IPHAK).

Both in silico modelling and splicing assays from a patient sample showed that this variant is responsible for splicing defects and defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm in yeast.

This gene has already been associated with relevant phenotype (MIM #620199) in OMIM, but not in Gene2Phenotype.
Sources: Literature
Mendeliome v1.665 WNT11 Achchuthan Shanmugasundram gene: WNT11 was added
gene: WNT11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WNT11 were set to 34875064
Phenotypes for gene: WNT11 were set to osteoporosis, MONDO:0005298; osteoarthritis, MONDO:0005178; recurrent fractures
Review for gene: WNT11 was set to GREEN
Added comment: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene.

Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures.

A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures.

A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met).

This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells.

This gene has not yet been reported with any phenotypes either in OMIM or in G2P.
Sources: Literature
Mendeliome v1.665 DEPDC5 Zornitza Stark Mode of inheritance for gene: DEPDC5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.664 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Mendeliome v1.663 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Mendeliome v1.663 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: NeurodevNeurodevelopmental disorder with poor growth and behavioral abnormalities, MIM# 620242
Mendeliome v1.663 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Mendeliome v1.662 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Mendeliome v1.661 GOLGA2 Zornitza Stark reviewed gene: GOLGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34424553; Phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.661 THSD1 Zornitza Stark Phenotypes for gene: THSD1 were changed from Aneurysm, intracranial berry, 12 , MIM# 618734; Hydrops fetalis MONDO:0015193, THSD1-related to Aneurysm, intracranial berry, 12 , MIM# 618734; Lymphatic malformation 13, MIM# 620244
Mendeliome v1.660 THSD1 Zornitza Stark Mode of inheritance for gene: THSD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.659 WDR11 Zornitza Stark Phenotypes for gene: WDR11 were changed from Intellectual disability; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858 to Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Mendeliome v1.658 WDR11 Zornitza Stark edited their review of gene: WDR11: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237, Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Mendeliome v1.658 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder, MONDO:0700092, TRPM3-related to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Mendeliome v1.657 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Mendeliome v1.657 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Mendeliome v1.657 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Mendeliome v1.656 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Mendeliome v1.655 WDR5 Bryony Thompson Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Mendeliome v1.654 WDR5 Bryony Thompson edited their review of gene: WDR5: Changed publications: 36408368
Mendeliome v1.654 KBTBD13 Bryony Thompson reviewed gene: KBTBD13: Rating: AMBER; Mode of pathogenicity: None; Publications: 36335629; Phenotypes: Cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.654 KLHL24 Zornitza Stark Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Hypertrophic cardiomyopathy to Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MIM# 620236
Mendeliome v1.653 ASNA1 Zornitza Stark Marked gene: ASNA1 as ready
Mendeliome v1.653 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Mendeliome v1.653 ASNA1 Zornitza Stark Classified gene: ASNA1 as Red List (low evidence)
Mendeliome v1.653 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Mendeliome v1.652 RRAGD Zornitza Stark Classified gene: RRAGD as Green List (high evidence)
Mendeliome v1.652 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Mendeliome v1.651 RRAGD Zornitza Stark Marked gene: RRAGD as ready
Mendeliome v1.651 RRAGD Zornitza Stark Gene: rragd has been removed from the panel.
Mendeliome v1.651 RRAGD Zornitza Stark Phenotypes for gene: RRAGD were changed from Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Mendeliome v1.650 PMEL Zornitza Stark Marked gene: PMEL as ready
Mendeliome v1.650 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Mendeliome v1.650 PMEL Zornitza Stark Classified gene: PMEL as Red List (low evidence)
Mendeliome v1.650 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Mendeliome v1.649 ASNA1 Naomi Baker gene: ASNA1 was added
gene: ASNA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASNA1 were set to 31461301; 16797549
Phenotypes for gene: ASNA1 were set to Dilated cardiomyopathy, MONDO:0001644, ASNA1-related
Review for gene: ASNA1 was set to RED
Added comment: Two siblings reported with biallelic variants - there were two variants on the paternal allele (c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*)) and one variant on the maternal allele (c.488T>C p.(Val163Ala)). Unaffected sibling was heterozygous for maternal allele. Western blotting demonstrated reduced protein expression. Knockout of asna1 in zebrafish mode resulted in cardiac defects and early lethality. The Asna1 knockout mice displayed early embryonic lethality, consistent with a role of Asna1 in early embryonic development.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore changed review comment from: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature; to: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore gene: RRAGD was added
gene: RRAGD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to PMID: 34607910
Phenotypes for gene: RRAGD were set to Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.649 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100; 36207673
Phenotypes for gene: PMEL were set to Oculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.

Some evidence that polymorphisms in this gene influence pigmentation in cattle.
Sources: Literature
Mendeliome v1.649 SPTSSA Seb Lunke Marked gene: SPTSSA as ready
Mendeliome v1.649 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.649 SPTSSA Seb Lunke Classified gene: SPTSSA as Amber List (moderate evidence)
Mendeliome v1.649 SPTSSA Seb Lunke Added comment: Comment on list classification: Three individuals but only two variants with different inheritance. Amber despite functional data.
Mendeliome v1.649 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.648 SPTSSA Seb Lunke gene: SPTSSA was added
gene: SPTSSA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTSSA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to complex hereditary spastic paraplegia, MONDO:0015150
Review for gene: SPTSSA was set to AMBER
Added comment: Three unrelated individuals with common neurological features of developmental delay, progressive motor impairment, progressive lower extremity spasticity, and epileptiform activity or seizures. Other additional features varied.

Two of the individuals had the same de-novo missense, Thr51Ile, while the third was homozygous for a late truncating variant, Gln58AlafsTer10. The patient with the hom variant was described as less severe.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in flies, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA.

The de-novo missense were shown to impact regulation more than the hom truncation, while the truncated region was shown to previously to be important for ORMDL regulation.

Mice with a hom KO of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature
Mendeliome v1.647 MIR145 Zornitza Stark Marked gene: MIR145 as ready
Mendeliome v1.647 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Mendeliome v1.647 MIR145 Zornitza Stark Classified gene: MIR145 as Red List (low evidence)
Mendeliome v1.647 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Marked gene: TRU-TCA1-1 as ready
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Phenotypes for gene: TRU-TCA1-1 were changed from Hyperthyroidism MONDO:0004425 to Inherited thyroid metabolism disease, MONDO:0045046, TRU-TCA1-1 related
Mendeliome v1.645 TRU-TCA1-1 Zornitza Stark Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.645 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.644 TRU-TCA1-1 Zornitza Stark Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.644 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.644 C1GALT1C1 Ain Roesley Phenotypes for gene: C1GALT1C1 were changed from Tn polyagglutination syndrome, somatic MIM#300622 to Tn polyagglutination syndrome, somatic MIM#300622; atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Mendeliome v1.643 C1GALT1C1 Ain Roesley Publications for gene: C1GALT1C1 were set to 18537974; 16251947
Mendeliome v1.642 CAMLG Seb Lunke Marked gene: CAMLG as ready
Mendeliome v1.642 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.642 C1GALT1C1 Ain Roesley edited their review of gene: C1GALT1C1: Added comment: Red association for aHUS

1x male with de novo p.(Thr89Ile) which is absent in gnomAD v2 and v3 and has very high conservation; Changed publications: 18537974, 16251947, 36599939; Changed phenotypes: Tn polyagglutination syndrome, somatic MIM#300622, atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Mendeliome v1.642 CAMLG Seb Lunke Phenotypes for gene: CAMLG were changed from Congenital disorder of glycosylation type IIz, 620201 to Congenital disorder of glycosylation type IIz, OMIM# 620201
Mendeliome v1.641 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Mendeliome v1.641 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.641 SPRY1 Elena Savva Phenotypes for gene: SPRY1 were changed from to Craniosynostosis, SPRY1-related, MONDO:0015469
Mendeliome v1.640 SPRY1 Elena Savva Publications for gene: SPRY1 were set to
Mendeliome v1.639 SPRY1 Elena Savva Mode of inheritance for gene: SPRY1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.638 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Mendeliome v1.638 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.637 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Mendeliome v1.637 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.636 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Mendeliome v1.636 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.636 CCDC84 Zornitza Stark Classified gene: CCDC84 as Amber List (moderate evidence)
Mendeliome v1.636 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.635 SPRY1 Elena Savva reviewed gene: SPRY1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36543535; Phenotypes: Craniosynostosis, SPRY1-related, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.635 TPCN2 Paul De Fazio reviewed gene: TPCN2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 36641477; Phenotypes: Hypopigmentation of the skin, TPCN2-related MONDO:0019290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.635 MIR145 Lucy Spencer gene: MIR145 was added
gene: MIR145 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIR145 were set to 36649075
Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452), MIR145-related
Review for gene: MIR145 was set to RED
Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p.

Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts.
Sources: Literature
Mendeliome v1.635 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Mendeliome v1.634 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Mendeliome v1.634 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Mendeliome v1.633 PCK2 Ain Roesley Phenotypes for gene: PCK2 were changed from PEPCK deficiency, mitochondrial - MIM#261650 to PEPCK deficiency, mitochondrial - MIM#261650; peripheral neuropathy (MONDO#0005244), PCK2-related
Mendeliome v1.632 PCK2 Ain Roesley reviewed gene: PCK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.632 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to PMID: 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Mendeliome v1.632 OGDH Zornitza Stark Publications for gene: OGDH were set to 32383294
Mendeliome v1.631 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Mendeliome v1.631 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Mendeliome v1.630 HTR2C Zornitza Stark Marked gene: HTR2C as ready
Mendeliome v1.630 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Mendeliome v1.630 TRU-TCA1-1 Paul De Fazio gene: TRU-TCA1-1 was added
gene: TRU-TCA1-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927
Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425
Review for gene: TRU-TCA1-1 was set to AMBER
gene: TRU-TCA1-1 was marked as current diagnostic
Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA.

PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy.
Sources: Literature
Mendeliome v1.630 HTR2C Zornitza Stark Classified gene: HTR2C as Green List (high evidence)
Mendeliome v1.630 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Mendeliome v1.629 HTR2C Zornitza Stark gene: HTR2C was added
gene: HTR2C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HTR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HTR2C were set to 36536256
Phenotypes for gene: HTR2C were set to Obesity disorder, MONDO:0011122, HTR2C-related
Review for gene: HTR2C was set to GREEN
Added comment: Exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Obesity was severe, childhood-onset. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Sources: Literature
Mendeliome v1.628 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.628 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Mendeliome v1.628 THBS1 Zornitza Stark Marked gene: THBS1 as ready
Mendeliome v1.628 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Mendeliome v1.628 THBS1 Zornitza Stark Classified gene: THBS1 as Green List (high evidence)
Mendeliome v1.628 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Mendeliome v1.627 OGDH Sarah Pantaleo reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, MIM# 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.627 NPTX1 Ain Roesley Marked gene: NPTX1 as ready
Mendeliome v1.627 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Mendeliome v1.627 NPTX1 Ain Roesley Classified gene: NPTX1 as Green List (high evidence)
Mendeliome v1.627 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Mendeliome v1.626 THBS1 Zornitza Stark gene: THBS1 was added
gene: THBS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THBS1 were set to 36453543
Phenotypes for gene: THBS1 were set to Congenital glaucoma MONDO:0020366, THBS1-related
Review for gene: THBS1 was set to GREEN
Added comment: Missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma.

Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure.
Sources: Literature
Mendeliome v1.625 NPTX1 Ain Roesley gene: NPTX1 was added
gene: NPTX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related
Review for gene: NPTX1 was set to GREEN
gene: NPTX1 was marked as current diagnostic
Added comment: PMID:34788392
5 families with multigenerational segregations - late onset ataxia
4 families with p.(Gly389Arg) + 1x p.(Glu327Gly)
functional studies done

Note: case report of a family member published elsewhere (PMID:35288776)

PMID:35285082
1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome
p.(Arg143Leu)

PMID:35560436
1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy
p.(Gln370Arg)
Sources: Literature
Mendeliome v1.624 GET4 Elena Savva Marked gene: GET4 as ready
Mendeliome v1.624 GET4 Elena Savva Gene: get4 has been classified as Red List (Low Evidence).
Mendeliome v1.624 GET4 Elena Savva gene: GET4 was added
gene: GET4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GET4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GET4 were set to 32395830
Phenotypes for gene: GET4 were set to ?Congenital disorder of glycosylation,, type IIy MIM#620200
Review for gene: GET4 was set to RED
Added comment: PMID: 32395830
- chet patient (missense x2), functionally shown to result in downregulation of three TRC proteins in patient cell lines.
- patient phenotype included ID, DD, seizures, dysmorphism and delayed bone age.
- functional studies on missense themselves not performed
Sources: Literature
Mendeliome v1.623 USP48 Zornitza Stark Phenotypes for gene: USP48 were changed from non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497 to Deafness, autosomal dominant 85, MIM# 620227
Mendeliome v1.622 USP48 Zornitza Stark edited their review of gene: USP48: Changed rating: GREEN; Changed phenotypes: Deafness, autosomal dominant 85, MIM# 620227; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.622 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Mendeliome v1.621 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Mendeliome v1.621 AGR2 Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Mendeliome v1.620 AGR2 Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Mendeliome v1.620 SLC4A3 Zornitza Stark Phenotypes for gene: SLC4A3 were changed from Short QT syndrome to Short QT syndrome 7, MIM#620231
Mendeliome v1.619 SARS Zornitza Stark Phenotypes for gene: SARS were changed from neurodevelopmental disorder MONDO#070009, SARS1-related to neurodevelopmental disorder MONDO#070009, SARS1-related; Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.618 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048; 36041817
Mendeliome v1.617 SARS Zornitza Stark Mode of inheritance for gene: SARS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.616 DRC1 Zornitza Stark Phenotypes for gene: DRC1 were changed from Ciliary dyskinesia, primary, 21, MIM# 615294; Male infertility to Ciliary dyskinesia, primary, 21, MIM# 615294; Spermatogenic failure 80, MIM# 620222
Mendeliome v1.615 DRC1 Zornitza Stark edited their review of gene: DRC1: Changed phenotypes: Ciliary dyskinesia, primary, 21, MIM# 615294, Spermatogenic failure 80, MIM# 620222
Mendeliome v1.615 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features. to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Mendeliome v1.614 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.614 LY96 Zornitza Stark Marked gene: LY96 as ready
Mendeliome v1.614 LY96 Zornitza Stark Gene: ly96 has been classified as Red List (Low Evidence).
Mendeliome v1.614 LY96 Zornitza Stark gene: LY96 was added
gene: LY96 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY96 were set to 36462957
Phenotypes for gene: LY96 were set to Inborn error of immunity, MONDO:0003778, LY96-related
Review for gene: LY96 was set to RED
Added comment: Single individual with infantile colitis associated with failure-to-thrive, bloody diarrhoea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Found to have homozygous inflame deletion. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation.
Sources: Expert Review
Mendeliome v1.613 FGF13 Zornitza Stark Phenotypes for gene: FGF13 were changed from Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual disability; epilepsy to Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual developmental disorder, X-linked 110, MIM# 301095
Mendeliome v1.612 FGF13 Zornitza Stark Publications for gene: FGF13 were set to 33245860
Mendeliome v1.611 FGF13 Zornitza Stark Tag 5'UTR tag was added to gene: FGF13.
Mendeliome v1.611 FGF13 Zornitza Stark edited their review of gene: FGF13: Added comment: PMID 34184986: 3 individuals reported with moderate to severe ID and maternally inherited 5' variant c.-32C-G; Changed publications: 33245860, 34184986
Mendeliome v1.611 FGF13 Zornitza Stark edited their review of gene: FGF13: Changed phenotypes: Developmental and epileptic encephalopathy 90, MIM# 301058, Intellectual developmental disorder, X-linked 110, MIM# 301095
Mendeliome v1.611 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Mendeliome v1.610 ZNF668 Zornitza Stark reviewed gene: ZNF668: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.610 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Mendeliome v1.609 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Mendeliome v1.609 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Mendeliome v1.608 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Mendeliome v1.608 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Mendeliome v1.608 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Mendeliome v1.608 NAE1 Zornitza Stark Classified gene: NAE1 as Green List (high evidence)
Mendeliome v1.608 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Mendeliome v1.607 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Mendeliome v1.606 SLC26A6 Zornitza Stark Marked gene: SLC26A6 as ready
Mendeliome v1.606 SLC26A6 Zornitza Stark Gene: slc26a6 has been classified as Red List (Low Evidence).
Mendeliome v1.606 SLC26A6 Zornitza Stark Phenotypes for gene: SLC26A6 were changed from Enteric hyperoxaluria and nephrolithiasis to Primary hyperoxaluria, MONDO:0002474, SLC26A6-related
Mendeliome v1.605 SLC26A6 Zornitza Stark Classified gene: SLC26A6 as Red List (low evidence)
Mendeliome v1.605 SLC26A6 Zornitza Stark Gene: slc26a6 has been classified as Red List (Low Evidence).
Mendeliome v1.604 SLC26A6 Zornitza Stark reviewed gene: SLC26A6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary hyperoxaluria, MONDO:0002474, SLC26A6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.604 TRPC5 Zornitza Stark Marked gene: TRPC5 as ready
Mendeliome v1.604 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.604 TRPC5 Zornitza Stark Phenotypes for gene: TRPC5 were changed from Intellectual disability; autistic spectrum disorder to Neurodevelopmental disorder, MONDO:0700092, TRPC5-related
Mendeliome v1.603 TRPC5 Zornitza Stark Classified gene: TRPC5 as Amber List (moderate evidence)
Mendeliome v1.603 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.602 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mendeliome v1.601 CRLS1 Zornitza Stark edited their review of gene: CRLS1: Changed phenotypes: Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mendeliome v1.601 TRPC5 Hazel Phillimore gene: TRPC5 was added
gene: TRPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.601 ZMYM3 Zornitza Stark Marked gene: ZMYM3 as ready
Mendeliome v1.601 ZMYM3 Zornitza Stark Gene: zmym3 has been classified as Green List (High Evidence).
Mendeliome v1.601 BSN Krithika Murali changed review comment from: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature; to: Ye et al 2022, Neurogenetics - https://jmg.bmj.com/content/early/2022/12/12/jmg-2022-108865
Identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Mendeliome v1.601 RIC1 Paul De Fazio reviewed gene: RIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36493769; Phenotypes: Cleft lip/palate MONDO:0016044, RIC1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.601 UHRF1 Zornitza Stark Phenotypes for gene: UHRF1 were changed from Multi locus imprinting disturbance in offspring to Multi locus imprinting disturbance in offspring; chromosome instability
Mendeliome v1.600 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982
Mendeliome v1.599 UHRF1 Zornitza Stark Mode of inheritance for gene: UHRF1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.598 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Mendeliome v1.597 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36562171; Phenotypes: Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.597 BSN Zornitza Stark Marked gene: BSN as ready
Mendeliome v1.597 BSN Zornitza Stark Added comment: Comment when marking as ready: We are aware of additional mono-allelic cases.
Mendeliome v1.597 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Mendeliome v1.597 BSN Zornitza Stark Mode of inheritance for gene: BSN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.596 BSN Zornitza Stark Classified gene: BSN as Green List (high evidence)
Mendeliome v1.596 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Mendeliome v1.595 UHRF1 Chern Lim changed review comment from: PMID: 29574422 Begemann et al. 2018
- Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense.; to: PMID: 29574422 Begemann et al. 2018
- Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense. Her cotwin was clinically and epigenetically normal
Mendeliome v1.595 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092 to neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Mendeliome v1.594 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Changed publications: 36458887, 29574422; Changed phenotypes: chromosome instability, Multi locus imprinting disturbance in offspring; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.593 ARHGEF38 Zornitza Stark Marked gene: ARHGEF38 as ready
Mendeliome v1.593 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Added comment: PMID: 36458887 Unoki et al. 2022
- One patient with compound het missense and nonsense variants, both parents are carriers (hets).
- The patient has chromosome instability with hypomethylation of the pericentromeric satellite-2 repeats and facial anomalies as typical symptoms of the ICF syndrome, but did not exhibit immunodeficiency, and developed an adrenocortical adenoma; characteristics that were atypical.
- Genome-wide methylation analysis revealed the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes.
- Structural and biochemical analyses revealed that the R296W variant disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1, and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and PAF15.; Changed publications: 36458887; Changed phenotypes: chromosome instability; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.593 ARHGEF38 Zornitza Stark Mode of inheritance for gene: ARHGEF38 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.592 ARHGEF38 Zornitza Stark Classified gene: ARHGEF38 as Amber List (moderate evidence)
Mendeliome v1.592 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.591 UHRF1 Chern Lim reviewed gene: UHRF1: Rating: RED; Mode of pathogenicity: None; Publications: 29574422; Phenotypes: Multi locus imprinting disturbance in offspring; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.591 EIF4A2 Zornitza Stark Marked gene: EIF4A2 as ready
Mendeliome v1.591 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Mendeliome v1.591 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Mendeliome v1.591 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Mendeliome v1.590 ARHGAP35 Dean Phelan reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36450800; Phenotypes: Developmental defect of the eye (MONDO:0020145), ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.590 SLC31A1 Alison Yeung Classified gene: SLC31A1 as Amber List (moderate evidence)
Mendeliome v1.590 SLC31A1 Alison Yeung Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.589 ARHGEF38 Paul De Fazio gene: ARHGEF38 was added
gene: ARHGEF38 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGEF38 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARHGEF38 were set to 36493769
Phenotypes for gene: ARHGEF38 were set to Cleft lip/palate MONDO:0016044, ARHGEF38-related
Review for gene: ARHGEF38 was set to AMBER
gene: ARHGEF38 was marked as current diagnostic
Added comment: PMID:36493769 identified an intragenic deletion by high-res microarray of the same exon (exon 3) in 4 individuals with non-syndromic cleft lip/palate. Deletion of exon 3 is present in 6 individuals in gnomAD. Inheritance information was not available.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Mendeliome v1.589 COBLL1 Zornitza Stark Marked gene: COBLL1 as ready
Mendeliome v1.589 COBLL1 Zornitza Stark Gene: cobll1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.589 COBLL1 Zornitza Stark Classified gene: COBLL1 as Amber List (moderate evidence)
Mendeliome v1.589 COBLL1 Zornitza Stark Gene: cobll1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.588 COBLL1 Paul De Fazio edited their review of gene: COBLL1: Changed rating: AMBER
Mendeliome v1.588 COBLL1 Paul De Fazio gene: COBLL1 was added
gene: COBLL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COBLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COBLL1 were set to 36493769
Phenotypes for gene: COBLL1 were set to Cleft lip/palate MONDO:0016044, COBLL1-related
gene: COBLL1 was marked as current diagnostic
Added comment: PMID:36493769 identified the same multi-exon intragenic deletion by high-res microarray in 3 individuals with non-syndromic cleft lip/palate. The deletion is absent from gnomAD. Inheritance information was only available for 1 individual, in whom it was inherited from an unaffected father. Note that the gene is not quite LOF constrained in gnomAD.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Mendeliome v1.588 BSN Krithika Murali gene: BSN was added
gene: BSN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BSN were set to Epilepsy MONDO:0005027
Review for gene: BSN was set to GREEN
Added comment: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Mendeliome v1.588 EIF4A2 Dean Phelan gene: EIF4A2 was added
gene: EIF4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to PMID: 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related
Mode of pathogenicity for gene: EIF4A2 was set to Other
Review for gene: EIF4A2 was set to GREEN
Added comment: PMID: 36528028
- EIF4A2 variants were observed in 15 individuals from 14 families. Affected individuals had a range of symptoms including global developmental delay (9/15), ID (7/15), epilepsy (11/15) and structural brain alterations (10/15). Monoallelic and biallelic variants were reported and functional studies showed both LOF and GOF disease mechanisms.
Sources: Literature
Mendeliome v1.588 OXGR1 Sarah Pantaleo edited their review of gene: OXGR1: Changed phenotypes: Nephrolithiasis/nephrocalcinosis, MONDO:0008171, OXGR1-related, MONDO:0001567, OXGR1-related
Mendeliome v1.588 PHLDB1 Seb Lunke Marked gene: PHLDB1 as ready
Mendeliome v1.588 PHLDB1 Seb Lunke Gene: phldb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.588 PHLDB1 Seb Lunke Classified gene: PHLDB1 as Amber List (moderate evidence)
Mendeliome v1.588 PHLDB1 Seb Lunke Gene: phldb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.587 PHLDB1 Seb Lunke gene: PHLDB1 was added
gene: PHLDB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHLDB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PHLDB1 were set to 36543534
Phenotypes for gene: PHLDB1 were set to osteogenesis imperfecta, MONDO:0019019
Review for gene: PHLDB1 was set to AMBER
Added comment: 5 children from two consanguineous families with recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment.

Two independent nonsense variants were identified in the families, NM_001144758.3:c.2392dup (p.Leu798Profs*4) and NM_001144758.3:c.2690_2693del (p.Leu897Glnfs*24). RT-PCR and western blot analysis confirmed loss of transcript and protein product, respectively, but no further functional data provided.
Sources: Literature
Mendeliome v1.586 OXGR1 Zornitza Stark Marked gene: OXGR1 as ready
Mendeliome v1.586 OXGR1 Zornitza Stark Gene: oxgr1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.586 OXGR1 Zornitza Stark Classified gene: OXGR1 as Amber List (moderate evidence)
Mendeliome v1.586 OXGR1 Zornitza Stark Gene: oxgr1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.585 CDK16 Alison Yeung Phenotypes for gene: CDK16 were changed from Intellectual disability to Neurodevelopmental disorder (MONDO#0700092) CDK16-related
Mendeliome v1.584 CDK16 Alison Yeung Publications for gene: CDK16 were set to 25644381
Mendeliome v1.583 OXGR1 Sarah Pantaleo gene: OXGR1 was added
gene: OXGR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OXGR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OXGR1 were set to PMID:35671463
Phenotypes for gene: OXGR1 were set to Nephrolithiasis/nephrocalcinosis MONDO:0008171, OXGR1-related
Penetrance for gene: OXGR1 were set to unknown
Review for gene: OXGR1 was set to AMBER
Added comment: Candidate disease gene for human calcium oxalate nephrolithiasis.

Performed exome sequencing and directed sequencing of the OXGR1 locus in a worldwide nephrolithiasis/nephrocalcinosis (NL/NC) cohort, and putatively deleterious rare OXGR1 variants were functionally characterised.

A heterozygous OXGR1 missense variant (c.371T>G; p.Leu124Arg) co-segregated with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals.

Interrogation of the OXGR1 locus in 1,107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls. Four missense variants and one frameshift variant.

Four of five NL/NC-associated missense variants revealed impaired AKG-dependent calcium ion uptake, demonstrating loss of function.

Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. Six potentially deleterious variants were identified in six of 1,108 NL/NC families (0.54%).

Limitations: only probands were able to be recruited for four of six families. In the future, it will be important to determine whether any of the affected family members share the identified OXGR1 variant. They also observe OXGR1 variants in 0.16% of ExAC subjects (selected on the basis of the absence of paediatric disease).
Sources: Literature
Mendeliome v1.583 CDK16 Alison Yeung reviewed gene: CDK16: Rating: GREEN; Mode of pathogenicity: None; Publications: 36323681, 31981491, 25644381; Phenotypes: Neurodevelopmental disorder (MONDO#0700092) CDK16-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.583 CDK16 Alison Yeung Classified gene: CDK16 as Green List (high evidence)
Mendeliome v1.583 CDK16 Alison Yeung Gene: cdk16 has been classified as Green List (High Evidence).
Mendeliome v1.582 CCIN Seb Lunke Marked gene: CCIN as ready
Mendeliome v1.582 CCIN Seb Lunke Gene: ccin has been classified as Green List (High Evidence).
Mendeliome v1.582 CCIN Seb Lunke Phenotypes for gene: CCIN were changed from Teratozoospermia to male infertility with teratozoospermia due to single gene mutation, MONDO:0018394
Mendeliome v1.581 CCIN Seb Lunke Classified gene: CCIN as Green List (high evidence)
Mendeliome v1.581 CCIN Seb Lunke Gene: ccin has been classified as Green List (High Evidence).
Mendeliome v1.580 CCIN Chern Lim gene: CCIN was added
gene: CCIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCIN were set to 36546111; 36527329
Phenotypes for gene: CCIN were set to Teratozoospermia
Review for gene: CCIN was set to GREEN
gene: CCIN was marked as current diagnostic
Added comment: Two papers with three unrelated patients with teratozoospermia:

PMID: 36546111
- Two families reported: One with homozygous missense (fam is consanguineous) and another with compound heterozygous missense + nonsense variants, patients suffering from teratozoospermia.
- Homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* knock-in mice generated. Spermatozoa from homozygous male mice exhibited abnormalities of sperm head shape revealed by Diff-Quick staining. When mated with WT mice, both homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* male mice were infertile, whereas the mutant female mice could generate offspring and displayed no defects in fertility.

PMID: 36527329
- One consanguineous family reported: homozygous missense, with asthenoteratozoospermia.
- Transfected HEK cells showed reduced CCIN protein level.
Sources: Literature
Mendeliome v1.580 TRA2B Seb Lunke Marked gene: TRA2B as ready
Mendeliome v1.580 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Mendeliome v1.580 TRA2B Seb Lunke Phenotypes for gene: TRA2B were changed from Neurodevelopmental disorder, TRA2B-related (MONDO#0700092) to Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092
Mendeliome v1.579 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Mendeliome v1.579 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Mendeliome v1.578 ZMYM3 Zornitza Stark Mode of inheritance for gene: ZMYM3 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 v1.577 ZMYM3 Zornitza Stark Phenotypes for gene: ZMYM3 were changed from Neurodevelopmental disorders (NDDs) to Neurodevelopmental disorder, MONDO:0700092, ZMYM3-related
Mendeliome v1.576 TRA2B Elena Savva gene: TRA2B was added
gene: TRA2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRA2B were set to PMID: 36549593
Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092)
Review for gene: TRA2B was set to GREEN
Added comment: PMID: 36549593
- 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12
- All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased.
- Apparently het mice K/O are normal, but complete K/O cannot develop embryonically.
- DN mechanism suggested
Sources: Literature
Mendeliome v1.575 ZMYM3 Zornitza Stark Classified gene: ZMYM3 as Green List (high evidence)
Mendeliome v1.575 ZMYM3 Zornitza Stark Gene: zmym3 has been classified as Green List (High Evidence).
Mendeliome v1.574 TUFT1 Zornitza Stark Marked gene: TUFT1 as ready
Mendeliome v1.574 TUFT1 Zornitza Stark Gene: tuft1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.574 TUFT1 Zornitza Stark Classified gene: TUFT1 as Amber List (moderate evidence)
Mendeliome v1.574 TUFT1 Zornitza Stark Gene: tuft1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.573 TUFT1 Zornitza Stark gene: TUFT1 was added
gene: TUFT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TUFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUFT1 were set to https://doi.org/10.1093/bjd/ljac026
Phenotypes for gene: TUFT1 were set to Ectodermal dysplasia, MONDO:0019287, TUFT1-related
Review for gene: TUFT1 was set to AMBER
Added comment: 9 individuals from three families reported with woolly hair and skin fragility. One of the variants, c.60+1G>A was present in two of the families, founder effect demonstrated by haplotype analysis. Another loss of function variant present in the third family. Some functional data but mostly expression studies.
Sources: Literature
Mendeliome v1.572 ZMYM3 Belinda Chong gene: ZMYM3 was added
gene: ZMYM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYM3 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: ZMYM3 were set to 36586412; 24721225
Phenotypes for gene: ZMYM3 were set to Neurodevelopmental disorders (NDDs)
Review for gene: ZMYM3 was set to GREEN
Added comment: PMID: 36586412
Using the MatchMaker Exchange - Described 27 individuals with rare, variation in the ZMYM3. Most individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) with de novo variants.
Overlapping features included developmental delay, intellectual disability, behavioural abnormalities, and a specific facial gestalt in a subset of males.
Variants in almost all individuals are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441 (R441W), a site at which variation has been previously seen in NDD-affected siblings (24721225), and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T).
ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect.
Sources: Literature
Mendeliome v1.572 KMT2D Zornitza Stark Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920; KMT2D-associated syndrome to Kabuki syndrome 1, MIM# 147920; Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186
Mendeliome v1.571 KMT2D Zornitza Stark edited their review of gene: KMT2D: Changed phenotypes: Kabuki syndrome 1, MIM# 147920, Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186
Mendeliome v1.571 BUB1 Zornitza Stark Phenotypes for gene: BUB1 were changed from Neurodevelopmental disorder, BUB1-related MONDO:0700092 to Primary microcephaly-30 (MCPH30), MIM#620183
Mendeliome v1.570 BUB1 Zornitza Stark edited their review of gene: BUB1: Changed phenotypes: primary microcephaly-30 (MCPH30), MIM#620183
Mendeliome v1.570 GOSR2 Zornitza Stark Phenotypes for gene: GOSR2 were changed from Epilepsy, progressive myoclonic 6 , MIM#614018 to Epilepsy, progressive myoclonic 6 , MIM#614018; Muscular dystrophy, congenital, with or without seizures, MIM# 620166
Mendeliome v1.569 GOSR2 Zornitza Stark edited their review of gene: GOSR2: Added comment: PMIDs 29855340; 33639315: at least three families reported with a muscular dystrophy presentation as well as seizures.; Changed publications: 21549339, 24458321, 30363482, 29855340, 33639315; Changed phenotypes: Epilepsy, progressive myoclonic 6 , MIM#614018, Muscular dystrophy, congenital, with or without seizures, MIM# 620166
Mendeliome v1.569 TNNC2 Zornitza Stark Phenotypes for gene: TNNC2 were changed from Congenital myopathy, MONDO:0019952, TNNC2-related to Myopathy, congenital, with neonatal respiratory insufficiency, MIM# 620161
Mendeliome v1.568 TNNC2 Zornitza Stark edited their review of gene: TNNC2: Changed phenotypes: Myopathy, congenital, with neonatal respiratory insufficiency, MIM# 620161
Mendeliome v1.568 C3orf52 Zornitza Stark Phenotypes for gene: C3orf52 were changed from Localized hypotrichosis to Hypotrichosis-15, MIM#620177
Mendeliome v1.567 C3orf52 Zornitza Stark edited their review of gene: C3orf52: Changed phenotypes: Hypotrichosis-15, MIM#620177
Mendeliome v1.567 TSPEAR Zornitza Stark Phenotypes for gene: TSPEAR were changed from Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180 to Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180; Selective tooth agenesis-10 (STHAG10), MIM#620173
Mendeliome v1.566 TSPEAR Zornitza Stark Publications for gene: TSPEAR were set to 27736875; 30046887
Mendeliome v1.565 TSPEAR Zornitza Stark edited their review of gene: TSPEAR: Added comment: More than 5 individuals reported with selective tooth agenesis.; Changed rating: GREEN; Changed publications: 30046887, 32112661, 34042254; Changed phenotypes: Selective tooth agenesis-10 (STHAG10), MIM#620173; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.565 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765
Mendeliome v1.564 CDK5 Zornitza Stark Classified gene: CDK5 as Amber List (moderate evidence)
Mendeliome v1.564 CDK5 Zornitza Stark Gene: cdk5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.563 CDK5 Zornitza Stark edited their review of gene: CDK5: Added comment: Upgraded to Amber following GenCC discrepancy resolution: single family with four affected individuals but extensive supportive experimental evidence including mouse models.; Changed rating: AMBER; Changed publications: 25560765, 32273484, 32097629, 28854363, 7490100
Mendeliome v1.563 SLC26A6 Arina Puzriakova gene: SLC26A6 was added
gene: SLC26A6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC26A6 were set to 35115415; 21170874; 32660969
Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)

SLC26A6 is currently not associated with any human phenotype in OMIM or G2P.
Sources: Literature
Mendeliome v1.563 WDFY3 Zornitza Stark Phenotypes for gene: WDFY3 were changed from Microcephaly 18, primary, autosomal dominant, MIM#617520 to Microcephaly 18, primary, autosomal dominant, MIM#617520; Neurodevelopmental disorder with macrocephaly
Mendeliome v1.562 PTPN4 Zornitza Stark Phenotypes for gene: PTPN4 were changed from Intellectual disability; developmental delay to Neurodevelopmental disorder, MONDO:0700092, PTPN4-related
Mendeliome v1.561 CLDN5 Zornitza Stark Phenotypes for gene: CLDN5 were changed from alternating hemiplegia, MONDO:0016210, CLDN5-related to Syndromic disorder, MONDO:0002254, CLDN5-related
Mendeliome v1.560 CLDN5 Zornitza Stark Publications for gene: CLDN5 were set to 35714222
Mendeliome v1.559 CLDN5 Zornitza Stark Mode of pathogenicity for gene: CLDN5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Mendeliome v1.558 CLDN5 Zornitza Stark Classified gene: CLDN5 as Green List (high evidence)
Mendeliome v1.558 CLDN5 Zornitza Stark Gene: cldn5 has been classified as Green List (High Evidence).
Mendeliome v1.557 SETD2 Zornitza Stark Phenotypes for gene: SETD2 were changed from Luscan-Lumish syndrome, MIM#616831; Luscan-Lumish syndrome, MIM#616831; Rabin-Pappas syndrome,MIM# 620155; Intellectual developmental disorder, autosomal dominant 70, MIM# 620157 to Luscan-Lumish syndrome, MIM#616831; Rabin-Pappas syndrome,MIM# 620155; Intellectual developmental disorder, autosomal dominant 70, MIM# 620157
Mendeliome v1.556 SETD2 Zornitza Stark Phenotypes for gene: SETD2 were changed from Luscan-Lumish syndrome, MIM#616831 to Luscan-Lumish syndrome, MIM#616831; Luscan-Lumish syndrome, MIM#616831; Rabin-Pappas syndrome,MIM# 620155; Intellectual developmental disorder, autosomal dominant 70, MIM# 620157
Mendeliome v1.555 SETD2 Zornitza Stark Publications for gene: SETD2 were set to 29681085
Mendeliome v1.554 SETD2 Zornitza Stark edited their review of gene: SETD2: Added comment: PMID 32710489: 12 unrelated patients, ranging from 1 month to 12 years of age, with a multisystemic neurodevelopmental disorder associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740W).

Key clinical features: severely impaired global development apparent from infancy, feeding difficulties with failure to thrive, small head circumference, and dysmorphic facial features. Affected individuals have impaired intellectual development and hypotonia; they do not achieve walking or meaningful speech. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and possibly endocrine.

Further 3 unrelated patients identified with mild to moderately impaired intellectual development associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740Q).

These are distinct clinically from Luscan-Lumish syndrome, which is characterised by overgrowth.; Changed publications: 29681085, 32710489; Changed phenotypes: Luscan-Lumish syndrome, MIM#616831, Rabin-Pappas syndrome,MIM# 620155, Intellectual developmental disorder, autosomal dominant 70, MIM# 620157
Mendeliome v1.554 RPS15 Zornitza Stark Marked gene: RPS15 as ready
Mendeliome v1.554 RPS15 Zornitza Stark Gene: rps15 has been classified as Red List (Low Evidence).
Mendeliome v1.554 RPS15 Zornitza Stark Phenotypes for gene: RPS15 were changed from Diamond-Blackfan anaemia to Diamond-Blackfan anaemia, MONDO:0015253, RPS15-related
Mendeliome v1.553 RPS15 Zornitza Stark gene: RPS15 was added
gene: RPS15 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RPS15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS15 were set to 19061985
Phenotypes for gene: RPS15 were set to Diamond-Blackfan anaemia
Review for gene: RPS15 was set to RED
Added comment: Single individual reported in 2008, no reports since.
Sources: Expert Review
Mendeliome v1.552 CLDN5 Suliman Khan reviewed gene: CLDN5: 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: 36477332; Phenotypes: seizures, developmental delay, microcephaly, brain calcifications; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.552 AMT Xinyu Zhang reviewed gene: AMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 35646099, 25231368, 27362913; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.552 KIF26A Zornitza Stark Phenotypes for gene: KIF26A were changed from Cerebral malformation MONDO:0016054, KIF26-related to Cortical dysplasia, complex, with other brain malformations 11, MIM# 620156
Mendeliome v1.551 KIF26A Zornitza Stark edited their review of gene: KIF26A: Changed phenotypes: Cortical dysplasia, complex, with other brain malformations 11, MIM# 620156
Mendeliome v1.551 ZFP36L1 Zornitza Stark Phenotypes for gene: ZFP36L1 were changed from to Oocyte maturation defect 13, MIM# 620154
Mendeliome v1.550 ZFP36L1 Zornitza Stark Publications for gene: ZFP36L1 were set to
Mendeliome v1.549 ZFP36L1 Zornitza Stark Mode of inheritance for gene: ZFP36L1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.548 ZFP36L1 Zornitza Stark reviewed gene: ZFP36L1: Rating: RED; Mode of pathogenicity: None; Publications: 34611029, 22367205; Phenotypes: Oocyte maturation defect 13, MIM# 620154; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.548 HSPG2 Zornitza Stark Phenotypes for gene: HSPG2 were changed from Dyssegmental dysplasia, Silverman-Handmaker type; Schwartz-Jampel syndrome, type 1 to Schwartz-Jampel syndrome, type 1, MIM# 255800; MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, MIM# 224410; MONDO:0009140
Mendeliome v1.547 IL2RB Zornitza Stark Tag immunological was removed from gene: IL2RB.
Mendeliome v1.547 IL2RB Zornitza Stark Tag treatable tag was added to gene: IL2RB.
Tag immunological tag was added to gene: IL2RB.
Mendeliome v1.547 IL2RB Zornitza Stark changed review comment from: Five families reported.
Sources: Expert list; to: Five families reported.

Affected individuals present in infancy with features of both abnormal activation of certain immune signaling pathways, resulting in lymphoid proliferation, dermatitis, enteropathy, and hypergammaglobulinemia, as well as features of immunodeficiency, such as recurrent infections and increased susceptibility to viral infections, especially CMV. Laboratory studies show increased NK cells that show impaired differentiation, as well as abnormal T cell populations or responses. Some patients may die in childhood; hematopoietic bone marrow transplantation is curative.

Sources: Expert list
Mendeliome v1.547 CACNA2D1 Zornitza Stark Phenotypes for gene: CACNA2D1 were changed from Developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related to Developmental and epileptic encephalopathy 110, MIM# 620149
Mendeliome v1.546 FZR1 Zornitza Stark Phenotypes for gene: FZR1 were changed from Developmental and epileptic encephalopathy, FZR1-related, MONDO:0100062 to Developmental and epileptic encephalopathy 109, MIM# 620145
Mendeliome v1.545 FZR1 Zornitza Stark reviewed gene: FZR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 109, MIM# 620145; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.545 SLC9A3R1 Zornitza Stark Tag refuted tag was added to gene: SLC9A3R1.
Mendeliome v1.545 IDS Zornitza Stark Mode of inheritance for gene: IDS was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.544 IDS Zornitza Stark edited their review of gene: IDS: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.544 RPS6KB1 Zornitza Stark Marked gene: RPS6KB1 as ready
Mendeliome v1.544 RPS6KB1 Zornitza Stark Gene: rps6kb1 has been classified as Green List (High Evidence).
Mendeliome v1.544 RPS6KB1 Zornitza Stark Phenotypes for gene: RPS6KB1 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy, MONDO:0005045, RPS6KB1-related
Mendeliome v1.543 RPS6KB1 Zornitza Stark Classified gene: RPS6KB1 as Green List (high evidence)
Mendeliome v1.543 RPS6KB1 Zornitza Stark Gene: rps6kb1 has been classified as Green List (High Evidence).
Mendeliome v1.542 TNNC2 Zornitza Stark Marked gene: TNNC2 as ready
Mendeliome v1.542 TNNC2 Zornitza Stark Gene: tnnc2 has been classified as Green List (High Evidence).
Mendeliome v1.542 TNNC2 Zornitza Stark Classified gene: TNNC2 as Green List (high evidence)
Mendeliome v1.542 TNNC2 Zornitza Stark Gene: tnnc2 has been classified as Green List (High Evidence).
Mendeliome v1.541 TNNC2 Zornitza Stark gene: TNNC2 was added
gene: TNNC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNNC2 were set to 33755597
Phenotypes for gene: TNNC2 were set to Congenital myopathy, MONDO:0019952, TNNC2-related
Review for gene: TNNC2 was set to GREEN
Added comment: Two families reported: Family 1: 4 individuals, three generations; missense variant p.(Asp34Tyr) Family 2: de novo variant, missense p.(Met79Ile)

Physiological studies in myofibers isolated from patients’ biopsies revealed a markedly reduced force response of the sarcomeres to [Ca2+]. This pathomechanism was further confirmed in experiments in which contractile dysfunction was evoked by replacing TnC in myofibers from healthy control subjects with recombinant, mutant TnC. Conversely, the contractile dysfunction of myofibers from patients was repaired by replacing endogenous, mutant TnC with recombinant, wild-type TnC.

Borderline Green: sufficient segregation in Fam 1 plus de novo status in Fam 2, plus functional data.
Sources: Literature
Mendeliome v1.540 JAK3 Zornitza Stark Tag treatable tag was added to gene: JAK3.
Mendeliome v1.540 CHUK Zornitza Stark Phenotypes for gene: CHUK were changed from Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339; Cocoon syndrome, MIM# 613630; AEC-like syndrome to Combined immunodeficiency, MONDO:0015131, CHUK-related; Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339; Cocoon syndrome, MIM# 613630; AEC-like syndrome
Mendeliome v1.539 CHUK Zornitza Stark Publications for gene: CHUK were set to 25691407; 20961246; 10195895; 10195896; 29523099; 28513979
Mendeliome v1.538 CHUK Zornitza Stark edited their review of gene: CHUK: Changed phenotypes: Combined immunodeficiency, MONDO:0015131, CHUK-related, Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339, Cocoon syndrome, MIM# 613630, AEC-like syndrome
Mendeliome v1.538 CHUK Zornitza Stark edited their review of gene: CHUK: Added comment: PMID 34533979: single individual reported with homozygous missense variant in this gene and recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine. Supportive functional data.; Changed publications: 25691407, 20961246, 10195895, 10195896, 29523099, 28513979, 34533979
Mendeliome v1.538 IRF7 Zornitza Stark Publications for gene: IRF7 were set to 25814066; 15800576
Mendeliome v1.537 IRF7 Zornitza Stark Classified gene: IRF7 as Green List (high evidence)
Mendeliome v1.537 IRF7 Zornitza Stark Gene: irf7 has been classified as Green List (High Evidence).
Mendeliome v1.536 IRF7 Zornitza Stark Classified gene: IRF7 as Green List (high evidence)
Mendeliome v1.536 IRF7 Zornitza Stark Gene: irf7 has been classified as Green List (High Evidence).
Mendeliome v1.535 IRF7 Zornitza Stark edited their review of gene: IRF7: Changed rating: GREEN
Mendeliome v1.535 IRF7 Zornitza Stark edited their review of gene: IRF7: Added comment: Additional individuals reported PMIDs 35986347, 35670811: total of 7; Changed publications: 25814066, 15800576, 35986347, 35670811
Mendeliome v1.535 LIG1 Zornitza Stark Phenotypes for gene: LIG1 were changed from Combined immunodeficiency; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis to Immunodeficiency 96, MIM# 619774; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis
Mendeliome v1.534 NLGN4X Zornitza Stark Marked gene: NLGN4X as ready
Mendeliome v1.534 NLGN4X Zornitza Stark Added comment: Comment when marking as ready: Definitive assessment by ClinGen noted, as well as 'limited' assessments by G2P and Genomics England. Many of the variants are multi-gene deletions; phenotypes are not well delineated, with several individuals not having ID.
Mendeliome v1.534 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Amber List (Moderate Evidence).
Mendeliome v1.534 NLGN4X Zornitza Stark Publications for gene: NLGN4X were set to 12669065; 18231125; 10071191; 29428674
Mendeliome v1.533 NLGN4X Zornitza Stark Classified gene: NLGN4X as Amber List (moderate evidence)
Mendeliome v1.533 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Amber List (Moderate Evidence).
Mendeliome v1.532 NLGN4X Krithika Murali reviewed gene: NLGN4X: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:26350204, PMID:14963808, PMID:12669065, PMID:23352163, PMID:28263302, PMID:16648374; Phenotypes: Intellectual developmental disorder, X-linked - MIM#300495; 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 v1.532 TIMMDC1 Zornitza Stark Classified gene: TIMMDC1 as Green List (high evidence)
Mendeliome v1.532 TIMMDC1 Zornitza Stark Gene: timmdc1 has been classified as Green List (High Evidence).
Mendeliome v1.531 MPC2 Zornitza Stark Marked gene: MPC2 as ready
Mendeliome v1.531 MPC2 Zornitza Stark Gene: mpc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.531 MPC2 Zornitza Stark Classified gene: MPC2 as Amber List (moderate evidence)
Mendeliome v1.531 MPC2 Zornitza Stark Gene: mpc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.530 MPC2 Zornitza Stark gene: MPC2 was added
gene: MPC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPC2 were set to 36417180
Phenotypes for gene: MPC2 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related
Review for gene: MPC2 was set to AMBER
Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels.
Sources: Literature
Mendeliome v1.529 Zornitza Stark removed gene:NPC1 from the panel
Mendeliome v1.528 ARF3 Zornitza Stark Publications for gene: ARF3 were set to 34346499
Mendeliome v1.527 ARF3 Zornitza Stark Classified gene: ARF3 as Green List (high evidence)
Mendeliome v1.527 ARF3 Zornitza Stark Gene: arf3 has been classified as Green List (High Evidence).
Mendeliome v1.526 TIMMDC1 Paul De Fazio reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36349561, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31 MIM#618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.526 LEMD2 Seb Lunke Phenotypes for gene: LEMD2 were changed from Marbach-Rustad progeroid syndrome, OMIM# 619322; progeroid disorder to Marbach-Rustad progeroid syndrome, OMIM# 619322; arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587; Cataract 46, juvenile-onset, OMIM# 212500
Mendeliome v1.525 LEMD2 Seb Lunke Publications for gene: LEMD2 were set to PMID: 30905398
Mendeliome v1.524 LEMD2 Seb Lunke Mode of inheritance for gene: LEMD2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.523 LEMD2 Seb Lunke reviewed gene: LEMD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31061923, 26788539, 30905398, 36377660; Phenotypes: Marbach-Rustad progeroid syndrome, OMIM# 619322, arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587, Cataract 46, juvenile-onset, OMIM# 212500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.523 NUP54 Zornitza Stark Marked gene: NUP54 as ready
Mendeliome v1.523 NUP54 Zornitza Stark Gene: nup54 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.523 NUP54 Zornitza Stark Phenotypes for gene: NUP54 were changed from Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia to Striatonigral degeneration, MONDO:0003122, NUP54-related; Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Mendeliome v1.522 NUP54 Zornitza Stark Mode of pathogenicity for gene: NUP54 was changed from None to None
Mendeliome v1.521 UQCRH Zornitza Stark Classified gene: UQCRH as Amber List (moderate evidence)
Mendeliome v1.521 UQCRH Zornitza Stark Gene: uqcrh has been classified as Amber List (Moderate Evidence).
Mendeliome v1.520 FEM1C Zornitza Stark Marked gene: FEM1C as ready
Mendeliome v1.520 FEM1C Zornitza Stark Gene: fem1c has been classified as Green List (High Evidence).
Mendeliome v1.520 FEM1C Zornitza Stark Classified gene: FEM1C as Green List (high evidence)
Mendeliome v1.520 FEM1C Zornitza Stark Gene: fem1c has been classified as Green List (High Evidence).
Mendeliome v1.519 DCLRE1B Zornitza Stark Phenotypes for gene: DCLRE1B were changed from Dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome to Dyskeratosis congenita, autosomal recessive 8, MIM# 620133
Mendeliome v1.518 DCLRE1B Zornitza Stark Publications for gene: DCLRE1B were set to 20479256; 21647296
Mendeliome v1.517 DCLRE1B Zornitza Stark Mode of inheritance for gene: DCLRE1B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.516 DCLRE1B Zornitza Stark Classified gene: DCLRE1B as Green List (high evidence)
Mendeliome v1.516 DCLRE1B Zornitza Stark Gene: dclre1b has been classified as Green List (High Evidence).
Mendeliome v1.515 DCLRE1B Zornitza Stark edited their review of gene: DCLRE1B: Added comment: Three additional families reported.; Changed rating: GREEN; Changed publications: 20479256, 21647296, 35007328
Mendeliome v1.515 NUP54 Zornitza Stark Mode of pathogenicity for gene: NUP54 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Mendeliome v1.514 NUP54 Zornitza Stark Classified gene: NUP54 as Amber List (moderate evidence)
Mendeliome v1.514 NUP54 Zornitza Stark Gene: nup54 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.513 NUP54 Hazel Phillimore gene: NUP54 was added
gene: NUP54 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUP54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP54 were set to PMID: 36333996
Phenotypes for gene: NUP54 were set to Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Mode of pathogenicity for gene: NUP54 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: NUP54 was set to AMBER
Added comment: From PMID: 36333996.; Harrer, P. et al. (2022) Ann Neurol. doi: 10.1002/ana.26544.

Three patients from unrelated families with dystonia and/or Leigh(-like) syndromes, with biallelic variants in NUP54, in the C-terminal protein region that interacts with NUP62. Onset was between 12 months and 5 years. All had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia.

Patient / Family A (consanguineous) was homozygous for c.1073T>G p.(Ile358Ser).

Patient / Family B was compound heterozygous for c.1073T>G p.(Ile358Ser) and c.1126A>G p.(Lys376Glu).

Patient / Family C was compound heterozygosity for c.1410_1412del p.(Gln471del) and two missense variants c.1414G>A, p.(Glu472Lys); c.1420C>T, p.(Leu474Phe)

The phenotypes were similar to those of NUP62 including early-onset dystonia with dysphagic choreoathetosis, and T2-hyperintense lesions in striatum.

Brain MRIs showed T2/FLAIR hyperintensities in the dorsal putamina.

Western blots showing reduced expression of NUP54 and its interaction partners NUP62/NUP58 in patient fibroblasts.
Sources: Literature
Mendeliome v1.513 GABRA3 Zornitza Stark Marked gene: GABRA3 as ready
Mendeliome v1.513 GABRA3 Zornitza Stark Gene: gabra3 has been classified as Green List (High Evidence).
Mendeliome v1.513 GABRA3 Zornitza Stark Phenotypes for gene: GABRA3 were changed from Epilepsy, intellectual disability, dysmorphic features, to Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, MIM# 301091
Mendeliome v1.512 ARF3 Dean Phelan reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36369169, 34346499; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), ARF3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.512 GABRA3 Zornitza Stark Classified gene: GABRA3 as Green List (high evidence)
Mendeliome v1.512 GABRA3 Zornitza Stark Gene: gabra3 has been classified as Green List (High Evidence).
Mendeliome v1.511 DCLRE1B Manny Jacobs reviewed gene: DCLRE1B: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 10699141, 20479256, 35007328; Phenotypes: Dyskeratosis congenita, autosomal recessive 8; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.511 NPC1 Naomi Baker gene: NPC1 was added
gene: NPC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPC1 were set to 36417180
Phenotypes for gene: NPC1 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related
Review for gene: NPC1 was set to AMBER
Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels.
Sources: Literature
Mendeliome v1.511 EMILIN1 Zornitza Stark Publications for gene: EMILIN1 were set to PMID: 31978608; 26462740.
Mendeliome v1.510 EMILIN1 Zornitza Stark Phenotypes for gene: EMILIN1 were changed from Neuronopathy, distal hereditary motor, type X, MIM# 620080 to Neuronopathy, distal hereditary motor, type X, MIM# 620080; Aortic aneurysm, MONDO:0005160, EMILIN2-related
Mendeliome v1.509 EMILIN1 Zornitza Stark Mode of inheritance for gene: EMILIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.508 EMILIN1 Zornitza Stark Classified gene: EMILIN1 as Green List (high evidence)
Mendeliome v1.508 EMILIN1 Zornitza Stark Gene: emilin1 has been classified as Green List (High Evidence).
Mendeliome v1.507 EMILIN1 Karina Sandoval reviewed gene: EMILIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36351433; Phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080, Peripheral neuropathy, aortic aneurysm; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.507 GABRA3 Sarah Pantaleo gene: GABRA3 was added
gene: GABRA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABRA3 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: GABRA3 were set to PMID: 29053855
Phenotypes for gene: GABRA3 were set to Epilepsy, intellectual disability, dysmorphic features,
Penetrance for gene: GABRA3 were set to Incomplete
Review for gene: GABRA3 was set to GREEN
Added comment: Six variants in GABRA3 encoding the alpha3-subunit of the GABA(A) receptor.
Five missense variants and one micro duplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus.
The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies.
Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype.
Mechanism suggested - three detected missense variants are localised in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the alpha3-subunit. Functional studies in Xenopus leaves oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype.
Results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.
Sources: Literature
Mendeliome v1.507 TCEAL1 Zornitza Stark Marked gene: TCEAL1 as ready
Mendeliome v1.507 TCEAL1 Zornitza Stark Gene: tceal1 has been classified as Green List (High Evidence).
Mendeliome v1.507 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features. to Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features.
Mendeliome v1.506 TCEAL1 Zornitza Stark Classified gene: TCEAL1 as Green List (high evidence)
Mendeliome v1.506 TCEAL1 Zornitza Stark Gene: tceal1 has been classified as Green List (High Evidence).
Mendeliome v1.505 TCEAL1 Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.505 SHROOM4 Alison Yeung Classified gene: SHROOM4 as Green List (high evidence)
Mendeliome v1.505 SHROOM4 Alison Yeung Gene: shroom4 has been classified as Green List (High Evidence).
Mendeliome v1.504 TCEAL1 Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.504 TCEAL1 Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.504 SHROOM4 Alison Yeung reviewed gene: SHROOM4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36379543, 35663265; Phenotypes: Congenital anomaly of the kidney and urinary tracy (CAKUT), SHROOM4-related, MONDO:0019719, epilepsy, idiopathic generalised, SHROOM4-related, MONDO:0005579; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.504 UQCRH Chern Lim gene: UQCRH was added
gene: UQCRH was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UQCRH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UQCRH were set to 34750991
Phenotypes for gene: UQCRH were set to Mitochondrial complex III deficiency, nuclear type 11, MIM#620137
Review for gene: UQCRH was set to AMBER
gene: UQCRH was marked as current diagnostic
Added comment: PMID: 34750991:
- Two affected cousins, presented with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy.
- Both have a 2.2 kb homozygous deletion of exons 2 and 3 of UQCRH, predicted to culminate in an in-frame deletion exons 2 and 3 of the four-exon UQCRH gene, resulting in a shortened product.
- Mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh-/-) also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death.
- Patient fibroblasts and Uqcrh-/- mouse tissues showed a CIII defect.
- Expression of wild-type UQCRH in patient fibroblasts ameliorates the CIII defect.
Sources: Literature
Mendeliome v1.504 FEM1C Paul De Fazio gene: FEM1C was added
gene: FEM1C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FEM1C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FEM1C were set to 36336956; 28135719; 33398170; 33398168
Phenotypes for gene: FEM1C were set to Neurodevelopmental disorder, FEM1C-related MONDO:0700092
Review for gene: FEM1C was set to GREEN
gene: FEM1C was marked as current diagnostic
Added comment: PMID:36336956 describes a 9-year-old boy with severe DD, lack of speech, pyramidal signs, and limb ataxia who had a de novo missense variant Asp126His in FEM1C ascertained by WES. The equivalent variant introduced into the nematode C.elegans resulted in disabled locomotion caused by synaptic abnormalities and not muscle dysfunction.

An alternate change Asp126Val was reported in the DDD study de novo in a patient with uncharacterised developmental delay (PMID:28135719).

The Asp126 residue (but not either of the variants above specifically) was shown to be functionally important by in vitro studies (PMID:33398170;33398168). The residue is highly conserved and located in a region of missense constraint.

Borderline green, 2 patients and an animal model. Note all evidence points to the Asp126 residue being of specific importance.
Sources: Literature
Mendeliome v1.504 TCEAL1 Melanie Marty gene: TCEAL1 was added
gene: TCEAL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCEAL1 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: TCEAL1 were set to PMID: 36368327
Phenotypes for gene: TCEAL1 were set to hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features.
Review for gene: TCEAL1 was set to GREEN
Added comment: 7 individuals (males and females) with de novo variants involving TCEAL1. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.504 KDM2B Ain Roesley changed review comment from: 27 individuals from 22 families were recruited
12 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)
Sources: Literature; to: 27 individuals from 22 families were recruited
13 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)
Sources: Literature
Mendeliome v1.504 KDM2B Ain Roesley Marked gene: KDM2B as ready
Mendeliome v1.504 KDM2B Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence).
Mendeliome v1.504 KDM2B Ain Roesley Classified gene: KDM2B as Green List (high evidence)
Mendeliome v1.504 KDM2B Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence).
Mendeliome v1.503 MAN2A2 Zornitza Stark Marked gene: MAN2A2 as ready
Mendeliome v1.503 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Red List (Low Evidence).
Mendeliome v1.503 KDM2B Ain Roesley gene: KDM2B was added
gene: KDM2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to 36322151
Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#070009, KDM2B-related
Review for gene: KDM2B was set to GREEN
gene: KDM2B was marked as current diagnostic
Added comment: 27 individuals from 22 families were recruited
12 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)
Sources: Literature
Mendeliome v1.502 MAN2A2 Zornitza Stark gene: MAN2A2 was added
gene: MAN2A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAN2A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2A2 were set to 36357165
Phenotypes for gene: MAN2A2 were set to Congenital disorder of glycosylation, MONDO:0015286, MAN2A2-reated
Review for gene: MAN2A2 was set to RED
Added comment: Single consanguineous family reported with homozygous truncating variant in two brothers with ID. Supportive biochemical data only.
Sources: Literature
Mendeliome v1.501 ARPC4 Zornitza Stark Phenotypes for gene: ARPC4 were changed from Neurodevelopmental disorder, ARPC4-related MONDO#0700092 to Developmental delay, language impairment, and ocular abnormalities, MIM# 620141
Mendeliome v1.500 ARPC4 Zornitza Stark edited their review of gene: ARPC4: Changed phenotypes: Developmental delay, language impairment, and ocular abnormalities, MIM# 620141
Mendeliome v1.500 MLIP Zornitza Stark Phenotypes for gene: MLIP were changed from MLIP-related myopathy with rhabdomyolysis to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Mendeliome v1.499 MLIP Zornitza Stark reviewed gene: MLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.499 UBE3C Zornitza Stark Marked gene: UBE3C as ready
Mendeliome v1.499 UBE3C Zornitza Stark Gene: ube3c has been classified as Green List (High Evidence).
Mendeliome v1.499 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM# to Neurodevelopmental disorder, MONDO:0700092, UBE3C-related
Mendeliome v1.498 UBE3C Zornitza Stark reviewed gene: UBE3C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, UBE3C-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.498 KIF26A Zornitza Stark Marked gene: KIF26A as ready
Mendeliome v1.498 KIF26A Zornitza Stark Gene: kif26a has been classified as Green List (High Evidence).
Mendeliome v1.498 KIF26A Zornitza Stark Phenotypes for gene: KIF26A were changed from Congenital brain malformations, no OMIM # to Cerebral malformation MONDO:0016054, KIF26-related
Mendeliome v1.497 KIF26A Zornitza Stark reviewed gene: KIF26A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral malformation MONDO:0016054, KIF26-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.497 BMP6 Zornitza Stark Phenotypes for gene: BMP6 were changed from Iron overload, mild to moderate to {Iron overload, susceptibility to} 620121
Mendeliome v1.496 BMP6 Zornitza Stark edited their review of gene: BMP6: Changed phenotypes: {Iron overload, susceptibility to} 620121
Mendeliome v1.496 UBE3C Chirag Patel Classified gene: UBE3C as Green List (high evidence)
Mendeliome v1.496 UBE3C Chirag Patel Gene: ube3c has been classified as Green List (High Evidence).
Mendeliome v1.495 UBE3C Chirag Patel gene: UBE3C was added
gene: UBE3C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBE3C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE3C were set to PMID: 36401616
Phenotypes for gene: UBE3C were set to Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM#
Review for gene: UBE3C was set to GREEN
Added comment: 3 patients/2 families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. WES found bi-allelic variants in UBE3C. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Mendeliome v1.494 HECTD4 Chirag Patel Classified gene: HECTD4 as Green List (high evidence)
Mendeliome v1.494 HECTD4 Chirag Patel Gene: hectd4 has been classified as Green List (High Evidence).
Mendeliome v1.493 HECTD4 Chirag Patel gene: HECTD4 was added
gene: HECTD4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HECTD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HECTD4 were set to PMID: 36401616
Phenotypes for gene: HECTD4 were set to Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM#
Review for gene: HECTD4 was set to GREEN
Added comment: 7 patients/5 families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. WES found bi-allelic variants in HECTD4. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Mendeliome v1.492 KIF26A Chirag Patel Classified gene: KIF26A as Green List (high evidence)
Mendeliome v1.492 KIF26A Chirag Patel Gene: kif26a has been classified as Green List (High Evidence).
Mendeliome v1.491 KIF26A Chirag Patel gene: KIF26A was added
gene: KIF26A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to PMID: 36228617
Phenotypes for gene: KIF26A were set to Congenital brain malformations, no OMIM #
Review for gene: KIF26A was set to GREEN
Added comment: 5 unrelated patients with biallelic loss-of-function variants in KIF26A (found through WES), exhibiting a spectrum of congenital brain malformations (schizencephaly, corpus callosum anomalies, polymicrgyria, and ventriculomegaly). Combining mice and human iPSC-derived organoid models, they discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways.
Sources: Literature
Mendeliome v1.490 TAMM41 Zornitza Stark Phenotypes for gene: TAMM41 were changed from inborn mitochondrial metabolism disorder MONDO:0004069; hypotonia; developmental delay; myopathy; ptosis to Combined oxidative phosphorylation deficiency-56 (COXPD56), MIM#620139; hypotonia; developmental delay; myopathy; ptosis
Mendeliome v1.489 TAMM41 Zornitza Stark reviewed gene: TAMM41: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency-56 (COXPD56), MIM#620139; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.489 PIGN Zornitza Stark edited their review of gene: PIGN: Added comment: Large cohort study of 21 new and review of 40 previously published cases in PMID 36322149

Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon.; Changed publications: 36322149; Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563, Fryns syndrome
Mendeliome v1.489 PIGN Zornitza Stark Phenotypes for gene: PIGN were changed from Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563 to Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563; Fryns syndrome
Mendeliome v1.488 SPTAN1 Zornitza Stark Publications for gene: SPTAN1 were set to 20493457; 22258530; 32811770; 33578420; 31332438
Mendeliome v1.487 SPTAN1 Zornitza Stark Mode of inheritance for gene: SPTAN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.486 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Added comment: PMID 36331550: further 31 individuals reported with mono-allelic variants. Three phenotypes observed:
1. DEE
2. Isolated DD/ID
3. HSP or ataxia; Changed publications: 20493457, 22258530, 32811770, 35150594, 34526651, 31515523, 36331550
Mendeliome v1.486 SEC16B Zornitza Stark Marked gene: SEC16B as ready
Mendeliome v1.486 SEC16B Zornitza Stark Gene: sec16b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.486 SEC16B Zornitza Stark Classified gene: SEC16B as Amber List (moderate evidence)
Mendeliome v1.486 SEC16B Zornitza Stark Gene: sec16b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.485 SEC16B Zornitza Stark gene: SEC16B was added
gene: SEC16B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SEC16B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEC16B were set to 28375157; 28862642; 30652979
Phenotypes for gene: SEC16B were set to Polycystic liver disease (with or without kidney cysts), MONDO:0000447, SEC16B-related
Review for gene: SEC16B was set to AMBER
Added comment: Two unrelated individuals with limited supporting functional data reported. Assessed as LIMITED by ClinGen.
Sources: Expert Review
Mendeliome v1.484 ADAMTS9 Zornitza Stark Phenotypes for gene: ADAMTS9 were changed from Nephronophthisis-Related Ciliopathy to Nephropathy-related ciliopathy, MONDO:0022409, ADAMTS9-related
Mendeliome v1.483 NDUFB7 Zornitza Stark Phenotypes for gene: NDUFB7 were changed from Congenital lactic acidosis; hypertrophic cardiomyopathy to Mitochondrial complex I deficiency nuclear type 39 (MC1DN39), MIM#620135; Congenital lactic acidosis; hypertrophic cardiomyopathy
Mendeliome v1.482 NDUFB7 Zornitza Stark reviewed gene: NDUFB7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency nuclear type 39 (MC1DN39), MIM#620135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.482 ADAMTS9 Chirag Patel Classified gene: ADAMTS9 as Amber List (moderate evidence)
Mendeliome v1.482 ADAMTS9 Chirag Patel Gene: adamts9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.481 ADAMTS9 Chirag Patel reviewed gene: ADAMTS9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.481 KCNJ16 Zornitza Stark Phenotypes for gene: KCNJ16 were changed from Renal tubulopathy; deafness to Inherited renal tubular disease, MONDO:0015962, KCNJ16-related; Renal tubulopathy; deafness
Mendeliome v1.480 KCNJ16 Zornitza Stark edited their review of gene: KCNJ16: Changed phenotypes: Inherited renal tubular disease, MONDO:0015962, KCNJ16-related, Renal tubulopathy, deafness
Mendeliome v1.480 MYCN Zornitza Stark reviewed gene: MYCN: Rating: RED; Mode of pathogenicity: None; Publications: 34590686; Phenotypes: cleft lip with or without cleft palate, MONDO:0016034, MYCN-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.480 AFDN Zornitza Stark Marked gene: AFDN as ready
Mendeliome v1.480 AFDN Zornitza Stark Gene: afdn has been classified as Red List (Low Evidence).
Mendeliome v1.480 AFDN Zornitza Stark gene: AFDN was added
gene: AFDN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AFDN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AFDN were set to 36384317
Phenotypes for gene: AFDN were set to Cleft lip/palate, MONDO:0016044, AFDN-related
Review for gene: AFDN was set to RED
Added comment: Over-representation of rare AFDN missense variants reported in a cohort of CL/P individuals of African and Brazilian origin. However, almost all of the variants reported have hets in gnomad. The one that is novel has alternative missense at the same aa position.
Sources: Literature
Mendeliome v1.479 FOXA2 Zornitza Stark Publications for gene: FOXA2 were set to 29329447; 28973288; 11445544
Mendeliome v1.478 FOXA2 Zornitza Stark edited their review of gene: FOXA2: Added comment: PMID 33999151: two further individuals reported.; Changed publications: 29329447, 28973288, 11445544, 33999151
Mendeliome v1.478 FOXI1 Zornitza Stark Deleted their review
Mendeliome v1.478 FOXI1 Zornitza Stark reviewed gene: FOXI1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive distal renal tubular acidosis MONDO:0018440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.478 FOXP3 Zornitza Stark Tag treatable tag was added to gene: FOXP3.
Mendeliome v1.478 CLEC3B Zornitza Stark Marked gene: CLEC3B as ready
Mendeliome v1.478 CLEC3B Zornitza Stark Gene: clec3b has been classified as Green List (High Evidence).
Mendeliome v1.478 CLEC3B Zornitza Stark Classified gene: CLEC3B as Green List (high evidence)
Mendeliome v1.478 CLEC3B Zornitza Stark Gene: clec3b has been classified as Green List (High Evidence).
Mendeliome v1.477 CLEC3B Zornitza Stark Tag founder tag was added to gene: CLEC3B.
Mendeliome v1.477 CLEC3B Chirag Patel gene: CLEC3B was added
gene: CLEC3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLEC3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLEC3B were set to PMID: 35331648
Phenotypes for gene: CLEC3B were set to Macular dystrophy, retinal, 4, OMIM #619977
Review for gene: CLEC3B was set to GREEN
Added comment: 12 affected individuals from 5 multigenerational Japanese families in a small village in Miyazaki diagnosed with autosomal dominant maculoretinopathy. WES identified a pathogenic variant (p.Ala180Asp) in CLEC3B, which encodes tetranectin, a plasminogen kringle-4 binding protein. Variant cosegregated with the ocular phenotype.

Mice that received subretinal injections with CLEC3B variant displayed multiple subretinal hyperreflective deposits, reduced retinal thickness, and decreased electroretinographic responses. The optokinetic tracking response indicated that spatial frequency was significantly lower (P < .05), implying impaired visual function in the mice.
Sources: Literature
Mendeliome v1.476 PDIA6 Chirag Patel edited their review of gene: PDIA6: Added comment: 2nd patient with large polycystic kidneys, death and end stage renal failure at 18 months, microcephaly, bilateral inguinal hernias, umbilical hernia, developmental delay, bilateral sensorineural hearing loss, visual impairment, steatorrhea, fibrotic changes in liver, and insulin-dependent diabetes. WGS found homozygous stop-gain variant (Tyr368*) in PDIA6. Segregation not performed.; Changed rating: AMBER; Changed publications: PMID: 35856135; Changed phenotypes: Polycystic kidney disease, infancy-onset diabetes, and microcephaly
Mendeliome v1.476 ARPC4 Zornitza Stark Phenotypes for gene: ARPC4 were changed from Microcephaly; mild motor delays; significant speech impairment to Neurodevelopmental disorder, ARPC4-related MONDO#0700092
Mendeliome v1.475 ARPC4 Zornitza Stark reviewed gene: ARPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35047857; Phenotypes: Neurodevelopmental disorder, ARPC4-related MONDO#0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.475 SPTBN5 Zornitza Stark Classified gene: SPTBN5 as Red List (low evidence)
Mendeliome v1.475 SPTBN5 Zornitza Stark Gene: sptbn5 has been classified as Red List (Low Evidence).
Mendeliome v1.474 SPTBN5 Zornitza Stark edited their review of gene: SPTBN5: Added comment: Some of the missense variants are present at high population frequencies, not compatible with Mendelian disease. Gene is tolerant of LoF in gnomad, raising questions about the pathogenicity of the LoF variant.
Commentaries questioning gene-disease relationship PMID: 36117916; 36238261; Changed rating: RED
Mendeliome v1.474 MTSS1 Zornitza Stark Mode of inheritance for gene: MTSS1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.473 MTSS1 Zornitza Stark edited their review of gene: MTSS1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.473 MTSS1 Zornitza Stark Marked gene: MTSS1 as ready
Mendeliome v1.473 MTSS1 Zornitza Stark Gene: mtss1 has been classified as Green List (High Evidence).
Mendeliome v1.473 MTSS1 Zornitza Stark Classified gene: MTSS1 as Green List (high evidence)
Mendeliome v1.473 MTSS1 Zornitza Stark Gene: mtss1 has been classified as Green List (High Evidence).
Mendeliome v1.472 MTSS1 Zornitza Stark gene: MTSS1 was added
gene: MTSS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTSS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTSS1 were set to 36067766
Phenotypes for gene: MTSS1 were set to Intellectual disability, MTSS1-related (MONDO#0001071)
Review for gene: MTSS1 was set to GREEN
Added comment: Five individuals with the same heterozygous de novo variant in MTSS2 (NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing.

The individuals presented with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms.

Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies.
Sources: Literature
Mendeliome v1.471 TPR Zornitza Stark Phenotypes for gene: TPR were changed from intellectual disability, MONDO:0001071; cerebellar ataxia, MONDO:0000437; microcephaly, MONDO:0001149 to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, TPR-related
Mendeliome v1.470 TPR Zornitza Stark reviewed gene: TPR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, TPR-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.470 TPR Zornitza Stark Marked gene: TPR as ready
Mendeliome v1.470 TPR Zornitza Stark Gene: tpr has been classified as Red List (Low Evidence).
Mendeliome v1.470 TPR Zornitza Stark Classified gene: TPR as Red List (low evidence)
Mendeliome v1.470 TPR Zornitza Stark Gene: tpr has been classified as Red List (Low Evidence).
Mendeliome v1.469 SMC5 Zornitza Stark Marked gene: SMC5 as ready
Mendeliome v1.469 SMC5 Zornitza Stark Gene: smc5 has been classified as Green List (High Evidence).
Mendeliome v1.469 SMC5 Zornitza Stark Classified gene: SMC5 as Green List (high evidence)
Mendeliome v1.469 SMC5 Zornitza Stark Gene: smc5 has been classified as Green List (High Evidence).
Mendeliome v1.468 SMC5 Zornitza Stark gene: SMC5 was added
gene: SMC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMC5 were set to 36333305
Phenotypes for gene: SMC5 were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID
Review for gene: SMC5 was set to GREEN
Added comment: Four individuals from three families with a chromosome breakage disorder and bi-allelic variants in this gene. However, three of the individuals had the same homozygous missense variant. Evidence for functional impact of the variant was limited. However, zebrafish model recapitulated the phenotype and was not rescued by the introduction of this variant, arguing for functional effect. Borderline Amber/Green
Sources: Literature
Mendeliome v1.467 SLF2 Zornitza Stark Marked gene: SLF2 as ready
Mendeliome v1.467 SLF2 Zornitza Stark Gene: slf2 has been classified as Green List (High Evidence).
Mendeliome v1.467 SLF2 Zornitza Stark Classified gene: SLF2 as Green List (high evidence)
Mendeliome v1.467 SLF2 Zornitza Stark Gene: slf2 has been classified as Green List (High Evidence).
Mendeliome v1.466 SLF2 Zornitza Stark gene: SLF2 was added
gene: SLF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLF2 were set to 36333305
Phenotypes for gene: SLF2 were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID
Review for gene: SLF2 was set to GREEN
Added comment: Seven individuals from 6 families with a chromosome breakage disorder and bi-allelic variants in this gene (LoF). Functional data including zebrafish model.
Sources: Literature
Mendeliome v1.465 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to intellectual disability, MONDO:0001071; cerebellar ataxia, MONDO:0000437; microcephaly, MONDO:0001149
Review for gene: TPR was set to RED
Added comment: This gene should be added to the following diseases: Intellectual disability, microcephaly and ataxia.

Comment on classification of this gene: This gene should be added with a RED rating as the association is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability.

Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.465 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34476477; Phenotypes: Neurofibromatosis, type 1, MIM# 162200, MONDO:0018975, renovascular hypertension, MONDO:0006947; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.465 IRF2BP2 Zornitza Stark Publications for gene: IRF2BP2 were set to 27016798
Mendeliome v1.464 IRF2BP2 Zornitza Stark Classified gene: IRF2BP2 as Green List (high evidence)
Mendeliome v1.464 IRF2BP2 Zornitza Stark Gene: irf2bp2 has been classified as Green List (High Evidence).
Mendeliome v1.463 IRF2BP2 Zornitza Stark edited their review of gene: IRF2BP2: Added comment: Reports of additional patients: 4yo with chronic diarrhea, severe eczema, anemia, failure to thrive, fevers, short stature, recurrent infections, cataracts, hypodontia, hypotrichosis alopecia, hypogammaglobulinemia. The 33-year-old male presented with recurrent respiratory infections since childhood, colitis and RA beginning at age 25 years.; Changed rating: GREEN; Changed publications: 27016798, 32048120, 36193988, 33864888; Changed phenotypes: Immunodeficiency, common variable, 14, MIM# 617765
Mendeliome v1.463 MAST3 Zornitza Stark Phenotypes for gene: MAST3 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 108, MIM#620115
Mendeliome v1.462 MAST3 Zornitza Stark edited their review of gene: MAST3: Changed phenotypes: Developmental and epileptic encephalopathy 108, MIM#620115
Mendeliome v1.462 ATP5F1 Zornitza Stark Marked gene: ATP5F1 as ready
Mendeliome v1.462 ATP5F1 Zornitza Stark Gene: atp5f1 has been classified as Red List (Low Evidence).
Mendeliome v1.462 ATP5F1 Zornitza Stark gene: ATP5F1 was added
gene: ATP5F1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATP5F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5F1 were set to 36239646
Phenotypes for gene: ATP5F1 were set to Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation-2 (HUMOP2), MIM#620085
Review for gene: ATP5F1 was set to RED
Added comment: Identical twins reported with a de novo missense variant in this gene and hyper metabolism: normal thyroid function, hyperphagia, tachypnea, increased basal temperature, and increased sweating. Biochemical studies demonstrated increased mitochondrial oxygen consumption with inefficient production of ATP in the final steps of oxidative phosphorylation due to an uncoupling defect
Sources: Expert list
Mendeliome v1.461 DUOX2 Zornitza Stark Classified gene: DUOX2 as Green List (high evidence)
Mendeliome v1.461 DUOX2 Zornitza Stark Gene: duox2 has been classified as Green List (High Evidence).
Mendeliome v1.460 DOCK8 Zornitza Stark Tag treatable tag was added to gene: DOCK8.
Mendeliome v1.460 DNMT3B Zornitza Stark Tag treatable tag was added to gene: DNMT3B.
Mendeliome v1.460 CACNA1I Zornitza Stark Phenotypes for gene: CACNA1I were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with variable intellectual disability and speech impairment, with or without seizures (NEDISS), MIM#620114
Mendeliome v1.459 CACNA1I Zornitza Stark reviewed gene: CACNA1I: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with variable intellectual disability and speech impairment, with or without seizures (NEDISS), MIM#620114; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.459 RPS6KB1 Arina Puzriakova gene: RPS6KB1 was added
gene: RPS6KB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS6KB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPS6KB1 were set to 34916228
Phenotypes for gene: RPS6KB1 were set to Hypertrophic cardiomyopathy
Review for gene: RPS6KB1 was set to GREEN
Added comment: Jain et al. 2022 (PMID: 34916228) reported on two unrelated HCM families with the same heterozygous missense RPS6KB1 variant (p.G47W), and subsequently three further unrelated probands with HCM harbouring distinct heterozygous variants (p.Q49K, p.Y62H, respectively). Variants segregated with disease, were predicted pathogenic by silico analyses and were ultrarare or absent in population databases. Functional studies in the HL-1 (mouse cardiomyocytes) cells showed that the patient-specific RPS6KB1 mutant significantly increased cell size and activated rpS6 and ERK1/2 signalling cascades. The relationship between RPS6KB1 and cardiac hypertrophy has also been explored in feline and mice models (PMID: 15226426; 17976640)
Sources: Literature
Mendeliome v1.459 HK1 Zornitza Stark Tag deep intronic tag was added to gene: HK1.
Mendeliome v1.459 HK1 Zornitza Stark edited their review of gene: HK1: Added comment: PMID 36333503: 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1) identified in individuals with hyperinsulinism.; Changed publications: 19536174, 30778173, 25316723, 25190649, 31621442, 32814480, 7655856, 12393545, 33361148, 31119733, 27282571, 36333503; Changed phenotypes: Hyperinsulinism MONDO:0002177, HK1-related, Neuropathy, hereditary motor and sensory, Russe type , MIM#605285, Haemolytic anaemia due to hexokinase deficiency, MIM# 235700, Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547, Retinitis pigmentosa 79, MIM# 617460
Mendeliome v1.459 FRA10AC1 Zornitza Stark Phenotypes for gene: FRA10AC1 were changed from Neurodevelopmental disorder, MONDO:0700092, FRA10AC1-related to Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113
Mendeliome v1.458 FRA10AC1 Zornitza Stark edited their review of gene: FRA10AC1: Changed phenotypes: Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113
Mendeliome v1.458 ITPR3 Zornitza Stark Phenotypes for gene: ITPR3 were changed from Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111
Mendeliome v1.457 ITPR3 Zornitza Stark Publications for gene: ITPR3 were set to 32949214
Mendeliome v1.456 ITPR3 Zornitza Stark Classified gene: ITPR3 as Green List (high evidence)
Mendeliome v1.456 ITPR3 Zornitza Stark Gene: itpr3 has been classified as Green List (High Evidence).
Mendeliome v1.455 ITPR3 Zornitza Stark edited their review of gene: ITPR3: Added comment: Additional family with 3 individuals in 2 generations reported in PMID 24627108.; Changed rating: GREEN; Changed publications: 32949214, 24627108; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111
Mendeliome v1.455 THAP1 Zornitza Stark Publications for gene: THAP1 were set to 21793105; 22377579
Mendeliome v1.454 THAP1 Zornitza Stark Mode of inheritance for gene: THAP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.453 WDR5 Bryony Thompson Marked gene: WDR5 as ready
Mendeliome v1.453 WDR5 Bryony Thompson Gene: wdr5 has been classified as Green List (High Evidence).
Mendeliome v1.453 WDR5 Bryony Thompson Classified gene: WDR5 as Green List (high evidence)
Mendeliome v1.453 WDR5 Bryony Thompson Gene: wdr5 has been classified as Green List (High Evidence).
Mendeliome v1.452 WDR5 Bryony Thompson gene: WDR5 was added
gene: WDR5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Phenotypes for gene: WDR5 were set to Neurodevelopmental disorder MONDO:0700092, WDR5-related
Mode of pathogenicity for gene: WDR5 was set to Other
Review for gene: WDR5 was set to GREEN
Added comment: Six different missense variants were identified (de novo) in 11 affected individuals with neurodevelopmental disorders, with a broad spectrum of additional features, including epilepsy, aberrant growth parameters, skeletal and cardiac abnormalities. In vivo and in vitro functional suggest that loss-of-function is not the mechanism of disease. The mechanism of disease is yet to be established.
Sources: Literature
Mendeliome v1.451 TOMM7 Bryony Thompson edited their review of gene: TOMM7: Changed publications: 36299998
Mendeliome v1.451 KPNA3 Zornitza Stark Phenotypes for gene: KPNA3 were changed from Hereditary Spastic Paraplegia, infantile onset to Spastic paraplegia-88 (SPG88), MIM#620106
Mendeliome v1.450 KPNA3 Zornitza Stark reviewed gene: KPNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia-88 (SPG88), MIM#620106; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.450 JARID2 Zornitza Stark Phenotypes for gene: JARID2 were changed from Intellectual disability to Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF), MIM#620098
Mendeliome v1.449 JARID2 Zornitza Stark edited their review of gene: JARID2: Changed phenotypes: Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF), MIM#620098
Mendeliome v1.449 PI4K2A Zornitza Stark Phenotypes for gene: PI4K2A were changed from Cutis laxa, intellectual disability, movement disorder to complex neurodevelopmental disorder with motor features, PI4K2A-related, MONDO:0100516; Cutis laxa, intellectual disability, movement disorder
Mendeliome v1.448 PI4K2A Zornitza Stark Publications for gene: PI4K2A were set to 32418222
Mendeliome v1.447 DNAJB4 Zornitza Stark Marked gene: DNAJB4 as ready
Mendeliome v1.447 DNAJB4 Zornitza Stark Gene: dnajb4 has been classified as Green List (High Evidence).
Mendeliome v1.447 DNAJB4 Zornitza Stark Classified gene: DNAJB4 as Green List (high evidence)
Mendeliome v1.447 DNAJB4 Zornitza Stark Gene: dnajb4 has been classified as Green List (High Evidence).
Mendeliome v1.446 DNAJB4 Karina Sandoval gene: DNAJB4 was added
gene: DNAJB4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJB4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJB4 were set to PMID: 36264506
Phenotypes for gene: DNAJB4 were set to Myopathy, MONDO:0005336, DNAJB4-related
Review for gene: DNAJB4 was set to GREEN
Added comment: 4 individuals from 3 unrelated families with bi-allelic LoF/missense variants in this gene, and either childhood/adult onset of muscle weakness and respiratory failure. One had HCM.

Functional studies including mouse model.
Sources: Literature
Mendeliome v1.446 ATP11A Zornitza Stark Publications for gene: ATP11A were set to PMID: 34403372; 35278131
Mendeliome v1.445 ATP11A Zornitza Stark edited their review of gene: ATP11A: Changed phenotypes: Leukodystrophy, hypomyelinating, 24 , MIM# 619851, Deafness, autosomal dominant 84 (MIM#619810)
Mendeliome v1.445 ATP11A Chern Lim reviewed gene: ATP11A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36300302; Phenotypes: Deafness, autosomal dominant 84 (MIM#619810); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.445 PI4K2A Seb Lunke Classified gene: PI4K2A as Green List (high evidence)
Mendeliome v1.445 PI4K2A Seb Lunke Gene: pi4k2a has been classified as Green List (High Evidence).
Mendeliome v1.444 PI4K2A Seb Lunke reviewed gene: PI4K2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30564627, 35880319, 19581584; Phenotypes: complex neurodevelopmental disorder with motor features, PI4K2A-related, MONDO:0100516; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.444 MYCBP2 Zornitza Stark Marked gene: MYCBP2 as ready
Mendeliome v1.444 MYCBP2 Zornitza Stark Gene: mycbp2 has been classified as Green List (High Evidence).
Mendeliome v1.444 MYCBP2 Zornitza Stark Classified gene: MYCBP2 as Green List (high evidence)
Mendeliome v1.444 MYCBP2 Zornitza Stark Gene: mycbp2 has been classified as Green List (High Evidence).
Mendeliome v1.443 CAMSAP1 Zornitza Stark Marked gene: CAMSAP1 as ready
Mendeliome v1.443 CAMSAP1 Zornitza Stark Gene: camsap1 has been classified as Green List (High Evidence).
Mendeliome v1.443 CAMSAP1 Zornitza Stark Classified gene: CAMSAP1 as Green List (high evidence)
Mendeliome v1.443 CAMSAP1 Zornitza Stark Gene: camsap1 has been classified as Green List (High Evidence).
Mendeliome v1.442 THAP1 Michelle Torres commented on gene: THAP1: Monoallelic is well established with reduced penetrance.

Biallelic was seen in 3 families generally with severe and early onset dystonia:

PMID: 36205328: consanguineous family (gene panel), proband homozygous for p.Lys162Asn with early onset multifocal dystonia with severe oromandibular/laryngeal dysfunction; both parents were confirmed carriers with milder features (47 yo father with tightness and difficulty with fine motor tasks, 41 yo mother with tightness).

PMID: 21425335: 3 siblings are homozygous for the p.Leu32His with early-onset generalized dystonia. Carriers were unaffected.

PMID: 20211909: a homozygous variant was identified in an individual with with writer's dystonia initially and then developing segmental dystonia, onset at 57 yo, parents could not be tested.
Mendeliome v1.442 CAMSAP1 Naomi Baker gene: CAMSAP1 was added
gene: CAMSAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related
Review for gene: CAMSAP1 was set to GREEN
Added comment: Five unrelated families with bi-allelic loss-of-function variants. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe neurodevelopmental delay, cortical visual impairment, and seizures.
Sources: Literature
Mendeliome v1.442 THAP1 Michelle Torres reviewed gene: THAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36205328, 21425335, 20211909; Phenotypes: Dystonia 6, torsion, (MIM#60262); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.442 MYCBP2 Suliman Khan gene: MYCBP2 was added
gene: MYCBP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYCBP2 were set to PMID: 36200388
Phenotypes for gene: MYCBP2 were set to Neurodevelopmental disorder, MONDO:0700092, MYCBP2-related; corpus callosum abnormalities
Penetrance for gene: MYCBP2 were set to Complete
Review for gene: MYCBP2 was set to GREEN
Added comment: PMID: 36200388 reported eight patients with neurodevelopmental disorder including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy, and autistic features. Each patient harbored a de novo LOF variant in MYCBP2 gene. Functional study supported a direct link between MYCBP2 and neurodevelopmental spectrum disorder specifically corpus callosum defects.
Sources: Literature
Mendeliome v1.442 KLHL20 Zornitza Stark Marked gene: KLHL20 as ready
Mendeliome v1.442 KLHL20 Zornitza Stark Gene: klhl20 has been classified as Green List (High Evidence).
Mendeliome v1.442 KLHL20 Zornitza Stark Classified gene: KLHL20 as Green List (high evidence)
Mendeliome v1.442 KLHL20 Zornitza Stark Gene: klhl20 has been classified as Green List (High Evidence).
Mendeliome v1.441 KLHL20 Dean Phelan gene: KLHL20 was added
gene: KLHL20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to PMID: 36214804
Phenotypes for gene: KLHL20 were set to Neurodevelopmental disorder (MONDO:0700092), KLHL20-related
Review for gene: KLHL20 was set to GREEN
Added comment: PMID: 36214804
- 14 patients with de novo missense variants in KLHL20. The patients had mild to severe ID, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity and subtle dysmorphic facial features.
Sources: Literature
Mendeliome v1.441 FICD Alison Yeung Marked gene: FICD as ready
Mendeliome v1.441 FICD Alison Yeung Gene: ficd has been classified as Green List (High Evidence).
Mendeliome v1.441 FICD Alison Yeung Classified gene: FICD as Green List (high evidence)
Mendeliome v1.441 FICD Alison Yeung Gene: ficd has been classified as Green List (High Evidence).
Mendeliome v1.440 FICD Alison Yeung gene: FICD was added
gene: FICD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36136088
Phenotypes for gene: FICD were set to Hereditary motor neurone disease, FICD-related, MONDO:0024257
Review for gene: FICD was set to GREEN
Added comment: Three unrelated families with recurrent homozygous missense variant: p.Arg374His
One further family with Chet variants: p.Arg 374His and p.Gly370GlufsTer53

Fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP.

Onset of symptoms in childhood with progressive course. Presentation with severe lower limb spasticity and mild upper limb spascticity, nerve conduction test shows motor neuropathy.
Sources: Literature
Mendeliome v1.439 METTL23 Lucy Spencer reviewed gene: METTL23: Rating: AMBER; Mode of pathogenicity: None; Publications: 36099048; Phenotypes: glaucoma MONDO:0005041; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.439 FOXI3 Zornitza Stark Marked gene: FOXI3 as ready
Mendeliome v1.439 FOXI3 Zornitza Stark Gene: foxi3 has been classified as Green List (High Evidence).
Mendeliome v1.439 FOXI3 Zornitza Stark Mode of inheritance for gene: FOXI3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.438 FOXI3 Zornitza Stark Classified gene: FOXI3 as Green List (high evidence)
Mendeliome v1.438 FOXI3 Zornitza Stark Gene: foxi3 has been classified as Green List (High Evidence).
Mendeliome v1.437 FOXI3 Paul De Fazio gene: FOXI3 was added
gene: FOXI3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXI3 were set to 36260083
Phenotypes for gene: FOXI3 were set to Dysostosis with predominant craniofacial involvement (MONDO:0800085)
Penetrance for gene: FOXI3 were set to Incomplete
Review for gene: FOXI3 was set to GREEN
gene: FOXI3 was marked as current diagnostic
Added comment: Ten affected individuals from 4 families reported with monoallelic variants, 2 with missense variants affecting the nuclear localisation sequence and 2 with frameshift variants.

The missense variants were associated with isolated microtia with aural atresia and affected subcellular localisation of the protein, while the frameshift variants were associated with microtia and mandubular hypoplasia, suggesting dosage sensitivity.

Rated green but CAUTION for incomplete penetrance. 3 of the 4 families had unaffected carriers. Family 1 in particular had 25 genotyped individuals, of which 15 were carriers, of which 5 were affected.
Sources: Literature
Mendeliome v1.437 TOMM7 Zornitza Stark Publications for gene: TOMM7 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100148
Mendeliome v1.436 TOMM7 Zornitza Stark edited their review of gene: TOMM7: Changed publications: 36299998, 36282599
Mendeliome v1.436 TOMM7 Zornitza Stark edited their review of gene: TOMM7: Added comment: Second family reported in PMID 36282599: single affected individual with homozygous missense variant; clinical presentation with progeroid features but functional data supports underlying mitochondrial aetiology.

Maintain Amber rating as the two patients have quite disparate clinical presentations.; Changed publications: 36282599
Mendeliome v1.436 CBFB Ain Roesley Marked gene: CBFB as ready
Mendeliome v1.436 CBFB Ain Roesley Gene: cbfb has been classified as Green List (High Evidence).
Mendeliome v1.436 CBFB Ain Roesley Classified gene: CBFB as Green List (high evidence)
Mendeliome v1.436 CBFB Ain Roesley Gene: cbfb has been classified as Green List (High Evidence).
Mendeliome v1.435 CBFB Ain Roesley gene: CBFB was added
gene: CBFB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CBFB were set to 36241386
Phenotypes for gene: CBFB were set to cleidocranial dysplasia (MONDO#0007340), CBFB-related
Penetrance for gene: CBFB were set to Complete
Review for gene: CBFB was set to GREEN
gene: CBFB was marked as current diagnostic
Added comment: 5 families with 8 individuals, including 2 de novos and 1 intragenic exon 4 deletion

In 1 family, the mother did not report skeletal concerns but had dental abnormalities during childhood
Sources: Literature
Mendeliome v1.434 CEBPE Zornitza Stark Phenotypes for gene: CEBPE were changed from Specific granule deficiency, MIM# 245480 to Specific granule deficiency, MIM# 245480; Immunodeficiency 108 with autoinflammation, MIM# 260570
Mendeliome v1.433 CEBPE Zornitza Stark Publications for gene: CEBPE were set to 10359588; 11313242; 31256937; 29651288
Mendeliome v1.432 CEBPE Zornitza Stark edited their review of gene: CEBPE: Added comment: Additional family with auto inflammatory phenotype published in 31201888, extensive functional data.; Changed publications: 10359588, 11313242, 31256937, 29651288, 31201888
Mendeliome v1.432 CEBPE Zornitza Stark edited their review of gene: CEBPE: Changed phenotypes: Specific granule deficiency, MIM# 245480, Immunodeficiency 108 with autoinflammation, MIM# 260570
Mendeliome v1.432 CXCR4 Zornitza Stark Tag treatable tag was added to gene: CXCR4.
Mendeliome v1.432 PGM1 Zornitza Stark Tag treatable tag was added to gene: PGM1.
Mendeliome v1.432 SFTPA1 Zornitza Stark Publications for gene: SFTPA1 were set to 31601679; 30854216; 28869238; 26792177
Mendeliome v1.431 SFTPA1 Zornitza Stark Classified gene: SFTPA1 as Green List (high evidence)
Mendeliome v1.431 SFTPA1 Zornitza Stark Gene: sftpa1 has been classified as Green List (High Evidence).
Mendeliome v1.430 SFTPA1 Zornitza Stark edited their review of gene: SFTPA1: Added comment: Additional 3 families reported with mono-allelic variants.; Changed rating: GREEN; Changed publications: 31601679, 30854216, 28869238, 26792177, 32855221
Mendeliome v1.430 GNPNAT1 Krithika Murali reviewed gene: GNPNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36097642, 35427807; Phenotypes: Rhizomelic dysplasia, Ain-Naz type, MIM#619598; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.430 SCNM1 Zornitza Stark Phenotypes for gene: SCNM1 were changed from Ciliopathy, SCNM1-related, MONDO:0005308 to Orofaciodigital syndrome XIX, MIM# 620107
Mendeliome v1.429 SCNM1 Zornitza Stark reviewed gene: SCNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Orofaciodigital syndrome XIX, MIM# 620107; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.429 FRMD5 Zornitza Stark Phenotypes for gene: FRMD5 were changed from Neurodevelopmental disorder MONDO:0700092, FRMD5-related to Neurodevelopmental disorder with eye movement abnormalities and ataxia, MIM# 620094
Mendeliome v1.428 FRMD5 Zornitza Stark edited their review of gene: FRMD5: Changed phenotypes: Neurodevelopmental disorder with eye movement abnormalities and ataxia, MIM# 620094
Mendeliome v1.428 FGL2 Zornitza Stark Marked gene: FGL2 as ready
Mendeliome v1.428 FGL2 Zornitza Stark Gene: fgl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.428 FGL2 Zornitza Stark Classified gene: FGL2 as Amber List (moderate evidence)
Mendeliome v1.428 FGL2 Zornitza Stark Gene: fgl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.427 FGL2 Zornitza Stark gene: FGL2 was added
gene: FGL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FGL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGL2 were set to 36243222
Phenotypes for gene: FGL2 were set to Autoinflammatory syndrome, MONDO:0019751, FGL2-related
Review for gene: FGL2 was set to AMBER
Added comment: Child with early onset systemic inflammation, autoantibodies, and vasculitis. Homozygous truncating variant, functional studies include rescue experiments.
Sources: Literature
Mendeliome v1.426 SP6 Zornitza Stark Phenotypes for gene: SP6 were changed from hypoplastic amelogenesis imperfecta to Amelogenesis imperfecta, type IK, MIM# 620104
Mendeliome v1.425 SP6 Zornitza Stark edited their review of gene: SP6: Changed phenotypes: Amelogenesis imperfecta, type IK, MIM# 620104
Mendeliome v1.425 FKBP6 Zornitza Stark Phenotypes for gene: FKBP6 were changed from Spermatogenic failure (MONDO:0004983), FKBP6-related to Spermatogenic failure 77, MIM# 620103
Mendeliome v1.424 FKBP6 Zornitza Stark reviewed gene: FKBP6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 77, MIM# 620103; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.424 COL13A1 Zornitza Stark Tag treatable tag was added to gene: COL13A1.
Mendeliome v1.424 OTC Zornitza Stark Tag treatable tag was added to gene: OTC.
Mendeliome v1.424 RAX2 Zornitza Stark Phenotypes for gene: RAX2 were changed from Cone-rod dystrophy 11, MIM# 610381 to Cone-rod dystrophy 11, MIM# 610381; Retinitis pigmentosa-95 (RP95), MIM#620102
Mendeliome v1.423 RAX2 Zornitza Stark edited their review of gene: RAX2: Changed phenotypes: Cone-rod dystrophy 11, MIM# 610381, Retinitis pigmentosa-95 (RP95), MIM#620102
Mendeliome v1.423 LETM1 Zornitza Stark Phenotypes for gene: LETM1 were changed from Mitochondrial disease MONDO#0044970, LETM1-related to Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM), MIM#620089
Mendeliome v1.422 LETM1 Zornitza Stark edited their review of gene: LETM1: Changed phenotypes: Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM), MIM#620089; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.422 UNC13D Zornitza Stark Tag treatable tag was added to gene: UNC13D.
Mendeliome v1.422 PAX4 Zornitza Stark Classified gene: PAX4 as Red List (low evidence)
Mendeliome v1.422 PAX4 Zornitza Stark Gene: pax4 has been classified as Red List (Low Evidence).
Mendeliome v1.421 PAX4 Zornitza Stark Tag refuted tag was added to gene: PAX4.
Mendeliome v1.421 CLCN7 Zornitza Stark changed review comment from: Two individuals reported with same missense variant and hypopigmentation, organomegaly, and delayed myelination and development. Variant is GoF. No osteopetrosis, biopsy findings from skin and other organs are consistent with a lysosomal storage disorder. IUGR, prematurity and polyhydramnios are features.

Bi-allelic variants in this gene are associated with osteopetrosis.; to: Two individuals reported with same missense variant and hypopigmentation, organomegaly, and delayed myelination and development. Variant is GoF. No osteopetrosis, biopsy findings from skin and other organs are consistent with a lysosomal storage disorder. IUGR, prematurity and polyhydramnios are features.

Mono- and bi-allelic variants in this gene are associated with osteopetrosis.
Mendeliome v1.421 CLCN7 Zornitza Stark edited their review of gene: CLCN7: Changed phenotypes: Hypopigmentation, organomegaly, and delayed myelination and development, MIM# 618541, Osteopetrosis, autosomal dominant 2, MIM# 166600, Osteopetrosis, autosomal recessive 4, MIM# 611490
Mendeliome v1.421 CLCN7 Zornitza Stark Tag treatable tag was added to gene: CLCN7.
Mendeliome v1.421 PAX4 Krithika Murali reviewed gene: PAX4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Maturity-onset diabetes of the young, type IX - MIM#612225; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.421 HNRNPH1 Zornitza Stark Phenotypes for gene: HNRNPH1 were changed from HNRNPH1‐related syndromic intellectual disability; early onset high myopia, MONDO:0001384 to Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, MIM# 620083
Mendeliome v1.420 HNRNPH1 Zornitza Stark edited their review of gene: HNRNPH1: Changed phenotypes: Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, MIM# 620083
Mendeliome v1.420 PRDM16 Zornitza Stark Publications for gene: PRDM16 were set to 23768516; 29367541; 34915728; 31965688; 29367541
Mendeliome v1.419 PRDM16 Zornitza Stark Classified gene: PRDM16 as Green List (high evidence)
Mendeliome v1.419 PRDM16 Zornitza Stark Gene: prdm16 has been classified as Green List (High Evidence).
Mendeliome v1.418 PRDM16 Paul De Fazio reviewed gene: PRDM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 29367541, 29447731, 30847666, 33082984, 32183154, 33500567, 34540771, 34350506, 34935411; Phenotypes: Cardiomyopathy, dilated, 1LL MIM#615373, Left ventricular noncompaction 8 MIM#615373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.418 CD79B Zornitza Stark Tag treatable tag was added to gene: CD79B.
Mendeliome v1.418 WNK4 Zornitza Stark changed review comment from: More than 5 unrelated families reported.; to: More than 5 unrelated families reported.

Caution: assessed as MODERATE by ClinGen. Although at least 9 individuals have been reported, all the reported variants are missense without other supportive functional or segregation data.
Mendeliome v1.418 CD79A Zornitza Stark Tag treatable tag was added to gene: CD79A.
Mendeliome v1.418 CD40LG Zornitza Stark Tag treatable tag was added to gene: CD40LG.
Mendeliome v1.418 CD3E Zornitza Stark Tag treatable tag was added to gene: CD3E.
Mendeliome v1.418 CD3D Zornitza Stark Tag treatable tag was added to gene: CD3D.
Mendeliome v1.418 G6PC Zornitza Stark Tag treatable tag was added to gene: G6PC.
Mendeliome v1.418 EMILIN1 Zornitza Stark Phenotypes for gene: EMILIN1 were changed from peripheral neuropathy to Neuronopathy, distal hereditary motor, type X, MIM# 620080
Mendeliome v1.417 EMILIN1 Zornitza Stark edited their review of gene: EMILIN1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.417 EMILIN1 Zornitza Stark reviewed gene: EMILIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.417 TMEM147 Zornitza Stark Phenotypes for gene: TMEM147 were changed from Neurodevelopmental disorder (MONDO:0700092), TMEM147-related to Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly, MIM# 620075
Mendeliome v1.416 TMEM147 Zornitza Stark reviewed gene: TMEM147: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly, MIM# 620075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.416 CCDC34 Zornitza Stark Marked gene: CCDC34 as ready
Mendeliome v1.416 CCDC34 Zornitza Stark Gene: ccdc34 has been classified as Green List (High Evidence).
Mendeliome v1.416 CCDC34 Zornitza Stark Classified gene: CCDC34 as Green List (high evidence)
Mendeliome v1.416 CCDC34 Zornitza Stark Gene: ccdc34 has been classified as Green List (High Evidence).
Mendeliome v1.415 CCDC34 Zornitza Stark gene: CCDC34 was added
gene: CCDC34 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CCDC34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC34 were set to 34348960
Phenotypes for gene: CCDC34 were set to Spermatogenic failure 76, MIM# 620084
Review for gene: CCDC34 was set to GREEN
Added comment: Two unrelated individuals reported with homozygous frameshift variants. Mouse model recapitulated phenotype.
Sources: Expert list
Mendeliome v1.414 ACTN2 Bryony Thompson reviewed gene: ACTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17097056, 20022194, 25173926, 25224718, 22767232, 27287556, 28436997, 31333075, 31956495, 32973354, 34802252, 33500567, 36078153, 36116040; Phenotypes: intrinsic cardiomyopathy MONDO:0000591; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.414 CAVIN1 Zornitza Stark Tag treatable tag was added to gene: CAVIN1.
Mendeliome v1.414 NFAT5 Zornitza Stark Phenotypes for gene: NFAT5 were changed from Recurrent infections; Autoimmune enterocolopathy to Immune deficiency disease, MONDO:0003778, NFAT5-related; Recurrent infections; Autoimmune enterocolopathy; EBV susceptibility; HLH
Mendeliome v1.413 NFAT5 Zornitza Stark Publications for gene: NFAT5 were set to 25667416
Mendeliome v1.412 NFAT5 Zornitza Stark Classified gene: NFAT5 as Amber List (moderate evidence)
Mendeliome v1.412 NFAT5 Zornitza Stark Gene: nfat5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.411 NFAT5 Zornitza Stark edited their review of gene: NFAT5: Added comment: Two additional individuals with missense variants reported in PMID 36238298: one with EBV infection with hepatitis and enterocolitis, and one with fatal HLH.; Changed rating: AMBER; Changed publications: 25667416, 36238298; Changed phenotypes: Immune deficiency disease, MONDO:0003778, NFAT5-related, Recurrent infections, Autoimmune enterocolopathy, EBV susceptibility, HLH
Mendeliome v1.411 PSMC1 Zornitza Stark Phenotypes for gene: PSMC1 were changed from 35861243; spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes to Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071
Mendeliome v1.410 PSMC1 Zornitza Stark edited their review of gene: PSMC1: Changed phenotypes: Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071
Mendeliome v1.410 CA2 Zornitza Stark Tag treatable tag was added to gene: CA2.
Mendeliome v1.410 LAMA5 Zornitza Stark Phenotypes for gene: LAMA5 were changed from bent bone dysplasia; nephrotic syndrome; Presynaptic congenital myasthenic syndrome; multisystem syndrome; developmental delay to Bent bone dysplasia syndrome 2, MIM# 620076; nephrotic syndrome; Presynaptic congenital myasthenic syndrome; multisystem syndrome; developmental delay
Mendeliome v1.409 LAMA5 Zornitza Stark edited their review of gene: LAMA5: Changed phenotypes: Nephrotic syndrome, type 26 620049, Bent bone dysplasia syndrome 2, MIM# 620076
Mendeliome v1.409 HNRNPR Zornitza Stark Phenotypes for gene: HNRNPR were changed from Intellectual disability; seizures to Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, MIM# 620073
Mendeliome v1.408 HNRNPR Zornitza Stark edited their review of gene: HNRNPR: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, MIM# 620073
Mendeliome v1.408 FGF14 Zornitza Stark Phenotypes for gene: FGF14 were changed from Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003 to Spinocerebellar ataxia 27, MIM# 609307; Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003
Mendeliome v1.407 FGF14 Zornitza Stark edited their review of gene: FGF14: Changed phenotypes: Spinocerebellar ataxia 27, MIM# 609307, Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003
Mendeliome v1.407 FGF14 Zornitza Stark Phenotypes for gene: FGF14 were changed from Spinocerebellar ataspinocerebellar ataxia type 27 MONDO:0012247; hereditary episodic ataxia MONDO:0016227 to Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003
Mendeliome v1.406 FGF14 Zornitza Stark reviewed gene: FGF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.406 SCNN1A Zornitza Stark Tag treatable tag was added to gene: SCNN1A.
Mendeliome v1.406 GATA2 Zornitza Stark Tag treatable tag was added to gene: GATA2.
Mendeliome v1.406 GAMT Zornitza Stark Tag treatable tag was added to gene: GAMT.
Mendeliome v1.406 GALNS Zornitza Stark Tag treatable tag was added to gene: GALNS.
Mendeliome v1.406 IMPA1 Bryony Thompson Marked gene: IMPA1 as ready
Mendeliome v1.406 IMPA1 Bryony Thompson Gene: impa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.406 IMPA1 Bryony Thompson Classified gene: IMPA1 as Amber List (moderate evidence)
Mendeliome v1.406 IMPA1 Bryony Thompson Gene: impa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.405 IMPA1 Bryony Thompson gene: IMPA1 was added
gene: IMPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IMPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IMPA1 were set to 26416544; 24554717; 32839513; 17460611
Phenotypes for gene: IMPA1 were set to intellectual disability, autosomal recessive 59 MONDO:0015020
Review for gene: IMPA1 was set to AMBER
Added comment: A homozygous frameshift variant identified in a large Brazilian consanguineous family with ID, also supporting functional studies and null mouse models.
Sources: Literature
Mendeliome v1.404 ARNT2 Bryony Thompson Marked gene: ARNT2 as ready
Mendeliome v1.404 ARNT2 Bryony Thompson Gene: arnt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.404 ARNT2 Bryony Thompson Classified gene: ARNT2 as Amber List (moderate evidence)
Mendeliome v1.404 ARNT2 Bryony Thompson Gene: arnt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.403 ARNT2 Bryony Thompson gene: ARNT2 was added
gene: ARNT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARNT2 were set to 11381139; 24022475
Phenotypes for gene: ARNT2 were set to Webb-Dattani syndrome MONDO:0014404
Review for gene: ARNT2 was set to AMBER
Added comment: A homozygous frameshift (c.1373_1374dupTC) in six affected children from a highly consanguineous family with a syndromic phenotype including microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract. In a Arnt2(-/-) mouse model embryos die perinatally and exhibit impaired hypothalamic development.
Sources: Literature
Mendeliome v1.402 HEATR3 Zornitza Stark reviewed gene: HEATR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anaemia 21, MIM# 620072; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.402 C6 Zornitza Stark Tag treatable tag was added to gene: C6.
Mendeliome v1.402 FAH Zornitza Stark Tag treatable tag was added to gene: FAH.
Mendeliome v1.402 ETHE1 Zornitza Stark Tag treatable tag was added to gene: ETHE1.
Mendeliome v1.402 FRMD5 Zornitza Stark Marked gene: FRMD5 as ready
Mendeliome v1.402 FRMD5 Zornitza Stark Gene: frmd5 has been classified as Green List (High Evidence).
Mendeliome v1.402 FRMD5 Zornitza Stark Classified gene: FRMD5 as Green List (high evidence)
Mendeliome v1.402 FRMD5 Zornitza Stark Gene: frmd5 has been classified as Green List (High Evidence).
Mendeliome v1.401 FRMD5 Zornitza Stark gene: FRMD5 was added
gene: FRMD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder MONDO:0700092, FRMD5-related
Review for gene: FRMD5 was set to GREEN
Added comment: Eight individuals reported with missense variants in this gene, de novo in 6 where parents were available. Clinical presentation was with ID, seizures, ataxia. Fly model.
Sources: Literature
Mendeliome v1.400 GIGYF1 Elena Savva Publications for gene: GIGYF1 were set to 33057194; 35917186
Mendeliome v1.400 GIGYF1 Elena Savva Publications for gene: GIGYF1 were set to 33057194
Mendeliome v1.399 GIGYF1 Elena Savva Phenotypes for gene: GIGYF1 were changed from Developmental disorder to Autism, Intellectual disability, GIGYF1-related (MONDO#0001071)
Mendeliome v1.398 GIGYF1 Elena Savva Classified gene: GIGYF1 as Green List (high evidence)
Mendeliome v1.398 GIGYF1 Elena Savva Gene: gigyf1 has been classified as Green List (High Evidence).
Mendeliome v1.397 GIGYF1 Elena Savva reviewed gene: GIGYF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33057194; Phenotypes: Intellectual disability, GIGYF1-related (MONDO#0001071); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.397 TOMM7 Zornitza Stark Phenotypes for gene: TOMM7 were changed from growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy MONDO:0014911 to Inborn mitochondrial disorder MONDO:0004069, TOMM7-related
Mendeliome v1.396 TOMM7 Zornitza Stark reviewed gene: TOMM7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn mitochondrial disorder MONDO:0004069, TOMM7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.396 DDC Zornitza Stark Tag treatable tag was added to gene: DDC.
Tag clinical trial tag was added to gene: DDC.
Mendeliome v1.396 DGAT1 Zornitza Stark Tag treatable tag was added to gene: DGAT1.
Mendeliome v1.396 CYP27B1 Zornitza Stark Tag treatable tag was added to gene: CYP27B1.
Mendeliome v1.396 CYP27A1 Zornitza Stark Tag treatable tag was added to gene: CYP27A1.
Mendeliome v1.396 CYP17A1 Zornitza Stark Tag treatable tag was added to gene: CYP17A1.
Mendeliome v1.396 CYP11B2 Zornitza Stark Tag treatable tag was added to gene: CYP11B2.
Mendeliome v1.396 CYP11B1 Zornitza Stark Tag treatable tag was added to gene: CYP11B1.
Mendeliome v1.396 CUBN Zornitza Stark Tag treatable tag was added to gene: CUBN.
Mendeliome v1.396 CTNS Zornitza Stark Tag treatable tag was added to gene: CTNS.
Mendeliome v1.396 CPS1 Zornitza Stark Tag treatable tag was added to gene: CPS1.
Mendeliome v1.396 TOMM7 Bryony Thompson Marked gene: TOMM7 as ready
Mendeliome v1.396 TOMM7 Bryony Thompson Gene: tomm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.396 TOMM7 Bryony Thompson Classified gene: TOMM7 as Amber List (moderate evidence)
Mendeliome v1.396 TOMM7 Bryony Thompson Gene: tomm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.395 TOMM7 Bryony Thompson gene: TOMM7 was added
gene: TOMM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOMM7 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100148
Phenotypes for gene: TOMM7 were set to growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy MONDO:0014911
Review for gene: TOMM7 was set to AMBER
Added comment: A single case identified with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. A mouse model of the missense variant demonstrated a bioenergetic defect and a phenotype of mitochondrial diseases. It also strongly suggested that the variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with a homozygous Tomm7 deletion.
Sources: Literature
Mendeliome v1.394 HECW2 Bryony Thompson Mode of inheritance for gene: HECW2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.393 HECW2 Bryony Thompson reviewed gene: HECW2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35753050, 35487419; Phenotypes: Neurodevelopmental disorder with hypotonia, seizures, and absent language MONDO:0014995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.393 SEPT4 Bryony Thompson Marked gene: SEPT4 as ready
Mendeliome v1.393 SEPT4 Bryony Thompson Gene: sept4 has been classified as Green List (High Evidence).
Mendeliome v1.393 SEPT4 Bryony Thompson Classified gene: SEPT4 as Green List (high evidence)
Mendeliome v1.393 SEPT4 Bryony Thompson Gene: sept4 has been classified as Green List (High Evidence).
Mendeliome v1.392 SEPT4 Bryony Thompson gene: SEPT4 was added
gene: SEPT4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEPT4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEPT4 were set to 36135717; 15737931; 15737930
Phenotypes for gene: SEPT4 were set to male infertility MONDO:0005372
Review for gene: SEPT4 was set to GREEN
Added comment: Two unrelated cases with primary male infertility (asthenoteratozoospermia) from consanguineous Chinsese families with 2 difference homozygous stopgain variants (Patient 1: c.721A>T, p.R241* and Patient 2: c.205C>T, p.R69*). Multiple supporting mouse models where the male mice are sterile.
Sources: Literature
Mendeliome v1.391 FAM20B Bryony Thompson Marked gene: FAM20B as ready
Mendeliome v1.391 FAM20B Bryony Thompson Gene: fam20b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.391 FAM20B Bryony Thompson Classified gene: FAM20B as Amber List (moderate evidence)
Mendeliome v1.391 FAM20B Bryony Thompson Gene: fam20b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.390 FAM20B Bryony Thompson gene: FAM20B was added
gene: FAM20B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: FAM20B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM20B were set to 30847897; 30105814; 22732358; 27405802
Phenotypes for gene: FAM20B were set to Desbuquois dysplasia MONDO:0015426
Review for gene: FAM20B was set to AMBER
Added comment: Two siblings from a single family with neonatal short limb dysplasia resembling Desbuquois dysplasia. One of the siblings underwent genetic testing and compound heterozygous variants were identified in FAM20B ((NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). Multiple mouse models reported with skeletal abnormalities.
Sources: Other
Mendeliome v1.389 EXOC6B Bryony Thompson Marked gene: EXOC6B as ready
Mendeliome v1.389 EXOC6B Bryony Thompson Gene: exoc6b has been classified as Green List (High Evidence).
Mendeliome v1.389 EXOC6B Bryony Thompson Classified gene: EXOC6B as Green List (high evidence)
Mendeliome v1.389 EXOC6B Bryony Thompson Gene: exoc6b has been classified as Green List (High Evidence).
Mendeliome v1.388 EXOC6B Bryony Thompson gene: EXOC6B was added
gene: EXOC6B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXOC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC6B were set to 26669664; 30284759; 36150098
Phenotypes for gene: EXOC6B were set to Spondyloepimetaphyseal dysplasia with joint laxity MONDO:0019675
Review for gene: EXOC6B was set to GREEN
Added comment: 6 affected individuals from 4 families, and supporting assays in patient cells
PMID: 26669664 - 2 brothers with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones from a consanguineous family, with a homozygous nonsense variant [c.906T>A/p.(Tyr302*)]
PMID: 30284759 - 2 sisters with dislocations of the hips and knees, long slender fingers with distal tapering, significant motor disability but normal (older sister) or low-normal intelligence (younger sister), with a homozygous in-frame deletion of exons 9-20
PMID: 36150098 - 2 unrelated probands from consanguineous families, one with a homozygous frameshift exon 20 deletion and one with a homozygous nonsense variant (c.401T>G p.Leu134Ter). Function assessment of patient fibroblast cell lines indicated abrogation of exocytosis leading to impaired primary ciliogenesis
Sources: Literature
Mendeliome v1.387 VPS33A Bryony Thompson Publications for gene: VPS33A were set to 28013294; 27547915
Mendeliome v1.386 VPS33A Bryony Thompson Classified gene: VPS33A as Green List (high evidence)
Mendeliome v1.386 VPS33A Bryony Thompson Gene: vps33a has been classified as Green List (High Evidence).
Mendeliome v1.385 VPS33A Bryony Thompson changed review comment from: PMID: 28013294 - 13 cases homozygous for VPS33A c.1492C>T p.(Arg498Trp) from non-consanguineous Yakuti families with a Mucopolysaccharidoses-like disease (coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, intellectual disability, and excess secretion of urinary glycosaminoglycans). Lysosomal over-acidification and heparan sulphate accumulation were detected in patient-derived and VPS33A-depleted HeLa cells.
PMID: 27547915 - 2 affected siblings homozygous for VPS33A p.(Arg498Trp) from a consanguineous Turkish family
PMID: 31936524 - 1 homozygous case from a non-consanguineous Yakuti family
PMID: 36153662 - an attenuated juvenile case with a new homozygous missense variant VPS33A c.599G>C p.(Arg200Pro). Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid and decreased abundance of VPS33A in patient-derived fibroblasts; to: Now two missense variants reported with disease in at least 15 probands/families
PMID: 28013294 - 13 cases homozygous for VPS33A c.1492C>T p.(Arg498Trp) from non-consanguineous Yakuti families with a Mucopolysaccharidoses-like disease (coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, intellectual disability, and excess secretion of urinary glycosaminoglycans). Lysosomal over-acidification and heparan sulphate accumulation were detected in patient-derived and VPS33A-depleted HeLa cells.
PMID: 27547915 - 2 affected siblings homozygous for VPS33A p.(Arg498Trp) from a consanguineous Turkish family
PMID: 31936524 - 1 homozygous case from a non-consanguineous Yakuti family
PMID: 36153662 - an attenuated juvenile case with a new homozygous missense variant VPS33A c.599G>C p.(Arg200Pro). Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid and decreased abundance of VPS33A in patient-derived fibroblasts
Mendeliome v1.385 DPH5 Zornitza Stark Marked gene: DPH5 as ready
Mendeliome v1.385 DPH5 Zornitza Stark Gene: dph5 has been classified as Green List (High Evidence).
Mendeliome v1.385 DPH5 Zornitza Stark Classified gene: DPH5 as Green List (high evidence)
Mendeliome v1.385 DPH5 Zornitza Stark Gene: dph5 has been classified as Green List (High Evidence).
Mendeliome v1.384 DPH5 Zornitza Stark gene: DPH5 was added
gene: DPH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH5 were set to 35482014
Phenotypes for gene: DPH5 were set to Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties, MIM# 620070
Review for gene: DPH5 was set to GREEN
Added comment: 5 individuals from 3 unrelated families reported with severe ID, feeding difficulties, dysmorphic features and congenital anomalies, though there was no consistent pattern to these.
Sources: Literature
Mendeliome v1.383 VPS33A Bryony Thompson reviewed gene: VPS33A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28013294, 27547915, 31936524, 36153662; Phenotypes: Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders MONDO:0015012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.383 SLC12A6 Zornitza Stark Phenotypes for gene: SLC12A6 were changed from Andermann syndrome; Agenesis of the corpus callosum with peripheral neuropathy, MIM#21800; Intermediate CMT to Andermann syndrome; Agenesis of the corpus callosum with peripheral neuropathy, MIM#21800; Charcot-Marie-Tooth disease, axonal, type 2II , MIM#620068
Mendeliome v1.382 SLC12A6 Zornitza Stark edited their review of gene: SLC12A6: Changed phenotypes: Andermann syndrome, Agenesis of the corpus callosum with peripheral neuropathy, MIM#21800, Charcot-Marie-Tooth disease, axonal, type 2II , MIM#620068
Mendeliome v1.382 ADGRL1 Zornitza Stark Phenotypes for gene: ADGRL1 were changed from Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092) to Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065
Mendeliome v1.381 ADGRL1 Zornitza Stark reviewed gene: ADGRL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.381 VPS45 Zornitza Stark Tag treatable tag was added to gene: VPS45.
Mendeliome v1.381 XIAP Zornitza Stark Tag treatable tag was added to gene: XIAP.
Mendeliome v1.381 BRIP1 Zornitza Stark Tag treatable tag was added to gene: BRIP1.
Mendeliome v1.381 ACAD9 Zornitza Stark Tag treatable tag was added to gene: ACAD9.
Mendeliome v1.381 GALT Zornitza Stark reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Galactosemia MIM#230400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.381 GALT Zornitza Stark Mode of inheritance for gene: GALT was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.380 ACAD8 Zornitza Stark Phenotypes for gene: ACAD8 were changed from to Isobutyryl-CoA dehydrogenase deficiency MIM#611283
Mendeliome v1.379 ALG5 Zornitza Stark Phenotypes for gene: ALG5 were changed from Cystic renal disease MONDO:0002473, ALG5-related to Polycystic kidney disease 7, MIM# 620056
Mendeliome v1.378 ALG5 Zornitza Stark reviewed gene: ALG5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Polycystic kidney disease 7, MIM# 620056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.378 SLC32A1 Zornitza Stark Phenotypes for gene: SLC32A1 were changed from Genetic epilepsy with febrile seizures plus to Genetic epilepsy with febrile seizures plus; Developmental and epileptic encephalopathy MONDO:0100062, SLC32A1-related
Mendeliome v1.377 SLC32A1 Zornitza Stark Publications for gene: SLC32A1 were set to 34038384
Mendeliome v1.376 SCNM1 Elena Savva Marked gene: SCNM1 as ready
Mendeliome v1.376 SCNM1 Elena Savva Gene: scnm1 has been classified as Green List (High Evidence).
Mendeliome v1.376 SCNM1 Elena Savva Classified gene: SCNM1 as Green List (high evidence)
Mendeliome v1.376 SCNM1 Elena Savva Gene: scnm1 has been classified as Green List (High Evidence).
Mendeliome v1.375 SCNM1 Elena Savva gene: SCNM1 was added
gene: SCNM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCNM1 were set to PMID: 36084634
Phenotypes for gene: SCNM1 were set to Ciliopathy, SCNM1-related, MONDO:0005308
Review for gene: SCNM1 was set to GREEN
Added comment: Iturrate (2022): three unrelated families (4 affected) w/ OFD, polydactyly, syndactyly and brachydactyly. All had biallelic variants (fs, missense, AluYc1 sequence insertion) and were consanguinous
- the missense variant was shown to have a splice outcome
Sources: Literature
Mendeliome v1.374 DEPDC5 Dean Phelan reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36067010, 32848577; Phenotypes: Neurodevelopmental disorder, DEPDC5-related, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.374 LETM1 Zornitza Stark Marked gene: LETM1 as ready
Mendeliome v1.374 LETM1 Zornitza Stark Gene: letm1 has been classified as Green List (High Evidence).
Mendeliome v1.374 LETM1 Zornitza Stark reviewed gene: LETM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.374 LETM1 Zornitza Stark Classified gene: LETM1 as Green List (high evidence)
Mendeliome v1.374 LETM1 Zornitza Stark Gene: letm1 has been classified as Green List (High Evidence).
Mendeliome v1.373 DACT1 Zornitza Stark Classified gene: DACT1 as Amber List (moderate evidence)
Mendeliome v1.373 DACT1 Zornitza Stark Gene: dact1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.372 LETM1 Ee Ming Wong gene: LETM1 was added
gene: LETM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214
Phenotypes for gene: LETM1 were set to Mitochondrial disease MONDO#0044970, LETM1-related
gene: LETM1 was marked as current diagnostic
Added comment: -18 affected individuals from 11 unrelated families harbouring ultra-rare bi-allelic missense and loss-of-function LETM1 variants
-Most of the affected individuals (14/18, 78%) had an infantile-onset disease manifestation,
and 4/18 (22%) presented first symptoms between the ages of 1.5 and 2 years
-Variant types included missense, frameshift, stop loss, in-frame deletion and splice defect
-From biochemical and morphological studies, bi-allelic LETM1 variants are associated with defective mitochondrial K efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components
Sources: Literature
Mendeliome v1.372 GABRG1 Seb Lunke Marked gene: GABRG1 as ready
Mendeliome v1.372 GABRG1 Seb Lunke Gene: gabrg1 has been classified as Red List (Low Evidence).
Mendeliome v1.372 GABBR1 Zornitza Stark Marked gene: GABBR1 as ready
Mendeliome v1.372 GABBR1 Zornitza Stark Gene: gabbr1 has been classified as Green List (High Evidence).
Mendeliome v1.372 GABBR1 Zornitza Stark Classified gene: GABBR1 as Green List (high evidence)
Mendeliome v1.372 GABBR1 Zornitza Stark Gene: gabbr1 has been classified as Green List (High Evidence).
Mendeliome v1.371 GABBR1 Zornitza Stark gene: GABBR1 was added
gene: GABBR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABBR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABBR1 were set to 36103875
Phenotypes for gene: GABBR1 were set to Neurodevelopmental disorder, GABBR1-related, MONDO:0700092
Review for gene: GABBR1 was set to GREEN
Added comment: Four individuals with de novo variants in this gene and varying severity of DD/ID, seizures and hypotonia.
Sources: Literature
Mendeliome v1.371 GABRG1 Seb Lunke Classified gene: GABRG1 as Red List (low evidence)
Mendeliome v1.371 GABRG1 Seb Lunke Gene: gabrg1 has been classified as Red List (Low Evidence).
Mendeliome v1.370 DUT Seb Lunke Marked gene: DUT as ready
Mendeliome v1.370 DUT Seb Lunke Gene: dut has been classified as Green List (High Evidence).
Mendeliome v1.370 DUT Seb Lunke Classified gene: DUT as Green List (high evidence)
Mendeliome v1.370 DUT Seb Lunke Gene: dut has been classified as Green List (High Evidence).
Mendeliome v1.369 DUT Daniel Flanagan gene: DUT was added
gene: DUT was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DUT were set to 28073829; 35611808
Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome (MIM#620044)
Review for gene: DUT was set to GREEN
Added comment: Homozygous missense (p.(Tyr142Cys)) identified in eight affected individuals from four unrelated consanguineous families (French, Egyptian, two Libyan) with diabetes and bone marrow failure. DUT silencing in human and rat pancreatic b-cells results in apoptosis via the intrinsic cell death pathway.

p.(Tyr142Cys) has 11 heterozygotes and no homozygotes in gnomAD.
Sources: Expert list
Mendeliome v1.369 DACT1 Paul De Fazio reviewed gene: DACT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36066768; Phenotypes: Townes-Brocks syndrome 2 MONDO:0054582; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.369 CENPP Seb Lunke Marked gene: CENPP as ready
Mendeliome v1.369 CENPP Seb Lunke Gene: cenpp has been classified as Red List (Low Evidence).
Mendeliome v1.369 CENPP Seb Lunke changed review comment from: Sources: Literature; to: Single family with dominant SNHL segregated through 5 family members. Truncating variant in NM_001012267.3(CENPP):c.849T>A (p.Cys283Ter). Note: misannotated as nonsense variant in paper.
Sources: Literature
Mendeliome v1.369 CENPP Seb Lunke gene: CENPP was added
gene: CENPP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CENPP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CENPP were set to 36071244
Phenotypes for gene: CENPP were set to autosomal dominant nonsyndromic hearing loss; MONDO:0019587
Review for gene: CENPP was set to RED
Added comment: Sources: Literature
Mendeliome v1.368 SLC13A1 Zornitza Stark Marked gene: SLC13A1 as ready
Mendeliome v1.368 SLC13A1 Zornitza Stark Gene: slc13a1 has been classified as Red List (Low Evidence).
Mendeliome v1.368 GABRG1 Anna Ritchie gene: GABRG1 was added
gene: GABRG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABRG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRG1 were set to PMID: 36121006
Phenotypes for gene: GABRG1 were set to Developmental and epileptic encephalopathy MONDO:0100062
Added comment: 2-year-old patient with epileptic encephalopathy, hypotonia, and global developmental delays. Clinical trio exome sequencing showed a novel, de novo missense variant in the GABRG1 gene.
Sources: Literature
Mendeliome v1.368 SLC32A1 Lucy Spencer reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36073542; Phenotypes: developmental and epileptic encephalopathy MONDO:0100062, SLC32A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.368 SLC13A1 Zornitza Stark Classified gene: SLC13A1 as Red List (low evidence)
Mendeliome v1.368 SLC13A1 Zornitza Stark Gene: slc13a1 has been classified as Red List (Low Evidence).
Mendeliome v1.367 MED11 Ain Roesley Marked gene: MED11 as ready
Mendeliome v1.367 MED11 Ain Roesley Gene: med11 has been classified as Green List (High Evidence).
Mendeliome v1.367 MED11 Ain Roesley Classified gene: MED11 as Green List (high evidence)
Mendeliome v1.367 MED11 Ain Roesley Gene: med11 has been classified as Green List (High Evidence).
Mendeliome v1.366 LAMA5 Belinda Chong reviewed gene: LAMA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29534211, 16790509, 29764427, 30808327, 24130771, 35419533; Phenotypes: Nephrotic syndrome, type 26 620049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.366 MED11 Ain Roesley gene: MED11 was added
gene: MED11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related
Review for gene: MED11 was set to GREEN
gene: MED11 was marked as current diagnostic
Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*).

Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes

NO evidence of founder effect from haplotype analysis

7/7 cerebral dysgyria, cortical atrophy
5/7 limb contracture
4/7 epilepsy
3/7 families with IUGR
3/7 GDD
3/7 hearing loss
3/7 undescended testis
2/7 nystagmus
1/7 congenital cataract
Sources: Literature
Mendeliome v1.365 ATP6V0C Naomi Baker reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36074901; Phenotypes: neurodevelopmental disorder (MONDO:0700092), ATP6V0C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.365 ATP6V0C Alison Yeung Classified gene: ATP6V0C as Green List (high evidence)
Mendeliome v1.365 ATP6V0C Alison Yeung Gene: atp6v0c has been classified as Green List (High Evidence).
Mendeliome v1.364 ATP6V0C Alison Yeung reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: neurodevelopmental disorder (MONDO:0700092), ATP6V0C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.364 SLC13A1 Lucy Spencer gene: SLC13A1 was added
gene: SLC13A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC13A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A1 were set to 36175384
Phenotypes for gene: SLC13A1 were set to sulfation-related bone disorder MONDO:0019688, SLC13A1-related
Review for gene: SLC13A1 was set to RED
Added comment: PMID: 36175384- 1 patient with a homozygous nonsense variant in SLC13A1. Patient has enlargements of the joints, and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. Also autistic features and hyposulfatemia and hypersulfaturia, and reduced serum cholesterol sulfate. However the variant in this individual (Arg12Ter) has 569 hets and 1 hom in gnomad.

Also this patient was homozygous for CFTR Ala455Gly which is a known pathogenic variant associated with a less severe CF phenotype.
Sources: Literature
Mendeliome v1.364 LAMA5 Zornitza Stark Classified gene: LAMA5 as Green List (high evidence)
Mendeliome v1.364 LAMA5 Zornitza Stark Gene: lama5 has been classified as Green List (High Evidence).
Mendeliome v1.363 LAMA5 Zornitza Stark reviewed gene: LAMA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 35419533; Phenotypes: Nephrotic syndrome, type 26 620049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.363 NAPB Alison Yeung Marked gene: NAPB as ready
Mendeliome v1.363 NAPB Alison Yeung Gene: napb has been classified as Green List (High Evidence).
Mendeliome v1.363 NAPB Alison Yeung Classified gene: NAPB as Green List (high evidence)
Mendeliome v1.363 NAPB Alison Yeung Gene: napb has been classified as Green List (High Evidence).
Mendeliome v1.362 FKBP6 Zornitza Stark Marked gene: FKBP6 as ready
Mendeliome v1.362 FKBP6 Zornitza Stark Gene: fkbp6 has been classified as Green List (High Evidence).
Mendeliome v1.362 FKBP6 Zornitza Stark Classified gene: FKBP6 as Green List (high evidence)
Mendeliome v1.362 FKBP6 Zornitza Stark Gene: fkbp6 has been classified as Green List (High Evidence).
Mendeliome v1.361 MTSS1L Elena Savva Marked gene: MTSS1L as ready
Mendeliome v1.361 MTSS1L Elena Savva Gene: mtss1l has been classified as Green List (High Evidence).
Mendeliome v1.361 SARS Ee Ming Wong edited their review of gene: SARS: Added comment: -Two missense variants within the aminoacylation domain identified in 16 affected individuals from 3 distinct CMT families
-Mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation; Changed rating: GREEN; Changed publications: 36088542; Changed phenotypes: Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.361 FOSL2 Zornitza Stark Marked gene: FOSL2 as ready
Mendeliome v1.361 FOSL2 Zornitza Stark Gene: fosl2 has been classified as Green List (High Evidence).
Mendeliome v1.361 FOSL2 Zornitza Stark Classified gene: FOSL2 as Green List (high evidence)
Mendeliome v1.361 FOSL2 Zornitza Stark Gene: fosl2 has been classified as Green List (High Evidence).
Mendeliome v1.360 MTSS1L Elena Savva Classified gene: MTSS1L as Green List (high evidence)
Mendeliome v1.360 MTSS1L Elena Savva Gene: mtss1l has been classified as Green List (High Evidence).
Mendeliome v1.359 MTSS1L Elena Savva gene: MTSS1L was added
gene: MTSS1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MTSS1L were set to PMID: 36067766
Phenotypes for gene: MTSS1L were set to Intellectual disability, MTSS2-related (MONDO#0001071)
Review for gene: MTSS1L was set to GREEN
Added comment: Alt gene name: MTSS2

Huang (2022): recurring de novo missense variant (p.R671W) causing syndromic intellectual disability in 5 unrelated individuals.
- Individuals present with GDD, mild ID (5/5), nystagmus (3/5), optic atrophy (1/5), ptosis (2/5), sensorineural hearing loss (2/4), microcephaly or relative microcephaly (5/5), and shared mild facial dysmorphisms.
- Overexpression supports a DN mechanism
Sources: Literature
Mendeliome v1.358 DAW1 Alison Yeung Marked gene: DAW1 as ready
Mendeliome v1.358 DAW1 Alison Yeung Gene: daw1 has been classified as Green List (High Evidence).
Mendeliome v1.358 DAW1 Alison Yeung Classified gene: DAW1 as Green List (high evidence)
Mendeliome v1.358 DAW1 Alison Yeung Gene: daw1 has been classified as Green List (High Evidence).
Mendeliome v1.357 DAW1 Alison Yeung gene: DAW1 was added
gene: DAW1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124
Phenotypes for gene: DAW1 were set to Primary ciliary dyskinesia, MONDO:0016575; Visceral heterotaxy, MONDO:0018677
Review for gene: DAW1 was set to GREEN
Added comment: Biallelic variants identified in two unrelated families. Zebrafish model recapitulates PCD and heterotaxy phenotype
Sources: Literature
Mendeliome v1.356 RABGAP1 Zornitza Stark Marked gene: RABGAP1 as ready
Mendeliome v1.356 RABGAP1 Zornitza Stark Gene: rabgap1 has been classified as Green List (High Evidence).
Mendeliome v1.356 RABGAP1 Zornitza Stark Classified gene: RABGAP1 as Green List (high evidence)
Mendeliome v1.356 RABGAP1 Zornitza Stark Gene: rabgap1 has been classified as Green List (High Evidence).
Mendeliome v1.355 RABGAP1 Zornitza Stark gene: RABGAP1 was added
gene: RABGAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RABGAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RABGAP1 were set to 36083289
Phenotypes for gene: RABGAP1 were set to Neurodevelopmental disorder, RABGAP1-related,MONDO:0700092
Review for gene: RABGAP1 was set to GREEN
Added comment: 5 individuals from three families reported with ID, microcephaly, SNHL and seizures. Mouse model recapitulated the phenotype.
Sources: Literature
Mendeliome v1.354 NAPB Paul De Fazio gene: NAPB was added
gene: NAPB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 26235277; 28097321; 33189936
Phenotypes for gene: NAPB were set to Developmental and epileptic encephalopathy 107 MIM#620033
Review for gene: NAPB was set to GREEN
gene: NAPB was marked as current diagnostic
Added comment: PMID 26235277: homozygous nonsense variant identified in a 6 year old girl by trio WES with early-onset epileptic encephalopathy characterised by multifocal seizures and profound GDD

PMID 28097321: exome sequencing in 152 consanguineous families with at least one member affected with ID. Homozygous nonsense variant identified in a patient with profound ID, seizures, feeding difficulties in infancy, muscularhypotonia, microcephaly, and impaired vision

PMID 33189936: homozygous canonical splice variant identified by trio exome sequencing in two siblings with seizures, intellectual disability and global developmental delay, microcephaly (<-3SD), and muscular hypotonia.
Sources: Literature
Mendeliome v1.354 FKBP6 Dean Phelan gene: FKBP6 was added
gene: FKBP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FKBP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FKBP6 were set to PMID: 36150389
Phenotypes for gene: FKBP6 were set to Spermatogenic failure (MONDO:0004983), FKBP6-related
Review for gene: FKBP6 was set to GREEN
Added comment: PMID: 36150389 - large cohort study of men with severe spermatogenic failure (SPGF), identified six individuals with rare bi-allelic loss of function variants in FKBP6. RT-qPCR and immunofluorescence confirmed lack of FKBP6 expression. In mice, Fkbp6 has also been shown to be essential for spermatogenesis.
Sources: Literature
Mendeliome v1.354 GCSH Ain Roesley Phenotypes for gene: GCSH were changed from Glycine encephalopathy, MIM# 605899 to Glycine encephalopathy MIM#605899; neurodevelopmental disorder MONDO#0700092, GCHS-related
Mendeliome v1.353 GCSH Ain Roesley Publications for gene: GCSH were set to 1671321
Mendeliome v1.352 GCSH Ain Roesley edited their review of gene: GCSH: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.352 GCSH Ain Roesley edited their review of gene: GCSH: Changed phenotypes: Glycine encephalopathy MIM#605899, neurodevelopmental disorder MONDO#0700092, GCHS-related
Mendeliome v1.352 GCSH Ain Roesley Classified gene: GCSH as Green List (high evidence)
Mendeliome v1.352 GCSH Ain Roesley Gene: gcsh has been classified as Green List (High Evidence).
Mendeliome v1.351 GCSH Ain Roesley reviewed gene: GCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 36190515; Phenotypes: glycine encephalopathy MONDO#0011612, GCSH-related, neurodevelopmental disorder MONDO#0700092, GCHS-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.351 NSD2 Zornitza Stark Publications for gene: NSD2 were set to 30345613; 31171569
Mendeliome v1.350 NSD2 Zornitza Stark edited their review of gene: NSD2: Changed publications: 36189577
Mendeliome v1.350 NSD2 Zornitza Stark Phenotypes for gene: NSD2 were changed from Rauch-Steindl syndrome, MIM# 619695; Microcephaly; intellectual disability to Rauch-Steindl syndrome, MIM# 619695; Microcephaly; intellectual disability; Neurodevelopmental disorder, NSD2-associated, GoF, MONDO:0700092
Mendeliome v1.349 NSD2 Zornitza Stark Publications for gene: NSD2 were set to 30345613; 31171569
Mendeliome v1.348 NSD2 Zornitza Stark edited their review of gene: NSD2: Added comment: PMID 36189577: two individuals reported with a GoF variant, p.Glu1099Lys, and a distinct phenotype: intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly.; Changed phenotypes: Rauch-Steindl syndrome, MIM# 619695, Microcephaly, intellectual disability, Neurodevelopmental disorder, NSD2-associated, GoF, MONDO:0700092
Mendeliome v1.348 FOSL2 Krithika Murali gene: FOSL2 was added
gene: FOSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOSL2 were set to 36197437
Phenotypes for gene: FOSL2 were set to Neurodevelopmental disorder, MONDO:0700092, FOSL2-related
Review for gene: FOSL2 was set to GREEN
Added comment: PMID 36197437 Cospain et al 2022 report 11 individuals from 10 families with heterozygous PTC variants in exon 4/4 of the FOSL2 gene. All variants were predicted to escape NMD resulting in a truncated protein, with the truncation occurring proximal to the C-terminal domain (supportive functional studies).

In 10/11 families the variant occurred de novo in a single affected proband. In one family with 2 affected siblings, the variant was present in the siblings but absent in the unaffected parent likely due to gonadal mosaicism.

Clinical features included:
- Cutis aplasia congenital of the scalp (10/11)
- Tooth enamel hypoplasia and discolouration (8/9)
- Multiple other ectodermal features also noted e.g. small brittle nails, hypotrichosis/hypertrichosis, lichen sclerosis
- 5 individuals had cataracts (mostly bilateral, congenital/early childhood onset)
- 6/9 IUGR
- 5/9 postnatal growth restriction
- 7/9 developmental delay/ID
- 5/7 ADHD/ASD
- 2/9 seizures
Sources: Literature
Mendeliome v1.348 TRAF3 Zornitza Stark Publications for gene: TRAF3 were set to 20832341
Mendeliome v1.347 TRAF3 Zornitza Stark Classified gene: TRAF3 as Green List (high evidence)
Mendeliome v1.347 TRAF3 Zornitza Stark Gene: traf3 has been classified as Green List (High Evidence).
Mendeliome v1.346 TRAF3 Zornitza Stark changed review comment from: Single individual reported.; to: Single individual reported with HSV-induced encephalopathy.
Mendeliome v1.346 TRAF3 Zornitza Stark edited their review of gene: TRAF3: Added comment: PMID 35960817: Nine individuals from five unrelated families with childhood-onset immune diseases and recurrent infections. All patients had suffered recurrent ear and sinopulmonary infections, including pneumonias from encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenza, resulting in early-onset bronchiectasis in several individuals; Changed rating: GREEN; Changed publications: 20832341, 35960817; Changed phenotypes: Autoinflammatory syndrome, TRAF3-related, MONDO:0019751, hypergammaglobulinemia, lymphadenopathy, splenomegaly, Sjögren’s syndrome, {?Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 5}, MIM# 614849
Mendeliome v1.346 KCNK3 Krithika Murali reviewed gene: KCNK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36195757; Phenotypes: eurodevelopmental disorder, MONDO:0700092, KCNK3-related, developmental delay with sleep apnoea (DDSA), Pulmonary hypertension, primary, 4-MIM#615344; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.346 MYSM1 Zornitza Stark Tag treatable tag was added to gene: MYSM1.
Mendeliome v1.346 MOCS1 Zornitza Stark Tag treatable tag was added to gene: MOCS1.
Mendeliome v1.346 MLYCD Zornitza Stark Tag treatable tag was added to gene: MLYCD.
Mendeliome v1.346 COQ8A Zornitza Stark Tag treatable tag was added to gene: COQ8A.
Mendeliome v1.346 COQ4 Zornitza Stark changed review comment from: Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. At least 9 unrelated families reported.; to: Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. At least 9 unrelated families reported.

Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations.
Mendeliome v1.346 COQ4 Zornitza Stark Tag treatable tag was added to gene: COQ4.
Mendeliome v1.346 COLQ Zornitza Stark Tag treatable tag was added to gene: COLQ.
Tag clinical trial tag was added to gene: COLQ.
Mendeliome v1.346 CHRNE Zornitza Stark Tag treatable tag was added to gene: CHRNE.
Mendeliome v1.346 CHRND Zornitza Stark Tag treatable tag was added to gene: CHRND.
Mendeliome v1.346 CHRNA1 Zornitza Stark Tag treatable tag was added to gene: CHRNA1.
Mendeliome v1.346 ADAMTS19 Zornitza Stark Phenotypes for gene: ADAMTS19 were changed from Non-syndromic heart valve disease to Cardiac valvular dysplasia 2, MIM# 620067
Mendeliome v1.345 ADAMTS19 Zornitza Stark edited their review of gene: ADAMTS19: Changed phenotypes: Cardiac valvular dysplasia 2, MIM# 620067
Mendeliome v1.345 DOHH Zornitza Stark Phenotypes for gene: DOHH were changed from Neurodevelopmental disorder, DOHH-related (MONDO#0700092) to Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066
Mendeliome v1.344 DOHH Zornitza Stark reviewed gene: DOHH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.344 DPH2 Zornitza Stark Phenotypes for gene: DPH2 were changed from Diphthamide-deficiency syndrome to Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MIM# 620062; Diphthamide-deficiency syndrome
Mendeliome v1.343 DPH2 Zornitza Stark reviewed gene: DPH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MIM# 620062; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.343 CHAT Zornitza Stark Tag treatable tag was added to gene: CHAT.
Mendeliome v1.343 CA5A Zornitza Stark Tag treatable tag was added to gene: CA5A.
Mendeliome v1.343 BTK Zornitza Stark Tag treatable tag was added to gene: BTK.
Mendeliome v1.343 ASL Zornitza Stark Tag treatable tag was added to gene: ASL.
Mendeliome v1.343 ARSB Zornitza Stark Tag clinical trial tag was added to gene: ARSB.
Mendeliome v1.343 ARSB Zornitza Stark Tag treatable tag was added to gene: ARSB.
Mendeliome v1.343 ARG1 Zornitza Stark Tag treatable tag was added to gene: ARG1.
Mendeliome v1.343 AHCY Zornitza Stark Tag treatable tag was added to gene: AHCY.
Mendeliome v1.343 SMN1 Zornitza Stark Tag treatable tag was added to gene: SMN1.
Tag clinical trial tag was added to gene: SMN1.
Mendeliome v1.343 ACADVL Zornitza Stark Tag treatable tag was added to gene: ACADVL.
Mendeliome v1.343 GALE Zornitza Stark Tag treatable tag was added to gene: GALE.
Mendeliome v1.343 GALK1 Zornitza Stark Tag treatable tag was added to gene: GALK1.
Mendeliome v1.343 GALT Zornitza Stark Tag treatable tag was added to gene: GALT.
Mendeliome v1.343 TAT Zornitza Stark Tag treatable tag was added to gene: TAT.
Mendeliome v1.343 PCCB Zornitza Stark Tag treatable tag was added to gene: PCCB.
Mendeliome v1.343 PCCA Zornitza Stark Tag treatable tag was added to gene: PCCA.
Mendeliome v1.343 PTS Zornitza Stark Tag treatable tag was added to gene: PTS.
Mendeliome v1.343 PAH Zornitza Stark Tag treatable tag was added to gene: PAH.
Mendeliome v1.343 ETFB Zornitza Stark Tag treatable tag was added to gene: ETFB.
Mendeliome v1.343 ETFA Zornitza Stark Tag treatable tag was added to gene: ETFA.
Mendeliome v1.343 ETFDH Zornitza Stark Tag treatable tag was added to gene: ETFDH.
Mendeliome v1.343 HADHB Zornitza Stark Tag treatable tag was added to gene: HADHB.
Mendeliome v1.343 HADHA Zornitza Stark Tag treatable tag was added to gene: HADHA.
Mendeliome v1.343 MMAB Zornitza Stark Tag treatable tag was added to gene: MMAB.
Mendeliome v1.343 MMAA Zornitza Stark Tag treatable tag was added to gene: MMAA.
Mendeliome v1.343 MUT Zornitza Stark Tag new gene name tag was added to gene: MUT.
Mendeliome v1.343 MUT Zornitza Stark Tag treatable tag was added to gene: MUT.
Mendeliome v1.343 ACADM Zornitza Stark Tag acadm was removed from gene: ACADM.
Tag treatable tag was added to gene: ACADM.
Mendeliome v1.343 ACADM Zornitza Stark Tag acadm tag was added to gene: ACADM.
Mendeliome v1.343 IVD Zornitza Stark Tag treatable tag was added to gene: IVD.
Mendeliome v1.343 BTD Zornitza Stark Tag treatable tag was added to gene: BTD.
Mendeliome v1.343 HLCS Zornitza Stark Tag treatable tag was added to gene: HLCS.
Mendeliome v1.343 GCDH Zornitza Stark Tag treatable tag was added to gene: GCDH.
Mendeliome v1.343 CBS Zornitza Stark Tag treatable tag was added to gene: CBS.
Mendeliome v1.343 MMADHC Zornitza Stark Tag treatable tag was added to gene: MMADHC.
Mendeliome v1.343 MMACHC Zornitza Stark Tag treatable tag was added to gene: MMACHC.
Mendeliome v1.343 SLC25A20 Zornitza Stark Tag treatable tag was added to gene: SLC25A20.
Mendeliome v1.343 SLC22A5 Zornitza Stark Tag treatable tag was added to gene: SLC22A5.
Mendeliome v1.343 MC2R Zornitza Stark Tag treatable tag was added to gene: MC2R.
Mendeliome v1.343 MAN2B1 Zornitza Stark Tag treatable tag was added to gene: MAN2B1.
Mendeliome v1.343 LYST Zornitza Stark Tag treatable tag was added to gene: LYST.
Mendeliome v1.343 LMBRD1 Zornitza Stark Tag treatable tag was added to gene: LMBRD1.
Mendeliome v1.343 LIPA Zornitza Stark Tag treatable tag was added to gene: LIPA.
Mendeliome v1.343 LIG4 Zornitza Stark Tag treatable tag was added to gene: LIG4.
Mendeliome v1.343 LHX4 Zornitza Stark Tag treatable tag was added to gene: LHX4.
Mendeliome v1.343 LHX3 Zornitza Stark Tag treatable tag was added to gene: LHX3.
Mendeliome v1.343 LEPR Zornitza Stark Tag treatable tag was added to gene: LEPR.
Tag clinical trial tag was added to gene: LEPR.
Mendeliome v1.343 CPT2 Zornitza Stark Tag treatable tag was added to gene: CPT2.
Mendeliome v1.343 CPT1A Zornitza Stark Tag treatable tag was added to gene: CPT1A.
Mendeliome v1.343 BCKDHB Zornitza Stark Tag treatable tag was added to gene: BCKDHB.
Mendeliome v1.343 BCKDHA Zornitza Stark Tag treatable tag was added to gene: BCKDHA.
Mendeliome v1.343 DBT Zornitza Stark Tag treatable tag was added to gene: DBT.
Mendeliome v1.343 HMGCL Zornitza Stark Tag treatable tag was added to gene: HMGCL.
Mendeliome v1.343 ACAT1 Zornitza Stark Tag treatable tag was added to gene: ACAT1.
Mendeliome v1.343 ASS1 Zornitza Stark Tag treatable tag was added to gene: ASS1.
Mendeliome v1.343 BLNK Zornitza Stark Tag treatable tag was added to gene: BLNK.
Mendeliome v1.343 TYMS Zornitza Stark Tag digenic tag was added to gene: TYMS.
Mendeliome v1.343 TYMS Zornitza Stark Phenotypes for gene: TYMS were changed from Dyskeratosis congenita MONDO:0015780 to Dyskeratosis congenita, digenic, MIM#620040
Mendeliome v1.342 TYMS Zornitza Stark edited their review of gene: TYMS: Changed phenotypes: Dyskeratosis congenita, digenic, MIM#620040
Mendeliome v1.342 ACVR1 Zornitza Stark Tag clinical trial tag was added to gene: ACVR1.
Mendeliome v1.342 ACVR1 Zornitza Stark changed review comment from: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner.

Multiple unrelated families reported. The R206H variant is recurrent.

Note variants in this gene are also associated with congenital heart disease, PMID 29089047.; to: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner.

Multiple unrelated families reported. The R206H variant is recurrent.

Clinical trial with palovarotene

Note variants in this gene are also associated with congenital heart disease, PMID 29089047.
Mendeliome v1.342 ALDOB Zornitza Stark Tag treatable tag was added to gene: ALDOB.
Mendeliome v1.342 ALDOB Zornitza Stark reviewed gene: ALDOB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fructose intolerance, hereditary, MIM# 229600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.342 ATP7A Zornitza Stark changed review comment from: ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein.; to: ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein.

Treatment for Menkes disease: subcutaneous injections of copper histidine or copper chloride

ClinGen has assessed as moderate evidence for actionability.

Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.
Mendeliome v1.342 ATP7A Zornitza Stark Tag treatable tag was added to gene: ATP7A.
Mendeliome v1.342 ATRX Zornitza Stark Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome; Mental retardation-hypotonic facies syndrome, X-linked to Alpha-thalassemia/mental retardation syndrome, MIM# 301040; Intellectual disability-hypotonic facies syndrome, X-linked, MIM# 309580
Mendeliome v1.341 PDCD6IP Zornitza Stark Phenotypes for gene: PDCD6IP were changed from Neurodevelopmental disorder MONDO:0700092; Microcephaly; intellectual disability to Microcephaly 29, primary, autosomal recessive, MIM# 620047; Microcephaly; intellectual disability
Mendeliome v1.340 PDCD6IP Zornitza Stark edited their review of gene: PDCD6IP: Changed phenotypes: Microcephaly 29, primary, autosomal recessive, MIM# 620047, Microcephaly, intellectual disability
Mendeliome v1.340 PDCD6IP Zornitza Stark edited their review of gene: PDCD6IP: Changed phenotypes: Microcephaly 29, primary, autosomal recessive , MIM# 620047, Microcephaly, intellectual disability
Mendeliome v1.340 DPP9 Zornitza Stark Marked gene: DPP9 as ready
Mendeliome v1.340 DPP9 Zornitza Stark Gene: dpp9 has been classified as Green List (High Evidence).
Mendeliome v1.340 DPP9 Zornitza Stark Classified gene: DPP9 as Green List (high evidence)
Mendeliome v1.340 DPP9 Zornitza Stark Gene: dpp9 has been classified as Green List (High Evidence).
Mendeliome v1.339 DPP9 Zornitza Stark gene: DPP9 was added
gene: DPP9 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DPP9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPP9 were set to 36112693
Phenotypes for gene: DPP9 were set to Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias
Review for gene: DPP9 was set to GREEN
Added comment: Three unrelated families with Hatipoğlu syndrome with biochemical and cellular assays, mouse and zebrafish models. Immunological features of recurrent fevers, repeated infections, herpes susceptibility, cytopenias.
Sources: Expert Review
Mendeliome v1.338 ATP6V1B1 Zornitza Stark Tag treatable tag was added to gene: ATP6V1B1.
Mendeliome v1.338 ATP6V0A4 Zornitza Stark Tag treatable tag was added to gene: ATP6V0A4.
Mendeliome v1.338 ARSA Zornitza Stark Tag treatable tag was added to gene: ARSA.
Tag clinical trial tag was added to gene: ARSA.
Mendeliome v1.338 ARPC1B Zornitza Stark changed review comment from: Three families with functional data.; to: Three families with functional data.

Treatment: BMT.
Mendeliome v1.338 ARPC1B Zornitza Stark Tag treatable tag was added to gene: ARPC1B.
Mendeliome v1.338 AVPR2 Zornitza Stark Tag clinical trial tag was added to gene: AVPR2.
Mendeliome v1.338 AVPR2 Zornitza Stark reviewed gene: AVPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes insipidus, nephrogenic 304800, Nephrogenic syndrome of inappropriate antidiuresis 300539; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.338 AVPR2 Zornitza Stark Tag treatable tag was added to gene: AVPR2.
Mendeliome v1.338 AVP Zornitza Stark reviewed gene: AVP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes insipidus, neurohypophyseal MIM#125700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.338 AVP Zornitza Stark Tag treatable tag was added to gene: AVP.
Tag clinical trial tag was added to gene: AVP.
Mendeliome v1.338 AQP2 Zornitza Stark Tag treatable tag was added to gene: AQP2.
Tag clinical trial tag was added to gene: AQP2.
Mendeliome v1.338 AQP2 Zornitza Stark changed review comment from: Dominant disease is caused by variants exerting a dominant negative effect, whereas recessive disease is caused by bi-allelic loss of function variants.; to: Dominant disease is caused by variants exerting a dominant negative effect, whereas recessive disease is caused by bi-allelic loss of function variants.

Onset in infancy. Causes severe dehydration, can be life-threatening.

Treatment: hydration, low-salt, low-protein diet, thiazide diuretics, amiloride, indomethacin.

Clinical trials.
Mendeliome v1.338 APRT Zornitza Stark changed review comment from: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic.; to: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic.

Treatable: allopurinol or febuxostat, low purine diet.
Mendeliome v1.338 APRT Zornitza Stark Tag treatable tag was added to gene: APRT.
Mendeliome v1.338 APRT Zornitza Stark reviewed gene: APRT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adenine phosphoribosyltransferase deficiency MIM#614723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.338 AP3B1 Zornitza Stark Tag treatable tag was added to gene: AP3B1.
Tag clinical trial tag was added to gene: AP3B1.
Mendeliome v1.338 ALPL Zornitza Stark Tag treatable tag was added to gene: ALPL.
Mendeliome v1.338 ANO1 Zornitza Stark Phenotypes for gene: ANO1 were changed from Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features to Intestinal dysmotility syndrome, MIM# 620045; Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features
Mendeliome v1.337 ANO1 Zornitza Stark reviewed gene: ANO1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intestinal dysmotility syndrome, MIM# 620045; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.337 ADAMTS13 Zornitza Stark Tag treatable tag was added to gene: ADAMTS13.
Mendeliome v1.337 AK2 Zornitza Stark Tag treatable tag was added to gene: AK2.
Mendeliome v1.337 AGRN Zornitza Stark Tag treatable tag was added to gene: AGRN.
Tag clinical trial tag was added to gene: AGRN.
Mendeliome v1.337 ABCG5 Zornitza Stark Tag treatable tag was added to gene: ABCG5.
Tag clinical trial tag was added to gene: ABCG5.
Mendeliome v1.337 ABCC6 Zornitza Stark Phenotypes for gene: ABCC6 were changed from Pseudoxanthoma elasticum, MIM# 264800; Pseudoxanthoma elasticum, forme fruste, MIM#177850 to Arterial calcification, generalized, of infancy, 2, MIM# 614473; Pseudoxanthoma elasticum, MIM# 264800; Pseudoxanthoma elasticum, forme fruste, MIM#177850
Mendeliome v1.336 ABCC6 Zornitza Stark Publications for gene: ABCC6 were set to 11536079; 28102862
Mendeliome v1.335 ABCC6 Zornitza Stark Tag treatable tag was added to gene: ABCC6.
Mendeliome v1.335 ABCC6 Zornitza Stark edited their review of gene: ABCC6: Added comment: GACI is a treatable disorder.; Changed rating: GREEN; Changed publications: 33005041, 34355424; Changed phenotypes: Arterial calcification, generalized, of infancy, 2, MIM# 614473; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.335 ALDH7A1 Zornitza Stark Tag treatable tag was added to gene: ALDH7A1.
Mendeliome v1.335 AKR1D1 Zornitza Stark Tag treatable tag was added to gene: AKR1D1.
Mendeliome v1.335 AGXT Zornitza Stark Tag treatable tag was added to gene: AGXT.
Tag clinical trial tag was added to gene: AGXT.
Mendeliome v1.335 NDNF Elena Savva Phenotypes for gene: NDNF were changed from Congenital hypogonadotropic hypogonadism (CHH) to Hypogonadotropic hypogonadism 25 with anosmia MIM#618841
Mendeliome v1.334 NDNF Elena Savva Classified gene: NDNF as Amber List (moderate evidence)
Mendeliome v1.334 NDNF Elena Savva Gene: ndnf has been classified as Amber List (Moderate Evidence).
Mendeliome v1.333 NDNF Elena Savva reviewed gene: NDNF: Rating: AMBER; Mode of pathogenicity: None; Publications: 31883645; Phenotypes: Hypogonadotropic hypogonadism 25 with anosmia MIM#618841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.333 GIF Zornitza Stark Marked gene: GIF as ready
Mendeliome v1.333 GIF Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CBLIF.
Mendeliome v1.333 GIF Zornitza Stark Gene: gif has been classified as Green List (High Evidence).
Mendeliome v1.333 GIF Zornitza Stark Tag new gene name tag was added to gene: GIF.
Mendeliome v1.333 PTPA Zornitza Stark Marked gene: PTPA as ready
Mendeliome v1.333 PTPA Zornitza Stark Gene: ptpa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.333 PTPA Zornitza Stark Classified gene: PTPA as Amber List (moderate evidence)
Mendeliome v1.333 PTPA Zornitza Stark Gene: ptpa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.332 PTPA Zornitza Stark gene: PTPA was added
gene: PTPA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPA were set to 36073231
Phenotypes for gene: PTPA were set to Intellectual disability, MONDO: 36073231, PTPA-related
Review for gene: PTPA was set to AMBER
Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp UK or SysID.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

------

Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Mendeliome v1.331 PKHD1 Zornitza Stark Phenotypes for gene: PKHD1 were changed from Polycystic kidney disease 4, with or without hepatic disease, MIM# 263200 to Polycystic kidney disease 4, with or without hepatic disease, MIM# 263200; Nephrocalcinosis, MONDO:0001567, PKHD1-related
Mendeliome v1.330 PKHD1 Zornitza Stark Publications for gene: PKHD1 were set to
Mendeliome v1.329 PKHD1 Zornitza Stark Mode of inheritance for gene: PKHD1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.328 PKHD1 Zornitza Stark edited their review of gene: PKHD1: Added comment: Notę heterozygous carriers reported to have liver cysts and nephrocalcinosis, gene-disease association considered MODERATE by ClinGen.; Changed publications: 28375157, 21945273; Changed phenotypes: Polycystic kidney disease 4, with or without hepatic disease, MIM# 263200, Nephrocalcinosis, MONDO:0001567, PKHD1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.328 PPP2R5C Zornitza Stark Phenotypes for gene: PPP2R5C were changed from macrocephaly; intellectual disability to Neurodevelopmental disorder, PPP2R5C-related (MONDO:070092); macrocephaly; intellectual disability
Mendeliome v1.327 PPP2R5C Zornitza Stark Publications for gene: PPP2R5C were set to
Mendeliome v1.326 PPP2R5C Zornitza Stark Classified gene: PPP2R5C as Green List (high evidence)
Mendeliome v1.326 PPP2R5C Zornitza Stark Gene: ppp2r5c has been classified as Green List (High Evidence).
Mendeliome v1.325 PPP2R5C Teresa Zhao changed review comment from: - ClinVar: two de novo missense variants (p.E177K and p.H188R), one has been reported for intellectual disability

- PMID 25972378: inframe del (T157del) found in a de novo individual with ID, facial asymmetry, conductive HL, overgrowth

- VCGS proband: additional de novo missense variant (p.K299E) found in one individual with syndromic intellectual disability; to: - ClinVar: two de novo missense variants (p.E177K and p.H188R), one has been reported for intellectual disability

- PMID 25972378: inframe del (T157del) found in a de novo individual with ID, facial asymmetry, conductive HL, overgrowth

- VCGS proband: additional de novo missense variant (p.K299E) found in one individual with syndromic intellectual disability
Mendeliome v1.325 PPP2R5C Teresa Zhao reviewed gene: PPP2R5C: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 25972378; Phenotypes: Neurodevelopmental disorder, PPP2R5C-related (MONDO:070092); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.325 MYH8 Ain Roesley reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: 15590965, 17041932, 15282353; Phenotypes: Carney complex variant MIM#60883; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v1.325 NODAL Zornitza Stark Publications for gene: NODAL were set to 9354794; 19064609
Mendeliome v1.324 NODAL Zornitza Stark Classified gene: NODAL as Amber List (moderate evidence)
Mendeliome v1.324 NODAL Zornitza Stark Gene: nodal has been classified as Amber List (Moderate Evidence).
Mendeliome v1.323 NODAL Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad.

The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED.

A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance.

Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987
Mendeliome v1.323 JAG1 Bryony Thompson reviewed gene: JAG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35819173, 30071989, 14993126, 18570795; Phenotypes: thoracic aortic aneurysm MONDO:0005396; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.323 OOEP Bryony Thompson Phenotypes for gene: OOEP were changed from Multi locus imprinting disturbance in offspring to Multi locus imprinting disturbance in offspring; female infertility due to oocyte meiotic arrest MONDO:0044626
Mendeliome v1.322 OOEP Bryony Thompson Publications for gene: OOEP were set to 29574422
Mendeliome v1.321 OOEP Bryony Thompson Classified gene: OOEP as Amber List (moderate evidence)
Mendeliome v1.321 OOEP Bryony Thompson Gene: ooep has been classified as Amber List (Moderate Evidence).
Mendeliome v1.320 OOEP Bryony Thompson reviewed gene: OOEP: Rating: AMBER; Mode of pathogenicity: None; Publications: 35946397, 18804437; Phenotypes: female infertility due to oocyte meiotic arrest MONDO:0044626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.320 UFSP2 Zornitza Stark Phenotypes for gene: UFSP2 were changed from Neurodevelopmental disorder; Hip dysplasia, Beukes type, MIM#142669; Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974 to Developmental and epileptic encephalopathy 106, MIM# 620028; Hip dysplasia, Beukes type, MIM#142669; Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974
Mendeliome v1.319 UFSP2 Zornitza Stark edited their review of gene: UFSP2: Changed phenotypes: Developmental and epileptic encephalopathy 106, MIM# 620028, Hip dysplasia, Beukes type, MIM#142669, Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974
Mendeliome v1.319 TRAPPC10 Zornitza Stark Phenotypes for gene: TRAPPC10 were changed from neurodevelopmental disorder (MONDO:0700092), TRAPPC10-related to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, MIM# 620027
Mendeliome v1.318 TRAPPC10 Zornitza Stark reviewed gene: TRAPPC10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, short stature, and speech delay, MIM# 620027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.318 UBAP2L Zornitza Stark changed review comment from: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).
Sources: Literature; to: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in 11 individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).
Sources: Literature
Mendeliome v1.318 UBAP2L Zornitza Stark Marked gene: UBAP2L as ready
Mendeliome v1.318 UBAP2L Zornitza Stark Gene: ubap2l has been classified as Green List (High Evidence).
Mendeliome v1.318 UBAP2L Zornitza Stark Classified gene: UBAP2L as Green List (high evidence)
Mendeliome v1.318 UBAP2L Zornitza Stark Gene: ubap2l has been classified as Green List (High Evidence).
Mendeliome v1.317 UBAP2L Zornitza Stark gene: UBAP2L was added
gene: UBAP2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related
Review for gene: UBAP2L was set to GREEN
Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).
Sources: Literature
Mendeliome v1.316 ALDH1A2 Zornitza Stark Phenotypes for gene: ALDH1A2 were changed from congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; dysmorphic features to Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025
Mendeliome v1.315 ALDH1A2 Zornitza Stark reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.315 CHKA Zornitza Stark Phenotypes for gene: CHKA were changed from Neurodevelopmental disorder, MONDO:0700092; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature to Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, MIM#620023
Mendeliome v1.314 CHKA Zornitza Stark reviewed gene: CHKA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, MIM#620023; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.314 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Mendeliome v1.314 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Red List (Low Evidence).
Mendeliome v1.314 SLC31A1 Zornitza Stark Classified gene: SLC31A1 as Red List (low evidence)
Mendeliome v1.314 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Red List (Low Evidence).
Mendeliome v1.313 PPFIBP1 Zornitza Stark Phenotypes for gene: PPFIBP1 were changed from Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, MIM# 620024
Mendeliome v1.312 PPFIBP1 Zornitza Stark edited their review of gene: PPFIBP1: Changed publications: 35830857
Mendeliome v1.312 PPFIBP1 Zornitza Stark edited their review of gene: PPFIBP1: Changed phenotypes: Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, MIM# 620024
Mendeliome v1.312 PDZD8 Zornitza Stark Marked gene: PDZD8 as ready
Mendeliome v1.312 PDZD8 Zornitza Stark Gene: pdzd8 has been classified as Green List (High Evidence).
Mendeliome v1.312 PDZD8 Zornitza Stark Classified gene: PDZD8 as Green List (high evidence)
Mendeliome v1.312 PDZD8 Zornitza Stark Gene: pdzd8 has been classified as Green List (High Evidence).
Mendeliome v1.311 PDZD8 Zornitza Stark gene: PDZD8 was added
gene: PDZD8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDZD8 were set to 35227461
Phenotypes for gene: PDZD8 were set to Intellectual developmental disorder with autism and dysmorphic facies, MIM# 620021
Review for gene: PDZD8 was set to GREEN
Added comment: Four individuals from two unrelated families, Drosophila and mouse models support gene-disease association.
Sources: Literature
Mendeliome v1.310 SLC31A1 Daniel Flanagan gene: SLC31A1 was added
gene: SLC31A1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to PMID: 35913762
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092)
Review for gene: SLC31A1 was set to RED
Added comment: SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert list
Mendeliome v1.310 HNRNPH1 Zornitza Stark Phenotypes for gene: HNRNPH1 were changed from HNRNPH1‐related syndromic intellectual disability to HNRNPH1‐related syndromic intellectual disability; early onset high myopia, MONDO:0001384
Mendeliome v1.309 HNRNPH1 Zornitza Stark Publications for gene: HNRNPH1 were set to 32335897; 29938792
Mendeliome v1.308 TMEM163 Zornitza Stark Marked gene: TMEM163 as ready
Mendeliome v1.308 TMEM163 Zornitza Stark Gene: tmem163 has been classified as Green List (High Evidence).
Mendeliome v1.308 TMEM163 Zornitza Stark Phenotypes for gene: TMEM163 were changed from Hypomyelinating leukodystrophy to Hypomyelinating leukodystrophy, MONDO:0019046
Mendeliome v1.307 TMEM163 Zornitza Stark Classified gene: TMEM163 as Green List (high evidence)
Mendeliome v1.307 TMEM163 Zornitza Stark Gene: tmem163 has been classified as Green List (High Evidence).
Mendeliome v1.306 NBAS Zornitza Stark Phenotypes for gene: NBAS were changed from Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800; Infantile liver failure syndrome 2, MIM# 616483 to Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800; Infantile liver failure syndrome 2, MIM# 616483; Haemophagocytic lymphohistiocytosis (HLH), MONDO:0015541
Mendeliome v1.305 NBAS Zornitza Stark Publications for gene: NBAS were set to 31761904
Mendeliome v1.304 NBAS Zornitza Stark edited their review of gene: NBAS: Added comment: PMID 35902954 - Biallelic NBAS variants identifed in three HLH patients who harbored no pathogenic variants in any of the known HLH genes. Functionally, impaired NK-cell cytotoxicity and degranulation were revealed in both NBAS biallelic variant patients and in an NBAS-defcient NK-cell line. Knockdown of NBAS in an NK-cell line (IMC-1) using short hairpin RNA (shRNA) resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus.; Changed publications: 31761904, 35902954; Changed phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800, Infantile liver failure syndrome 2, MIM# 616483, Haemophagocytic lymphohistiocytosis (HLH), MONDO:0015541
Mendeliome v1.304 TYMS Zornitza Stark Marked gene: TYMS as ready
Mendeliome v1.304 TYMS Zornitza Stark Gene: tyms has been classified as Amber List (Moderate Evidence).
Mendeliome v1.304 TYMS Zornitza Stark Classified gene: TYMS as Amber List (moderate evidence)
Mendeliome v1.304 TYMS Zornitza Stark Gene: tyms has been classified as Amber List (Moderate Evidence).
Mendeliome v1.303 TYMS Zornitza Stark reviewed gene: TYMS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskeratosis congenita MONDO:0015780; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.303 COX11 Zornitza Stark Marked gene: COX11 as ready
Mendeliome v1.303 COX11 Zornitza Stark Gene: cox11 has been classified as Green List (High Evidence).
Mendeliome v1.303 COX11 Zornitza Stark Classified gene: COX11 as Green List (high evidence)
Mendeliome v1.303 COX11 Zornitza Stark Gene: cox11 has been classified as Green List (High Evidence).
Mendeliome v1.302 COX11 Zornitza Stark gene: COX11 was added
gene: COX11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551
Phenotypes for gene: COX11 were set to Mitochondrial disease (MONDO:0044970), COX11-related
Review for gene: COX11 was set to GREEN
Added comment: PMID: 36030551
- Biallelic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated consanguineous families, one with homozygous missense variant, another with homozygous frameshift variant.
- Functional studies supported pathogenicity of the missense variant, and showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10.
- RNA studies suggested the mutant transcript with p.(Val12Glyfs*21) is not degraded by nonsense mediated decay.
Sources: Literature
Mendeliome v1.301 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048
Mendeliome v1.300 TMEM147 Zornitza Stark Marked gene: TMEM147 as ready
Mendeliome v1.300 TMEM147 Zornitza Stark Gene: tmem147 has been classified as Green List (High Evidence).
Mendeliome v1.300 TMEM147 Zornitza Stark Classified gene: TMEM147 as Green List (high evidence)
Mendeliome v1.300 TMEM147 Zornitza Stark Gene: tmem147 has been classified as Green List (High Evidence).
Mendeliome v1.299 SAT1 Zornitza Stark Phenotypes for gene: SAT1 were changed from to Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Keratosis follicularis spinulosa decalvans
Mendeliome v1.298 SAT1 Zornitza Stark Publications for gene: SAT1 were set to
Mendeliome v1.297 SAT1 Zornitza Stark Mode of inheritance for gene: SAT1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.296 SAT1 Zornitza Stark Classified gene: SAT1 as Amber List (moderate evidence)
Mendeliome v1.296 SAT1 Zornitza Stark Gene: sat1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.295 CEP104 Zornitza Stark Phenotypes for gene: CEP104 were changed from Joubert syndrome 25, MIM# 616781; MONDO:0014770 to Joubert syndrome 25, MIM# 616781; MONDO:0014770; Neurodevelopmental disorder; MONDO:0014770, CEP104-related
Mendeliome v1.294 CEP104 Zornitza Stark Publications for gene: CEP104 were set to 26477546
Mendeliome v1.293 GATA1 Zornitza Stark Phenotypes for gene: GATA1 were changed from Thrombocytopaenia, X-linked, with or without dyserythropoietic anaemia, MIM# 300367; Haemolytic anaemia due to elevated adenosine deaminase, MIM# 301083; Anemia, X-linked, with/without neutropenia and/or platelet abnormalities, MIM# 300835 to Thrombocytopaenia, X-linked, with or without dyserythropoietic anaemia, MIM# 300367; Haemolytic anaemia due to elevated adenosine deaminase, MIM# 301083; Anemia, X-linked, with/without neutropenia and/or platelet abnormalities, MIM# 300835; Diamond-Blackfan anemia (MONDO:0015253)
Mendeliome v1.292 GATA1 Zornitza Stark Publications for gene: GATA1 were set to
Mendeliome v1.291 GATA1 Zornitza Stark edited their review of gene: GATA1: Added comment: PMID 36029112: De novo GATA1 initiation codon variant (c.3G>A) identified in a Diamond-Blackfan Anaemia patient. Functional evidence showed that the variant does not affect the GATA1 mRNA but brings about a shorter GATA1 isoform (GATA1s) and reduced full-length functional GATA1 protein (GATA1fl), thereby contributing to an erythropoietic defect. Four other GATA1 variants (c.2T>C, c.220G>C, c.220delG, c.220+2T>C) found in eight families have been described as DBA phenotype.; Changed publications: 36029112; Changed phenotypes: Thrombocytopaenia, X-linked, with or without dyserythropoietic anaemia, MIM# 300367, Haemolytic anaemia due to elevated adenosine deaminase, MIM# 301083, Anemia, X-linked, with/without neutropenia and/or platelet abnormalities, MIM# 300835, Diamond-Blackfan anemia (MONDO:0015253)
Mendeliome v1.291 LGI3 Zornitza Stark Marked gene: LGI3 as ready
Mendeliome v1.291 LGI3 Zornitza Stark Gene: lgi3 has been classified as Green List (High Evidence).
Mendeliome v1.291 LGI3 Zornitza Stark Phenotypes for gene: LGI3 were changed from Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi to Neurodevelopmental disorder, MONDO:0700092, LGI3-related; Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi
Mendeliome v1.290 LGI3 Zornitza Stark Classified gene: LGI3 as Green List (high evidence)
Mendeliome v1.290 LGI3 Zornitza Stark Gene: lgi3 has been classified as Green List (High Evidence).
Mendeliome v1.289 LGI3 Zornitza Stark reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, LGI3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.289 TMEM147 Naomi Baker gene: TMEM147 was added
gene: TMEM147 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM147 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM147 were set to PMID: 36044892
Phenotypes for gene: TMEM147 were set to Neurodevelopmental disorder (MONDO:0700092), TMEM147-related
Review for gene: TMEM147 was set to GREEN
Added comment: PMID: 36044892; Twelve different variants reported in 23 affected individuals from 15 unrelated families with biallelic variants. All individuals had global developmental delay and intellectual disability. Consistent facial dysmorphisms included coarse facies, prominent forehead, board depressed nasal root, tented mouth, long smooth philtrum, and low-set ears. In vitro studies of missense variants demonstrated accelerated protein degradation via the autophagy-lysosomal pathway, while analysis of primary fibroblasts and granulocytes provided functional evidence of ER and nuclear envelope dysfunction.
Sources: Literature
Mendeliome v1.289 SARS Ee Ming Wong reviewed gene: SARS: Rating: RED; Mode of pathogenicity: Other; Publications: 36041817; Phenotypes: neurodevelopmental disorder, MONDO#070009, SARS1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.289 ADAMTS15 Zornitza Stark Marked gene: ADAMTS15 as ready
Mendeliome v1.289 ADAMTS15 Zornitza Stark Gene: adamts15 has been classified as Green List (High Evidence).
Mendeliome v1.289 ADAMTS15 Zornitza Stark Classified gene: ADAMTS15 as Green List (high evidence)
Mendeliome v1.289 ADAMTS15 Zornitza Stark Gene: adamts15 has been classified as Green List (High Evidence).
Mendeliome v1.288 CAPRIN1 Zornitza Stark Marked gene: CAPRIN1 as ready
Mendeliome v1.288 CAPRIN1 Zornitza Stark Gene: caprin1 has been classified as Green List (High Evidence).
Mendeliome v1.288 CAPRIN1 Zornitza Stark Classified gene: CAPRIN1 as Green List (high evidence)
Mendeliome v1.288 CAPRIN1 Zornitza Stark Gene: caprin1 has been classified as Green List (High Evidence).
Mendeliome v1.287 CBLB Alison Yeung Marked gene: CBLB as ready
Mendeliome v1.287 CBLB Alison Yeung Gene: cblb has been classified as Green List (High Evidence).
Mendeliome v1.287 CBLB Alison Yeung Classified gene: CBLB as Green List (high evidence)
Mendeliome v1.287 CBLB Alison Yeung Gene: cblb has been classified as Green List (High Evidence).
Mendeliome v1.286 CBLB Alison Yeung gene: CBLB was added
gene: CBLB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBLB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBLB were set to 36006710
Phenotypes for gene: CBLB were set to Autoimmune disease, MONDO:0007179
Review for gene: CBLB was set to GREEN
Added comment: Distinct homozygous mutations in CBLB were identified in three unrelated children with early onset autoimmunity. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyper-proliferation in response to antigen receptor cross-linking.
Sources: Literature
Mendeliome v1.285 TYMS Lucy Spencer gene: TYMS was added
gene: TYMS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TYMS was set to Other
Publications for gene: TYMS were set to 35931051
Phenotypes for gene: TYMS were set to Dyskeratosis congenita MONDO:0015780
Review for gene: TYMS was set to RED
Added comment: 8 families with dyskeratosis congenita and heterozygous variants in TYMS. 4 PTCs, 2 missense and 1 splice (2 families had the same frameshift). However in all families 1 unaffected parent was also heterozygous for the same TYSM variant.

The other parent in 3 of these families was then shown to carry a heterozygous variant in ENOSF1 which each affected child was also heterozygous for. ENOSF1 has been shown to modify TYMS expression at the RNA level by acting as an antisense molecule to TYMS. ENOSF1 partially overlaps TYMS on chromosome 18 and is transcribed in the opposite direction to TYMS. This paper is suggesting digenic inheritance.

The TYMS wild type parent from another family was seen to have a TYMSOS variant which was also observed along with the TYMS variant in their 2 affected children.

Immunoblotting showed a stark reduction in TYMS protein level in the cells of affected probands when compared to the parent carrier, wild-type parent, and the controls.

Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1.
Sources: Literature
Mendeliome v1.285 CEP104 Belinda Chong reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 34196201, 35359234; Phenotypes: CEP104 Neurodevelopmental disorder, MONDO:0014770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.285 LGI3 Melanie Marty edited their review of gene: LGI3: Changed phenotypes: Global developmental delay, Intellectual disability, Distal deformities, Diminished reflexes, Facial myokymia, Hyporeflexia/areflexia
Mendeliome v1.285 HNRNPH1 Hazel Phillimore changed review comment from: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2).
In gnomAD, there are very few LOF variants. (LOF shows pLI = 1).
The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma.; to: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2.
In gnomAD, there are very few LOF variants. (LOF shows pLI = 1).
The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma.
Mendeliome v1.285 HNRNPH1 Hazel Phillimore reviewed gene: HNRNPH1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35989590; Phenotypes: early onset high myopia, blindness; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.285 TMEM163 Teresa Zhao changed review comment from: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures and two have ID.
Sources: Literature; to: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures.
Sources: Literature
Mendeliome v1.285 MET Zornitza Stark Phenotypes for gene: MET were changed from Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884 to Arthrogryposis, distal, type 11 (MIM#620019), AD; Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884
Mendeliome v1.284 MET Zornitza Stark Publications for gene: MET were set to
Mendeliome v1.283 MET Zornitza Stark changed review comment from: PMID 30777867:
Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.; to: PMID 30777867:
Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.

AMBER for this association
Mendeliome v1.283 MET Zornitza Stark edited their review of gene: MET: Added comment: PMID 30777867:
Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.; Changed publications: 30777867
Mendeliome v1.283 TMEM163 Teresa Zhao gene: TMEM163 was added
gene: TMEM163 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM163 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM163 were set to PMID: 35953447
Phenotypes for gene: TMEM163 were set to Hypomyelinating leukodystrophy
Review for gene: TMEM163 was set to GREEN
Added comment: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures and two have ID.
Sources: Literature
Mendeliome v1.283 LGI3 Melanie Marty gene: LGI3 was added
gene: LGI3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to PMID: 35948005
Phenotypes for gene: LGI3 were set to Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi
Review for gene: LGI3 was set to GREEN
Added comment: Sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3.
Lgi3-null mice showed reduced and mis-local-ized Kv1 channel complexes in myelinated peripheral axons.
Sources: Literature
Mendeliome v1.283 NOTCH1 Zornitza Stark Phenotypes for gene: NOTCH1 were changed from Adams-Oliver syndrome 5 (MIM#616028) to Adams-Oliver syndrome 5 (MIM#616028); Genetic cerebral small vessel disease (MONDO:0018787), NOTCH1-related
Mendeliome v1.282 NOTCH1 Zornitza Stark Publications for gene: NOTCH1 were set to 25963545; 25132448
Mendeliome v1.281 NOTCH1 Zornitza Stark Mode of pathogenicity for gene: NOTCH1 was changed from to Other
Mendeliome v1.280 BUD13 Alison Yeung Marked gene: BUD13 as ready
Mendeliome v1.280 BUD13 Alison Yeung Gene: bud13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.280 BUD13 Alison Yeung Classified gene: BUD13 as Amber List (moderate evidence)
Mendeliome v1.280 BUD13 Alison Yeung Gene: bud13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.279 BUD13 Alison Yeung gene: BUD13 was added
gene: BUD13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BUD13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUD13 were set to 35670808
Phenotypes for gene: BUD13 were set to Lipodystrophy, MONDO:0006573
Review for gene: BUD13 was set to AMBER
Added comment: 5 individuals with a lipodystrophy phenotype with a typical facial appearance, corneal clouding, achalasia, progressive hearing loss, and variable severity. Although 3 individuals showed stunted growth, intellectual disability, and died within the first decade of life, 2 are adults with normal intellectual development. All individuals harbored an identical homozygous nonsense variant affecting the retention and splicing complex component BUD13. Individuals from only two Algerian families.
Sources: Literature
Mendeliome v1.278 GRIN2A Zornitza Stark Publications for gene: GRIN2A were set to 30544257
Mendeliome v1.277 GRIN2A Zornitza Stark Mode of inheritance for gene: GRIN2A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.276 SAT1 Ee Ming Wong reviewed gene: SAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35977808; Phenotypes: Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v1.276 NOTCH1 Chern Lim changed review comment from: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Missense and small inframe insertion variants in the negative regulatory region.; to: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Other clinical features include intellectual disability, spasticity and etc. Childhood onset in most individuals however 15y and 40y reported in two individuals.
- Missense and small inframe insertion variants in the negative regulatory region.
Mendeliome v1.276 ADAMTS15 Naomi Baker changed review comment from: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5).
Sources: Literature; to: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: contractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5).
Sources: Literature
Mendeliome v1.276 ADAMTS15 Naomi Baker gene: ADAMTS15 was added
gene: ADAMTS15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS15 were set to PMID: 35962790
Phenotypes for gene: ADAMTS15 were set to Arthrogryposis (MONDO:0008779), ADMATS15-related
Review for gene: ADAMTS15 was set to GREEN
Added comment: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5).
Sources: Literature
Mendeliome v1.276 NOTCH1 Chern Lim edited their review of gene: NOTCH1: Changed phenotypes: Genetic cerebral small vessel disease (MONDO:0018787), NOTCH1-related
Mendeliome v1.276 CAPRIN1 Paul De Fazio gene: CAPRIN1 was added
gene: CAPRIN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPRIN1 were set to 35979925
Phenotypes for gene: CAPRIN1 were set to Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092
Review for gene: CAPRIN1 was set to GREEN
gene: CAPRIN1 was marked as current diagnostic
Added comment: 12 individuals reported with ID and language impairment. Other features included seizures (4 individuals), hands and feet malformations (5 individuals), breathing problems (6 individuals), ocular problems (4 individuals) and hearing problems (3 individuals).

All of the variants were nonsense (NMD-predicted) or splicing variants. 10 were de novo, 1 was inherited from an affected father. Functional studies supported pathogenicity.
Sources: Literature
Mendeliome v1.276 LHX8 Alison Yeung gene: LHX8 was added
gene: LHX8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LHX8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LHX8 were set to 36029299
Phenotypes for gene: LHX8 were set to Inherited premature ovarian failure, MONDO:0019852, LHX8-related
Review for gene: LHX8 was set to GREEN
Added comment: Heterozygous LOF variants identified in 6 families with premature ovarian failure due to oocyte maturation arrest.
Sources: Literature
Mendeliome v1.275 NOTCH1 Chern Lim reviewed gene: NOTCH1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 35947102; Phenotypes: leukoencephalopathy and calcifications; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.275 GRIN2A Teresa Zhao reviewed gene: GRIN2A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35983985; Phenotypes: Epilepsy, focal, with speech disorder and with or without impaired intellectual development (MIM#245570); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.275 LEF1 Zornitza Stark Phenotypes for gene: LEF1 were changed from Ectodermal dysplasia, no OMIM# yet to Syndromic disease, MONDO:0002254, LEF1-related
Mendeliome v1.274 LEF1 Zornitza Stark Publications for gene: LEF1 were set to 32022899
Mendeliome v1.273 LEF1 Zornitza Stark Mode of inheritance for gene: LEF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.272 LEF1 Zornitza Stark Classified gene: LEF1 as Green List (high evidence)
Mendeliome v1.272 LEF1 Zornitza Stark Gene: lef1 has been classified as Green List (High Evidence).
Mendeliome v1.271 LEF1 Zornitza Stark edited their review of gene: LEF1: Added comment: Monoallelic variants in LEF1 reported in 11 affected individuals from 4 unrelated families, and a biallelic variant reported in an affected individual from a consanguineous family. The phenotypic spectrum included various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Haploinsufficiency or loss of DNA binding postulated to be responsible for a mild to moderate phenotype, whereas loss of β-catenin binding caused by biallelic variants postulated to be associated with a severe phenotype.; Changed rating: GREEN; Changed publications: 32022899, 35583550; Changed phenotypes: Syndromic disease, MONDO:0002254, LEF1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.271 REEP1 Zornitza Stark Phenotypes for gene: REEP1 were changed from Neuronopathy, distal hereditary motor, type VB MIM#614751; Spastic paraplegia 31, autosomal dominant MIM#610250; Charcot-Marie-Tooth; severe congenital distal SMA with diaphragmatic paralysis; congenital axonal neuropathy and diaphragmatic palsy to Spinal muscular atrophy, distal, autosomal recessive, 6, MIM#620011; Neuronopathy, distal hereditary motor, type VB MIM#614751; Spastic paraplegia 31, autosomal dominant MIM#610250
Mendeliome v1.270 REEP1 Zornitza Stark reviewed gene: REEP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy, distal, autosomal recessive, 6, MIM#620011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.270 CCDC82 Zornitza Stark Marked gene: CCDC82 as ready
Mendeliome v1.270 CCDC82 Zornitza Stark Gene: ccdc82 has been classified as Green List (High Evidence).
Mendeliome v1.270 CCDC82 Zornitza Stark Phenotypes for gene: CCDC82 were changed from Intellectual disability and spastic paraparesis, no OMIM # to Neurodevelopmental disorder, MONDO:0700092, CCDC82-related
Mendeliome v1.269 CCDC82 Zornitza Stark Publications for gene: CCDC82 were set to PMID: 35373332, 35118659, 27457812
Mendeliome v1.268 CCDC82 Zornitza Stark reviewed gene: CCDC82: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CCDC82-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.268 NPNT Zornitza Stark Marked gene: NPNT as ready
Mendeliome v1.268 NPNT Zornitza Stark Gene: npnt has been classified as Green List (High Evidence).
Mendeliome v1.268 NPNT Zornitza Stark Phenotypes for gene: NPNT were changed from Renal agenesis, no OMIM # to Renal agenesis, MONDO:0018470, NPNT-related
Mendeliome v1.267 NPNT Zornitza Stark Publications for gene: NPNT were set to PMID: 35246978, 34049960, 17537792
Mendeliome v1.266 NPNT Zornitza Stark reviewed gene: NPNT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal agenesis, MONDO:0018470, NPNT-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.266 KIF5B Zornitza Stark Phenotypes for gene: KIF5B were changed from Skeletal dysplasia, MONDO:0018230 to Skeletal dysplasia, MONDO:0018230, KIF5B-related; Kyphomelic dysplasia
Mendeliome v1.265 KIF5B Zornitza Stark Marked gene: KIF5B as ready
Mendeliome v1.265 KIF5B Zornitza Stark Gene: kif5b has been classified as Green List (High Evidence).
Mendeliome v1.265 KIF5B Zornitza Stark Phenotypes for gene: KIF5B were changed from Kyphomelic dysplasia, no OMIM # to Skeletal dysplasia, MONDO:0018230
Mendeliome v1.264 KIF5B Zornitza Stark reviewed gene: KIF5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia, MONDO:0018230; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.264 COL9A3 Zornitza Stark Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome AR; Deafness AD; Peripheral vitreoretinal degeneration and retinal detachment, AD to Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome, type VI, MIM# 620022; Deafness AD; Peripheral vitreoretinal degeneration and retinal detachment, AD
Mendeliome v1.263 COL9A3 Zornitza Stark edited their review of gene: COL9A3: Changed phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969, Stickler syndrome, type VI, MIM# 620022, Deafness
Mendeliome v1.263 LNPK Chirag Patel Classified gene: LNPK as Green List (high evidence)
Mendeliome v1.263 LNPK Chirag Patel Gene: lnpk has been classified as Green List (High Evidence).
Mendeliome v1.262 LNPK Chirag Patel reviewed gene: LNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35599435; Phenotypes: Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, MIM# 618090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.262 CCDC82 Chirag Patel Classified gene: CCDC82 as Green List (high evidence)
Mendeliome v1.262 CCDC82 Chirag Patel Gene: ccdc82 has been classified as Green List (High Evidence).
Mendeliome v1.261 CCDC82 Chirag Patel gene: CCDC82 was added
gene: CCDC82 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to PMID: 35373332, 35118659, 27457812
Phenotypes for gene: CCDC82 were set to Intellectual disability and spastic paraparesis, no OMIM #
Review for gene: CCDC82 was set to GREEN
Added comment: 4 consanguineous families with 9 affected individuals with developmental delay/intellectual disability, and 2 families had spasticity and 1 had epilepsy. WES identified 3 homozgyous truncating variants, segregating with disease and parents as carriers. No functional studies.
Sources: Literature
Mendeliome v1.260 NPNT Chirag Patel Classified gene: NPNT as Green List (high evidence)
Mendeliome v1.260 NPNT Chirag Patel Gene: npnt has been classified as Green List (High Evidence).
Mendeliome v1.260 NPNT Chirag Patel Classified gene: NPNT as Green List (high evidence)
Mendeliome v1.260 NPNT Chirag Patel Gene: npnt has been classified as Green List (High Evidence).
Mendeliome v1.259 NPNT Chirag Patel gene: NPNT was added
gene: NPNT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPNT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPNT were set to PMID: 35246978, 34049960, 17537792
Phenotypes for gene: NPNT were set to Renal agenesis, no OMIM #
Review for gene: NPNT was set to GREEN
Added comment: 3 consanguineous families with multiple affecteds with bilateral renal agenesis. Whole-exome sequencing (WES)-based homozygosity mapping identified 2 homozygous truncating variants. Reverse transcription polymerase chain reaction data showing complete nonsense-mediated decay of the NPNT transcript. Loss of nephronectin (NPNT) is known to lead to failure of metanephric kidney development with resulting renal agenesis in murine models.
Sources: Literature
Mendeliome v1.258 KIF5B Chirag Patel Classified gene: KIF5B as Green List (high evidence)
Mendeliome v1.258 KIF5B Chirag Patel Gene: kif5b has been classified as Green List (High Evidence).
Mendeliome v1.258 KIF5B Chirag Patel Classified gene: KIF5B as Green List (high evidence)
Mendeliome v1.258 KIF5B Chirag Patel Gene: kif5b has been classified as Green List (High Evidence).
Mendeliome v1.257 KIF5B Chirag Patel gene: KIF5B was added
gene: KIF5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5B were set to PMID: 35342932
Phenotypes for gene: KIF5B were set to Kyphomelic dysplasia, no OMIM #
Review for gene: KIF5B was set to GREEN
Added comment: 4 individuals with Kyphomelic dysplasia (severe bowing of the limbs, sharp angulation of the femora and humeri, short stature, narrow thorax, distinctive facial features, and neonatal respiratory distress. WES found de novo heterozygous missense variants in KIF5B encoding kinesin-1 heavy chain. All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. No functional studies of variants. Previously 2 animal model experiments showed that loss of function of KIF5B can cause kyphomelic dysplasia. First, chondrocyte-specific knockout of Kif5b in mice was shown to produce a disorganized growth plate, leading to bone deformity. Second, double mutants disrupting the two zebrafish kif5b caused abnormal skeletal morphogenesis and the curvature of Meckel's and ceratohyal cartilages.
Sources: Literature
Mendeliome v1.256 FBXW7 Zornitza Stark Phenotypes for gene: FBXW7 were changed from neurodevelopmental disorder MONDO:0700092; FBXW7-related neurodevelopmental syndrome; Wilms tumor MONDO:0006058 to Developmental delay, hypotonia, and impaired language, MIM# 620012; Wilms tumour predisposition
Mendeliome v1.255 FBXW7 Zornitza Stark edited their review of gene: FBXW7: Changed phenotypes: Developmental delay, hypotonia, and impaired language, MIM# 620012, Wilms tumour predisposition
Mendeliome v1.255 MDFIC Zornitza Stark Phenotypes for gene: MDFIC were changed from Hydrops fetalis MONDO:0015193 to Lymphatic malformation 12, MIM# 620014
Mendeliome v1.254 MDFIC Zornitza Stark reviewed gene: MDFIC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lymphatic malformation 12, MIM# 620014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.254 ACADS Zornitza Stark Classified gene: ACADS as Amber List (moderate evidence)
Mendeliome v1.254 ACADS Zornitza Stark Gene: acads has been classified as Amber List (Moderate Evidence).
Mendeliome v1.253 ACADS Zornitza Stark changed review comment from: Definitive by ClinGen.; to: Definitive by ClinGen. However, largely just causes a biochemical abnormality, and association with clinical disease is debated.
Mendeliome v1.253 ACADS Zornitza Stark edited their review of gene: ACADS: Changed rating: AMBER
Mendeliome v1.253 FOCAD Zornitza Stark Marked gene: FOCAD as ready
Mendeliome v1.253 FOCAD Zornitza Stark Gene: focad has been classified as Green List (High Evidence).
Mendeliome v1.253 FOCAD Zornitza Stark Classified gene: FOCAD as Green List (high evidence)
Mendeliome v1.253 FOCAD Zornitza Stark Gene: focad has been classified as Green List (High Evidence).
Mendeliome v1.252 FOCAD Zornitza Stark gene: FOCAD was added
gene: FOCAD was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FOCAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOCAD were set to 35864190
Phenotypes for gene: FOCAD were set to Liver disease, severe congenital, MIM# 619991
Review for gene: FOCAD was set to GREEN
Added comment: Moreno Traspas et al 2022 reported 14 children from ten unrelated families with syndromic form of pediatric liver cirrhosis. Genome/exome sequencing analysis reveled biallelic variants in the FOCAD gene. Most of the mutations were nonsense, frameshift, or splice site alterations, predicted to result in a loss of function, but there were also 3 missense variants at highly conserved residues. Western blot analysis of dermal fibroblasts derived from 2 patients showed near absent FOCAD expression in cellular extracts. There were also decreased levels of the SKIC2 protein, suggesting that FOCAD may contribute to the stability of RNA helicase (OMIM: 619991).
Sources: Expert Review
Mendeliome v1.251 TAF4 Zornitza Stark Phenotypes for gene: TAF4 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, TAF4-related
Mendeliome v1.250 TAF4 Zornitza Stark Publications for gene: TAF4 were set to 33875846; 28191890
Mendeliome v1.249 TAF4 Zornitza Stark Classified gene: TAF4 as Green List (high evidence)
Mendeliome v1.249 TAF4 Zornitza Stark Gene: taf4 has been classified as Green List (High Evidence).
Mendeliome v1.248 TAF4 Zornitza Stark edited their review of gene: TAF4: Changed rating: GREEN; Changed publications: 33875846, 28191890, 35904126; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TAF4-related
Mendeliome v1.248 ZMYND8 Zornitza Stark Marked gene: ZMYND8 as ready
Mendeliome v1.248 ZMYND8 Zornitza Stark Gene: zmynd8 has been classified as Green List (High Evidence).
Mendeliome v1.248 ZMYND8 Zornitza Stark Classified gene: ZMYND8 as Green List (high evidence)
Mendeliome v1.248 ZMYND8 Zornitza Stark Gene: zmynd8 has been classified as Green List (High Evidence).
Mendeliome v1.247 ZMYND8 Zornitza Stark gene: ZMYND8 was added
gene: ZMYND8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Expert Review
Mendeliome v1.246 TRAC Zornitza Stark Tag founder tag was added to gene: TRAC.
Mendeliome v1.246 TRAC Seb Lunke Classified gene: TRAC as Amber List (moderate evidence)
Mendeliome v1.246 TRAC Seb Lunke Added comment: Comment on list classification: Single variant reported to date in 6 patients; 2 unrelated children from consanguineous families of Pakistani descent (PMID: 21206088); 1 non-consanguineous family from North-west India (PMID: 33909184) and 1 consanguineous parents of East Indian (https://lymphosign.com/doi/10.14785/lymphosign-2022-0001) Also note annotation issues in certain variant curation and annotation tools.
Mendeliome v1.246 TRAC Seb Lunke Gene: trac has been classified as Amber List (Moderate Evidence).
Mendeliome v1.245 PAX5 Zornitza Stark Phenotypes for gene: PAX5 were changed from Neurodevelopmental disorder MONDO:0700092, PAX5-related to Neurodevelopmental disorder MONDO:0700092, PAX5-related; Hypogammaglobulinaemia
Mendeliome v1.244 PAX5 Zornitza Stark Publications for gene: PAX5 were set to 35094443; 31452935; 28263302; 25418537; 8001127; 27626380
Mendeliome v1.243 PAX5 Zornitza Stark Mode of inheritance for gene: PAX5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.242 PAX5 Zornitza Stark reviewed gene: PAX5: Rating: AMBER; Mode of pathogenicity: None; Publications: 35947077; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PAX5-related, Hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.242 PRIM1 Zornitza Stark Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, MIM# 620005
Mendeliome v1.241 PRIM1 Zornitza Stark edited their review of gene: PRIM1: Changed phenotypes: Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, MIM# 620005
Mendeliome v1.241 SMG9 Zornitza Stark Phenotypes for gene: SMG9 were changed from Heart and brain malformation syndrome, MIM# 616920 to Heart and brain malformation syndrome, MIM# 616920; Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Mendeliome v1.240 SMG9 Zornitza Stark Publications for gene: SMG9 were set to 27018474; 31390136
Mendeliome v1.239 SMG9 Zornitza Stark edited their review of gene: SMG9: Added comment: PMID 35087184: 5 individuals from 3 unrelated Finnish families reported with same homozygous missense variant (founder effect) and predominantly neurological phenotype. Uncertain if this is a distinct disorder or part of a spectrum with the previously reported cases.; Changed publications: 27018474, 31390136, 35087184; Changed phenotypes: Heart and brain malformation syndrome, MIM# 616920, Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Mendeliome v1.239 THUMPD1 Zornitza Stark Phenotypes for gene: THUMPD1 were changed from Syndromic disease, MONDO:0002254, THUMPD1-related to Neurodevelopmental disorder with speech delay and variable ocular anomalies, MIM# 619989
Mendeliome v1.238 THUMPD1 Zornitza Stark reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and variable ocular anomalies, MIM# 619989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.238 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Susceptibility to infection with Staphylococcus aureus; Hereditary predisposition to infections, MONDO:0015979, OTULIN-related to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.237 OTULIN Zornitza Stark edited their review of gene: OTULIN: Changed phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099, Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.237 TAF4 Ee Ming Wong reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846, 28191890, 35904126; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TAF4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.237 SPTBN5 Zornitza Stark Phenotypes for gene: SPTBN5 were changed from Sacral agenesis; congenital anomalies to Neurodevelopmental disorder, MONDO:0700092, SPTBN5-related; Sacral agenesis; congenital anomalies
Mendeliome v1.236 SPTBN5 Zornitza Stark Publications for gene: SPTBN5 were set to 32732226; 28007035
Mendeliome v1.235 SPTBN5 Zornitza Stark Mode of inheritance for gene: SPTBN5 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.234 SPTBN5 Zornitza Stark Classified gene: SPTBN5 as Green List (high evidence)
Mendeliome v1.234 SPTBN5 Zornitza Stark Gene: sptbn5 has been classified as Green List (High Evidence).
Mendeliome v1.233 SPTBN5 Zornitza Stark changed review comment from: Identified as a candidate gene in a sacral agenesis cohort.

PMID 32732226: compound het variants identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis.
Sources: Literature; to: Bi-allelic variants: Identified as a candidate gene in a sacral agenesis cohort.

PMID 32732226: compound het variants identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis.
Sources: Literature
Mendeliome v1.233 SPTBN5 Zornitza Stark edited their review of gene: SPTBN5: Added comment: Monoallelic variants:
- Four probands from unrelated families (1x Pakistani and 3x Italian) with de novo heterozygous SPTBN5 variants
- 3x missense variants and 1x LoF variant were reported
- Phenotypes include intellectual disability (mild to severe), aggressive tendencies and variable features such as craniofacial and physical dysmorphisms, autistic behavior, and gastroesophageal reflux; Changed rating: GREEN; Changed publications: 35782384, 32732226, 28007035; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SPTBN5-related, Sacral agenesis, congenital anomalies; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.233 CPS1 Zornitza Stark Phenotypes for gene: CPS1 were changed from to Carbamoylphosphate synthetase I deficiency MIM#237300
Mendeliome v1.232 CPS1 Zornitza Stark Mode of inheritance for gene: CPS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.231 CPS1 Zornitza Stark reviewed gene: CPS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Pulmonary hypertension, neonatal, susceptibility to} 615371; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.231 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099 to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Susceptibility to infection with Staphylococcus aureus; Hereditary predisposition to infections, MONDO:0015979, OTULIN-related
Mendeliome v1.230 OTULIN Zornitza Stark Publications for gene: OTULIN were set to 27523608; 27559085
Mendeliome v1.229 OTULIN Zornitza Stark Mode of inheritance for gene: OTULIN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.228 OTULIN Zornitza Stark changed review comment from: Autoinflammatory disorder presenting in the newborn period with recurrent fever, erythematous rash with painful nodules, painful joints, diarrhoea and lipodystrophy.; to: Bi-allelic variants: Autoinflammatory disorder presenting in the newborn period with recurrent fever, erythematous rash with painful nodules, painful joints, diarrhoea and lipodystrophy.
Mendeliome v1.228 OTULIN Zornitza Stark edited their review of gene: OTULIN: Added comment: PMID 35587511: Multiple individuals reported with haploinsufficiency of OTULIN and severe staphylococcal disease, with life-threatening skin or pulmonary necrosis. Functional data.; Changed publications: 27523608, 27559085, 35587511; Changed phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099, Susceptibility to infection with Staphylococcus aureus, Hereditary predisposition to infections, MONDO:0015979, OTULIN-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.228 NOX1 Zornitza Stark gene: NOX1 was added
gene: NOX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NOX1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NOX1 were set to 29091079; 32064493
Phenotypes for gene: NOX1 were set to Inflammatory bowel disease, MONDO:0005265, NOX1-related
Review for gene: NOX1 was set to AMBER
Added comment: 8 IBD patients with early onset of IBD with progressive and severe colonic disease, refractory to conventional therapy and functional studies suggesting variant-dependent loss of NOX1-mediated superoxide generation. However, high frequency of nonsynonymous mutations in NOX1 suggests that NOX1 is not a highly penetrant Mendelian disorder and that other genetic modifiers or environmental factors may contribute to disease pathogenesis.

The variant reported in PMID 32064493 is present in 6 hets in gnomad.
Sources: Literature
Mendeliome v1.227 BICD2 Zornitza Stark Phenotypes for gene: BICD2 were changed from Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM# 615290; MONDO:0014121; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, MIM# 618291 to Neurodevelopmental disorder (MONDO#0700092), BICD2-related; Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM# 615290; MONDO:0014121; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, MIM# 618291
Mendeliome v1.226 BICD2 Zornitza Stark Publications for gene: BICD2 were set to 23664116; 23664119; 23664120; 27751653; 28635954; 30054298; 29528393
Mendeliome v1.225 BICD2 Zornitza Stark Mode of inheritance for gene: BICD2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.224 KIF15 Alison Yeung Phenotypes for gene: KIF15 were changed from ?Braddock-Carey syndrome 2 - MIM#619981 to Braddock-Carey syndrome 2 - MIM#619981
Mendeliome v1.223 KIF15 Alison Yeung Marked gene: KIF15 as ready
Mendeliome v1.223 KIF15 Alison Yeung Gene: kif15 has been classified as Red List (Low Evidence).
Mendeliome v1.223 KIF15 Alison Yeung Classified gene: KIF15 as Red List (low evidence)
Mendeliome v1.223 KIF15 Alison Yeung Gene: kif15 has been classified as Red List (Low Evidence).
Mendeliome v1.222 SARS Ain Roesley Publications for gene: SARS were set to 28236339; 34570399
Mendeliome v1.222 SARS Ain Roesley Classified gene: SARS as Green List (high evidence)
Mendeliome v1.222 SARS Ain Roesley Gene: sars has been classified as Green List (High Evidence).
Mendeliome v1.222 SARS Ain Roesley Phenotypes for gene: SARS were changed from Intellectual disability to neurodevelopmental disorder MONDO#070009, SARS1-related
Mendeliome v1.221 PSMC1 Zornitza Stark Marked gene: PSMC1 as ready
Mendeliome v1.221 PSMC1 Zornitza Stark Gene: psmc1 has been classified as Red List (Low Evidence).
Mendeliome v1.221 PSMC1 Zornitza Stark Phenotypes for gene: PSMC1 were changed from spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes to 35861243; spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes
Mendeliome v1.220 SARS Ain Roesley reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: neurodevelopmental disorder MONDO#070009, SARS1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.220 PSMC1 Zornitza Stark Mode of pathogenicity for gene: PSMC1 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Mendeliome v1.219 PSMC1 Zornitza Stark Classified gene: PSMC1 as Red List (low evidence)
Mendeliome v1.219 PSMC1 Zornitza Stark Gene: psmc1 has been classified as Red List (Low Evidence).
Mendeliome v1.218 PSMC1 Zornitza Stark edited their review of gene: PSMC1: Changed phenotypes: Syndromic disease MONDO:0002254, PSMC1-related
Mendeliome v1.218 PSMC1 Zornitza Stark commented on gene: PSMC1: Single family only, homozygous missense variant.
Mendeliome v1.218 PSMC1 Zornitza Stark reviewed gene: PSMC1: Rating: RED; Mode of pathogenicity: None; Publications: 35861243; Phenotypes: Syndromic disease MONDO:0002254, PSMC1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.218 WARS Seb Lunke Publications for gene: WARS were set to PMID: 28369220; 31321409; 31069783.
Mendeliome v1.217 DOHH Zornitza Stark Marked gene: DOHH as ready
Mendeliome v1.217 DOHH Zornitza Stark Gene: dohh has been classified as Green List (High Evidence).
Mendeliome v1.217 WARS Seb Lunke Phenotypes for gene: WARS were changed from Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); distal wasting; distal weakness; length-dependent motor axonal degeneration to Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); Neurodevelopmental disorder (MONDO:0700092), WARS-related
Mendeliome v1.216 DOHH Zornitza Stark Classified gene: DOHH as Green List (high evidence)
Mendeliome v1.216 DOHH Zornitza Stark Gene: dohh has been classified as Green List (High Evidence).
Mendeliome v1.215 WARS Seb Lunke Mode of inheritance for gene: WARS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.214 PPFIBP1 Zornitza Stark Publications for gene: PPFIBP1 were set to https://www.medrxiv.org/content/10.1101/2022.04.04.22273309v1
Mendeliome v1.213 SLITRK2 Zornitza Stark Marked gene: SLITRK2 as ready
Mendeliome v1.213 SLITRK2 Zornitza Stark Gene: slitrk2 has been classified as Green List (High Evidence).
Mendeliome v1.213 BICD2 Lucy Spencer reviewed gene: BICD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35896821; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), BICD2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.213 KIF15 Krithika Murali reviewed gene: KIF15: Rating: AMBER; Mode of pathogenicity: None; Publications: 28150392; Phenotypes: ?Braddock-Carey syndrome 2 - MIM#619981; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.213 WARS Anna Ritchie reviewed gene: WARS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35815345, PMID: 35790048; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), WARS-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.213 SLITRK2 Zornitza Stark Classified gene: SLITRK2 as Green List (high evidence)
Mendeliome v1.213 SLITRK2 Zornitza Stark Gene: slitrk2 has been classified as Green List (High Evidence).
Mendeliome v1.212 KIF15 Krithika Murali Deleted their review
Mendeliome v1.212 PSMC1 Hazel Phillimore gene: PSMC1 was added
gene: PSMC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC1 were set to PMID: 35861243
Phenotypes for gene: PSMC1 were set to spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes
Mode of pathogenicity for gene: PSMC1 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: PSMC1 was set to AMBER
Added comment: Homozygosity mapping on one large consanguineous Bedouin kindred showed three affected children (out of the ten) to be homozygous for NM_002802.3:c.983T>C; p.(Ile328Thr).

Drosophila rescue experiments were carried out. Transgenic studies using drosophila with the silenced ortholog Rpt2 gene were rescued by the human wild-type PSMC1.

Three of the ten offspring of healthy consanguineous parents of Bedouin Israeli ancestry were affected with a similar phenotype of failure to thrive, developmental delay and severe intellectual disability, spastic tetraplegia with central hypotonia, chorea, as well as hearing loss. None of the three achieved verbal communication or ambulation (sitting / standing) at any age. They had mild dysmorphism of borderline dolichocephaly and microcephaly, prominent bushy eyebrows, flat midface, long nasal bridge and micrognathia. All three had micropenis with undescended testes. One of the affected (as a toddler) underwent thorough endocrinological analysis: testosterone and gonadotropin levels were low.
Sources: Literature
Mendeliome v1.212 KIF15 Krithika Murali gene: KIF15 was added
gene: KIF15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF15 were set to 28150392
Phenotypes for gene: KIF15 were set to ?Braddock-Carey syndrome 2 - MIM#619981
Review for gene: KIF15 was set to GREEN
Added comment: PMID 28150392 Sleiman et al 2017 report one individual with homozygous R501* variant (NMD-predicted) from a consanguineous family. The child had thrombocytopenia, PRS, microcephaly -3SD by age 6, dysmorphic facies, bilateral external auditory canal atresia and deafness, microphthalmia, clinodactyly, short stature. Variant absent from gnomAD. Parents confirmed to be carriers and unaffected siblings were carriers/homozygous wild-type.

No other SNVs reported in ClinVar. Variant is absent from gnomAD. Authors note phenotypic similarities with Braddock-Carey syndrome (21q22 contiguous deletion also involving RUNX1).
Sources: Literature
Mendeliome v1.212 BMP3 Seb Lunke Marked gene: BMP3 as ready
Mendeliome v1.212 BMP3 Seb Lunke Gene: bmp3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.212 BMP3 Seb Lunke Classified gene: BMP3 as Amber List (moderate evidence)
Mendeliome v1.212 BMP3 Seb Lunke Gene: bmp3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.211 BMP3 Seb Lunke gene: BMP3 was added
gene: BMP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP3 were set to 35089417
Phenotypes for gene: BMP3 were set to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129
Review for gene: BMP3 was set to AMBER
Added comment: Single missense variant identified segregating with disease following WES screen in a family with coloboma and/or microphthalmia in BMP3. Two additional unrelated patients identified with different missense in BMP3. Pathogenicity however largely on in-silicos, with one of the 3 missense having 29 hets in gnomAD. Additional functional work in bmp3 -/- zebra fish and some supporting evidence but not conclusive
Sources: Literature
Mendeliome v1.210 C18orf32 Alison Yeung Marked gene: C18orf32 as ready
Mendeliome v1.210 C18orf32 Alison Yeung Gene: c18orf32 has been classified as Red List (Low Evidence).
Mendeliome v1.210 C18orf32 Alison Yeung Classified gene: C18orf32 as Red List (low evidence)
Mendeliome v1.210 C18orf32 Alison Yeung Gene: c18orf32 has been classified as Red List (Low Evidence).
Mendeliome v1.209 ALG5 Zornitza Stark Marked gene: ALG5 as ready
Mendeliome v1.209 ALG5 Zornitza Stark Gene: alg5 has been classified as Green List (High Evidence).
Mendeliome v1.209 ALG5 Zornitza Stark Classified gene: ALG5 as Green List (high evidence)
Mendeliome v1.209 ALG5 Zornitza Stark Gene: alg5 has been classified as Green List (High Evidence).
Mendeliome v1.208 ALG5 Chern Lim edited their review of gene: ALG5: Changed phenotypes: Cystic renal disease MONDO:0002473, ALG5-related, Multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline, few or no liver cysts.
Mendeliome v1.208 ALG5 Chern Lim gene: ALG5 was added
gene: ALG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALG5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALG5 were set to 35896117
Phenotypes for gene: ALG5 were set to Cystic renal disease MONDO:0002473, ALG5-related
Review for gene: ALG5 was set to GREEN
gene: ALG5 was marked as current diagnostic
Added comment: PMID:35896117:
- Five unrelated families, including 23 affected individuals with non-enlarged cystic kidneys and few or no liver cysts, 8 of them reached end-stage kidney disease from 62 to 91 years of age. Variant confirmed in all but one individual.
- Various variant types: frameshift, nonsense, two missense, splice.
- Functional studies showed haploinsufficiency is the disease mechanism.
Sources: Literature
Mendeliome v1.208 DOHH Daniel Flanagan gene: DOHH was added
gene: DOHH was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to PMID: 35858628
Phenotypes for gene: DOHH were set to Neurodevelopmental disorder, DOHH-related (MONDO#0700092)
Review for gene: DOHH was set to GREEN
Added comment: Bi-allelic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. Clinical features were developmental delay and/or intellectual disability (5/5), microcephaly (5/5), visual impairment (nystagmus (3/5), strabismus (3/5), and cortical visual impairment (1/5)) and congenital heart malformations (3/5 individuals).
Sources: Expert list
Mendeliome v1.208 PPFIBP1 Ee Ming Wong reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35830857; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.208 SLITRK2 Paul De Fazio gene: SLITRK2 was added
gene: SLITRK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLITRK2 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: SLITRK2 were set to 35840571
Phenotypes for gene: SLITRK2 were set to Neurodevelopmental disorder, SLITRK2-related MONDO:0700092
Review for gene: SLITRK2 was set to GREEN
gene: SLITRK2 was marked as current diagnostic
Added comment: 6 missense variants and 1 nonsense variant (NOT NMD-predicted, single-exon gene) reported in 7 males and 1 female with neurodevelopmental disorders. Phenotypes included dev delay, mild to severe ID, delayed or absent speech, seizures and brain MRI anomalies (in some patients).

The nonsense variant was identified in two affected brothers but not in the mother, suggesting it was de novo in the maternal germline. The variant in the one affected female was de novo. All other variants in hemizygous males were inherited from an unaffected mother. In one case, the variant was also identified in the unaffected grandmother.

Functional studies showed some but not all variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Conditional knockout mice exhibited impaired long-term memory and abnormal gait.
Sources: Literature
Mendeliome v1.208 RFC1 Ain Roesley Publications for gene: RFC1 were set to 30926972
Mendeliome v1.208 RFC1 Ain Roesley Phenotypes for gene: RFC1 were changed from Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome OMIM 614575 to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575
Mendeliome v1.207 RFC1 Ain Roesley Classified gene: RFC1 as Amber List (moderate evidence)
Mendeliome v1.207 RFC1 Ain Roesley Gene: rfc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.206 C18orf32 Naomi Baker gene: C18orf32 was added
gene: C18orf32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C18orf32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C18orf32 were set to PMID:35107634
Phenotypes for gene: C18orf32 were set to Neurodevelopmental disorder (MONDO:0700092), C18orf32-related
Review for gene: C18orf32 was set to RED
Added comment: Two siblings reported as affected, although sequencing only performed in one sibling, with homozygous loss-of-function variant identified. Clinical presentation included developmental delay, recurrent lower respiratory tract infections, sparse rough hair, roving eye movements, hypotonia, bilateral ankle contractures and inverted nipples.
Sources: Literature
Mendeliome v1.206 ADGRL1 Elena Savva Classified gene: ADGRL1 as Green List (high evidence)
Mendeliome v1.206 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Green List (High Evidence).
Mendeliome v1.205 RFC1 Ain Roesley reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35883251; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.205 ADGRL1 Elena Savva Classified gene: ADGRL1 as Green List (high evidence)
Mendeliome v1.205 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Green List (High Evidence).
Mendeliome v1.204 ADGRL1 Elena Savva Marked gene: ADGRL1 as ready
Mendeliome v1.204 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Red List (Low Evidence).
Mendeliome v1.204 ADGRL1 Elena Savva gene: ADGRL1 was added
gene: ADGRL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADGRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ADGRL1 were set to PMID: 35907405
Phenotypes for gene: ADGRL1 were set to Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092)
Review for gene: ADGRL1 was set to GREEN
Added comment: PMID: 35907405 - 9 patients w/ ADHD (3/9), autism (4/9), mild-moderate ID (5/9) and epilepsy (2/9) and facial dysmorphism (7/9). Variants include missense (4) and PTCs (5), and were either de novo (7/9) or inherited from parents with learning difficulties/ID (2/9).

Functional studies on both PTCs and missense variants show significant reductions in calcium signalling and surface protein.

Het null mouse model shows neurological and developmental abnormalities, with hom null mice non-viable.
Sources: Literature
Mendeliome v1.203 EHHADH Zornitza Stark Classified gene: EHHADH as Amber List (moderate evidence)
Mendeliome v1.203 EHHADH Zornitza Stark Gene: ehhadh has been classified as Amber List (Moderate Evidence).
Mendeliome v1.202 EHHADH Zornitza Stark edited their review of gene: EHHADH: Added comment: https://clinmedjournals.org/articles/jcnrc/journal-of-clinical-nephrology-and-renal-care-jcnrc-3-027.pdf

Second case report, same variant, de novo. Also, experimental evidence. Assessed as MODERATE by ClinGen.; Changed rating: AMBER
Mendeliome v1.202 DUOX2 Zornitza Stark Phenotypes for gene: DUOX2 were changed from Thyroid dyshormonogenesis 6 - MIM#607200 to Thyroid dyshormonogenesis 6 - MIM#607200; Inflammatory bowel disease, MONDO:0005265, DUOX2-related
Mendeliome v1.201 DUOX2 Zornitza Stark Publications for gene: DUOX2 were set to
Mendeliome v1.200 DUOX2 Zornitza Stark Mode of inheritance for gene: DUOX2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.199 DUOX2 Zornitza Stark Classified gene: DUOX2 as Amber List (moderate evidence)
Mendeliome v1.199 DUOX2 Zornitza Stark Gene: duox2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.198 DUOX2 Zornitza Stark reviewed gene: DUOX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35429653, 27373512, 26301257, 28683258; Phenotypes: Inflammatory bowel disease, MONDO:0005265, DUOX2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.198 CWH43 Zornitza Stark Marked gene: CWH43 as ready
Mendeliome v1.198 CWH43 Zornitza Stark Gene: cwh43 has been classified as Red List (Low Evidence).
Mendeliome v1.198 CWH43 Zornitza Stark Phenotypes for gene: CWH43 were changed from normal pressure hydrocephalus to Hydrocephalus MONDO:0001150, CWH43-related
Mendeliome v1.197 CWH43 Zornitza Stark Classified gene: CWH43 as Red List (low evidence)
Mendeliome v1.197 CWH43 Zornitza Stark Gene: cwh43 has been classified as Red List (Low Evidence).
Mendeliome v1.196 CWH43 Zornitza Stark Tag cnv tag was added to gene: CWH43.
Mendeliome v1.196 CWH43 Zornitza Stark reviewed gene: CWH43: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrocephalus MONDO:0001150, CWH43-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.196 CWH43 Anna Le Fevre gene: CWH43 was added
gene: CWH43 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CWH43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CWH43 were set to PMID: 33459505; 34380733
Phenotypes for gene: CWH43 were set to normal pressure hydrocephalus
Penetrance for gene: CWH43 were set to Incomplete
Review for gene: CWH43 was set to AMBER
Added comment: Sources: Literature
Mendeliome v1.196 ADGRA3 Zornitza Stark Marked gene: ADGRA3 as ready
Mendeliome v1.196 ADGRA3 Zornitza Stark Gene: adgra3 has been classified as Red List (Low Evidence).
Mendeliome v1.196 ADGRA3 Zornitza Stark gene: ADGRA3 was added
gene: ADGRA3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ADGRA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADGRA3 were set to 23105016
Phenotypes for gene: ADGRA3 were set to Retinitis pigmentosa, MONDO:0019200, ADGRA3-related
Review for gene: ADGRA3 was set to RED
Added comment: Only one report of a missense that is a VUS identified as a candidate through autozygome analysis (PMID: 23105016)
Sources: Expert Review
Mendeliome v1.195 TAF8 Zornitza Stark Phenotypes for gene: TAF8 were changed from Neurodevelopmental disorder, MONDO:0700092, TAF8-related to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, MIM# 619972
Mendeliome v1.194 TAF8 Zornitza Stark edited their review of gene: TAF8: Changed phenotypes: Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, MIM# 619972
Mendeliome v1.194 POU3F3 Zornitza Stark Phenotypes for gene: POU3F3 were changed from Intellectual disability to Snijders Blok-Fisher syndrome MIM#618604
Mendeliome v1.193 POU3F3 Zornitza Stark edited their review of gene: POU3F3: Changed phenotypes: Snijders Blok-Fisher syndrome MIM#618604
Mendeliome v1.193 ROBO4 Zornitza Stark Phenotypes for gene: ROBO4 were changed from bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation to Aortic valve disease 8, MIM#618496; bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation
Mendeliome v1.192 ROBO4 Zornitza Stark Publications for gene: ROBO4 were set to 30455415
Mendeliome v1.191 ROBO4 Zornitza Stark Classified gene: ROBO4 as Amber List (moderate evidence)
Mendeliome v1.191 ROBO4 Zornitza Stark Gene: robo4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.190 EIF2B1 Zornitza Stark Phenotypes for gene: EIF2B1 were changed from leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; Neonatal diabetes mellitus, MONDO:0016391, EIF2B1-related
Mendeliome v1.189 EIF2B1 Zornitza Stark Publications for gene: EIF2B1 were set to 11835386; 26285592; 15776425; 18263758; 25843247; 25761052; 30014503
Mendeliome v1.188 EIF2B1 Zornitza Stark Mode of inheritance for gene: EIF2B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.187 EIF2B1 Zornitza Stark reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neonatal diabetes mellitus, MONDO:0016391, EIF2B1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.187 MCM10 Zornitza Stark Publications for gene: MCM10 were set to 32865517; 33712616
Mendeliome v1.186 MCM10 Zornitza Stark Classified gene: MCM10 as Amber List (moderate evidence)
Mendeliome v1.186 MCM10 Zornitza Stark Gene: mcm10 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.185 MCM10 Zornitza Stark edited their review of gene: MCM10: Added comment: PMID 33712616: further functional validation.; Changed rating: AMBER; Changed publications: 32865517, 33712616, 33712616
Mendeliome v1.185 IKZF1 Zornitza Stark Phenotypes for gene: IKZF1 were changed from Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset to Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset; Immune dysregulation
Mendeliome v1.184 IKZF1 Zornitza Stark Publications for gene: IKZF1 were set to 21548011; 26981933; 29889099; 31057532; 7923373; 11805317
Mendeliome v1.183 IKZF1 Zornitza Stark edited their review of gene: IKZF1: Added comment: PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation.; Changed publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317, 35333544; Changed phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset, Immune dysregulation
Mendeliome v1.183 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immune dysregulation to Immunodeficiency, MONDO:0021094, IKZF2-related; Immune dysregulation
Mendeliome v1.182 IKZF2 Zornitza Stark Publications for gene: IKZF2 were set to 34920454
Mendeliome v1.181 IKZF2 Zornitza Stark Mode of inheritance for gene: IKZF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.180 IKZF2 Zornitza Stark edited their review of gene: IKZF2: Added comment: Iranian male with homozygous missense variant with recurrent infection, hypogammaglobulinaemia. Extends inheritance to AR. Supportive functional data.; Changed publications: 34920454, 34826259; Changed phenotypes: Immunodeficiency, MONDO:0021094, IKZF2-related, Immune dysregulation; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.180 TMEM63C Zornitza Stark Marked gene: TMEM63C as ready
Mendeliome v1.180 TMEM63C Zornitza Stark Gene: tmem63c has been classified as Green List (High Evidence).
Mendeliome v1.180 TMEM63C Zornitza Stark Phenotypes for gene: TMEM63C were changed from Hereditary spastic paraplegia, MONDO:0019064, TMEM63C-related to Spastic paraplegia 87, autosomal recessive, MIM# 619966
Mendeliome v1.179 TMEM63C Zornitza Stark reviewed gene: TMEM63C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 87, autosomal recessive, MIM# 619966; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.179 ROBO4 Elena Savva reviewed gene: ROBO4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:30455415, 32748548; Phenotypes: Aortic valve disease 8 MIM#618496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.179 EIF2B1 Elena Savva reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31882561; Phenotypes: Leukoencephalopathy with vanishing white matter MIM#603896, permanent neonatal/early onset diabetes and transient liver dysfunction; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.179 ARFGEF1 Zornitza Stark Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619964
Mendeliome v1.178 ARFGEF1 Zornitza Stark edited their review of gene: ARFGEF1: Changed phenotypes: Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619964
Mendeliome v1.178 PAK2 Zornitza Stark Phenotypes for gene: PAK2 were changed from Knobloch 2 syndrome to Knobloch 2 syndrome, MIM#618458
Mendeliome v1.177 INPP5E Zornitza Stark Publications for gene: INPP5E were set to 19668216; 32139166; 29230161; 29052317; 27998989; 27401686; 19668215
Mendeliome v1.176 INPP5E Zornitza Stark edited their review of gene: INPP5E: Added comment: Additional MORM family reported in PMID 34211432, hmz LoF.; Changed publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686, 19668215, 34211432
Mendeliome v1.176 WASL Zornitza Stark Marked gene: WASL as ready
Mendeliome v1.176 WASL Zornitza Stark Gene: wasl has been classified as Red List (Low Evidence).
Mendeliome v1.176 WASL Zornitza Stark gene: WASL was added
gene: WASL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASL were set to 33571872
Phenotypes for gene: WASL were set to Parkinson's disease, MONDO:0005180, WASL-related
Review for gene: WASL was set to RED
Added comment: Single family reported, where bi-allelic variants segregated with PD in three affected individuals.
Sources: Literature
Mendeliome v1.175 PMM2 Zornitza Stark Phenotypes for gene: PMM2 were changed from Congenital disorder of glycosylation, type Ia (MIM#212065) to Congenital disorder of glycosylation, type Ia (MIM#212065); Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease (HIPKD), MONDO:0020642, PMM2-related
Mendeliome v1.174 PMM2 Zornitza Stark Publications for gene: PMM2 were set to 28108845
Mendeliome v1.173 PMM2 Zornitza Stark changed review comment from: Well established gene-disease association.; to: CDG: Well established gene-disease association.
Mendeliome v1.173 PMM2 Zornitza Stark edited their review of gene: PMM2: Added comment: Association with HIPKD:
Cabezas et al (2017) reported co-occurrence of hyperinsulinaemic hypoglycaemia and polycystic kidney disease (HIPKD in 17 children from 11 unrelated families. Patients presented with hyperinsulinaemic hypoglycaemia in infancy and enlarged kidneys with multiple kidney cysts. Some progressed to ESKD and some had liver cysts. Whole-genome linkage analysis in 5 informative families identified a single significant locus on chromosome 16p13.2. Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, they found in all patients a promoter mutation (c.-167G>T) in PMM2, either homozygous or in trans with PMM2 coding mutations. They found deglycosylation in cultured pancreatic β cells altered insulin secretion. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2. They proposed that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. None of the patients exhibited the typical clinical or diagnostic features of CDG1A. Serum transferrin glycosylation was normal in 11 patients who had assessment.; Changed publications: 28108845, 28373276, 32595772; Changed phenotypes: Congenital disorder of glycosylation, type Ia (MIM#212065), Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease (HIPKD), MONDO:0020642, PMM2-related
Mendeliome v1.173 SLCO2A1 Zornitza Stark Phenotypes for gene: SLCO2A1 were changed from Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100; Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441 to Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100; Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441; Inflammatory bowel disease, MONDO:0005265, SLCO2A1-related
Mendeliome v1.172 SLCO2A1 Zornitza Stark Publications for gene: SLCO2A1 were set to 23509104; 27134495; 33852188; 22331663; 27134495
Mendeliome v1.171 SLCO2A1 Zornitza Stark edited their review of gene: SLCO2A1: Added comment: PMID 29313109: Over 40 Japanese individuals reported with bi-allelic variants in this gene and multiple small intestinal ulcers of nonspecific histology. Some overlap with the hypertrophic osteoarthropathy also associated with bi-allelic variants in this gene. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO.; Changed publications: 23509104, 27134495, 33852188, 22331663, 27134495, 29313109; Changed phenotypes: Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100, Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441, Inflammatory bowel disease, MONDO:0005265, SLCO2A1-related
Mendeliome v1.171 CTR9 Zornitza Stark Phenotypes for gene: CTR9 were changed from Neurodevelopmental disorder (MONDO:0700092), CTR9 related to Neurodevelopmental disorder (MONDO:0700092), CTR9 related; Familial Wilms tumour, MONDO:0006058, CTR9-related
Mendeliome v1.170 CTR9 Zornitza Stark Publications for gene: CTR9 were set to PMID: 35499524
Mendeliome v1.169 CTR9 Zornitza Stark reviewed gene: CTR9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25099282, 29292210; Phenotypes: Familial Wilms tumour, MONDO:0006058, CTR9-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.169 C20orf24 Zornitza Stark Tag new gene name tag was added to gene: C20orf24.
Mendeliome v1.169 C20orf24 Zornitza Stark Marked gene: C20orf24 as ready
Mendeliome v1.169 C20orf24 Zornitza Stark Gene: c20orf24 has been classified as Red List (Low Evidence).
Mendeliome v1.169 C20orf24 Zornitza Stark gene: C20orf24 was added
gene: C20orf24 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C20orf24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C20orf24 were set to 35614220; 24194475
Phenotypes for gene: C20orf24 were set to Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2, MIM# 616994
Review for gene: C20orf24 was set to RED
Added comment: Bi-allelic LoF variant identified in patient originally reported in PMID 24194475.

HGNC approved name is RAB5IF.
Sources: Literature
Mendeliome v1.168 IL23R Zornitza Stark edited their review of gene: IL23R: Changed phenotypes: Immunodeficiency disease, MONDO:0021094, Susceptibility to mycobacteria and Salmonella Edit
Mendeliome v1.168 IL23R Zornitza Stark edited their review of gene: IL23R: Changed phenotypes: Immunodeficiency disease, MONDO:0021094
Mendeliome v1.168 IL23R Zornitza Stark Phenotypes for gene: IL23R were changed from Susceptibility to mycobacteria and Salmonella to Immunodeficiency disease, MONDO:0021094; Susceptibility to mycobacteria and Salmonella
Mendeliome v1.167 IL23R Zornitza Stark Publications for gene: IL23R were set to 30578351
Mendeliome v1.166 IL23R Zornitza Stark Classified gene: IL23R as Amber List (moderate evidence)
Mendeliome v1.166 IL23R Zornitza Stark Gene: il23r has been classified as Amber List (Moderate Evidence).
Mendeliome v1.165 IL23R Zornitza Stark edited their review of gene: IL23R: Added comment: PMID 35829840: 48yo male with disseminated NTM homozygous (p.R381X) with supportive functional data.; Changed rating: AMBER; Changed publications: 30578351, 35829840
Mendeliome v1.165 HYOU1 Zornitza Stark Classified gene: HYOU1 as Amber List (moderate evidence)
Mendeliome v1.165 HYOU1 Zornitza Stark Gene: hyou1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.164 HYOU1 Zornitza Stark edited their review of gene: HYOU1: Added comment: Second individual reported in PMID: 35822684 with severe neutropenia.; Changed rating: AMBER; Changed publications: 27913302, 35822684; Changed phenotypes: Immunodeficiency 59 and hypoglycemia, MIM# 233600
Mendeliome v1.164 PPP1R13L Zornitza Stark Phenotypes for gene: PPP1R13L were changed from Dilated cardiomyopathy, onset in infancy to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related; Dilated cardiomyopathy, onset in infancy
Mendeliome v1.163 CHD5 Elena Savva Phenotypes for gene: CHD5 were changed from Intellectual disability; Epilepsy to Parenti-Mignot neurodevelopmental syndrome MIM#619873
Mendeliome v1.162 CHD5 Elena Savva reviewed gene: CHD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33944996; Phenotypes: Parenti-Mignot neurodevelopmental syndrome MIM#619873; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.162 PPP1R13L Krithika Murali reviewed gene: PPP1R13L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.162 GINS3 Zornitza Stark Marked gene: GINS3 as ready
Mendeliome v1.162 GINS3 Zornitza Stark Gene: gins3 has been classified as Green List (High Evidence).
Mendeliome v1.162 GINS3 Zornitza Stark Classified gene: GINS3 as Green List (high evidence)
Mendeliome v1.162 GINS3 Zornitza Stark Gene: gins3 has been classified as Green List (High Evidence).
Mendeliome v1.161 GINS3 Zornitza Stark gene: GINS3 was added
gene: GINS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS3 were set to 35603789
Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome, MONDO:0016817, GINS3-related
Review for gene: GINS3 was set to GREEN
Added comment: 7 individuals from 5 families reported, presenting with prenatal and postnatal growth deficiency as well as other features. Three unique missense variants identified, two affecting p.Asp24. These variants are thought to be hypomorphic. Supportive mouse model.
Sources: Literature
Mendeliome v1.160 UBA2 Zornitza Stark Phenotypes for gene: UBA2 were changed from Split-Hand/Foot Malformation; Aplasia Cutis Congenita; Ectrodactyly to ACCES syndrome, MIM# 619959; Split-Hand/Foot Malformation; Aplasia Cutis Congenita; Ectrodactyly
Mendeliome v1.159 UBA2 Zornitza Stark reviewed gene: UBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ACCES syndrome, MIM# 619959; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.159 C9orf84 Zornitza Stark Marked gene: C9orf84 as ready
Mendeliome v1.159 C9orf84 Zornitza Stark Gene: c9orf84 has been classified as Green List (High Evidence).
Mendeliome v1.159 C9orf84 Zornitza Stark Classified gene: C9orf84 as Green List (high evidence)
Mendeliome v1.159 C9orf84 Zornitza Stark Gene: c9orf84 has been classified as Green List (High Evidence).
Mendeliome v1.158 C9orf84 Zornitza Stark Tag new gene name tag was added to gene: C9orf84.
Mendeliome v1.158 C9orf84 Zornitza Stark changed review comment from: 8 families reported with bi-allelic variants in this gene and spermatogenic failure.
Sources: Literature; to: 8 families reported with bi-allelic variants in this gene and spermatogenic failure. A male germ cell-specific Shoc1 knockout mouse model recapitulates the phenotype (germline knockout: early lethality).

HGNC approved name is SHOC1.

Sources: Literature
Mendeliome v1.158 C9orf84 Zornitza Stark gene: C9orf84 was added
gene: C9orf84 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C9orf84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C9orf84 were set to 32741963; 32900840; 35485979
Phenotypes for gene: C9orf84 were set to Spermatogenic failure 75, MIM# 619949
Review for gene: C9orf84 was set to GREEN
Added comment: 8 families reported with bi-allelic variants in this gene and spermatogenic failure.
Sources: Literature
Mendeliome v1.157 HIST1H4E Zornitza Stark Phenotypes for gene: HIST1H4E were changed from Neurodevelopmental disorder, HIST1H4E-related MONDO:0700092 to Tessadori-van Haaften neurodevelopmental syndrome 3, MIM# 619950
Mendeliome v1.156 HIST1H4E Zornitza Stark Tag new gene name tag was added to gene: HIST1H4E.
Mendeliome v1.156 HIST1H4E Zornitza Stark reviewed gene: HIST1H4E: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 3, MIM# 619950; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.156 KMT2B Zornitza Stark Publications for gene: KMT2B were set to 27839873; 27992417
Mendeliome v1.155 KMT2B Zornitza Stark edited their review of gene: KMT2B: Added comment: Nine individuals reported in PMID 33150406 with heterozygous variants in this gene and intellectual disability, speech delay, microcephaly, growth delay, feeding problems, and dysmorphic features, including epicanthic folds, posteriorly rotated ears, syndactyly/clinodactyly of toes, and fifth finger clinodactyly, normal MRIs and NO dystonia.; Changed publications: 27839873, 27992417, 33150406; Changed phenotypes: Dystonia 28, childhood-onset 617284, MONDO:0015004, Intellectual developmental disorder, autosomal dominant 68, MIM# 619934
Mendeliome v1.155 LMAN2L Zornitza Stark Phenotypes for gene: LMAN2L were changed from Mental retardation, autosomal recessive, 52; OMIM #616887 to Mental retardation, autosomal recessive, 52 OMIM #616887; Intellectual developmental disorder, autosomal dominant 69 , MIM# 617863
Mendeliome v1.154 LMAN2L Zornitza Stark edited their review of gene: LMAN2L: Changed phenotypes: Mental retardation, autosomal recessive, 52 OMIM #616887, Intellectual developmental disorder, autosomal dominant 69 , MIM# 617863
Mendeliome v1.154 CDH2 Zornitza Stark edited their review of gene: CDH2: Changed phenotypes: Intellectual disability, corpus callosum abnormalities, congenital abnormalities, Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929, Attention deficit-hyperactivity disorder 8 , MIM# 619957
Mendeliome v1.154 CDH2 Zornitza Stark Phenotypes for gene: CDH2 were changed from Intellectual disability; corpus callosum abnormalities; congenital abnormalities; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929 to Intellectual disability; corpus callosum abnormalities; congenital abnormalities; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929; Attention deficit-hyperactivity disorder 8 , MIM# 619957
Mendeliome v1.153 CDH2 Zornitza Stark Mode of inheritance for gene: CDH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.152 CDH2 Zornitza Stark edited their review of gene: CDH2: Added comment: PMID 34702855: three sibs with homozygous missense and strikingly severe ADHD. Mouse model of same variant recapitulated the phenotype. AMBER for bi-allelic association (segregation and functional data).; Changed publications: 31585109, 34702855; Changed phenotypes: Intellectual disability, corpus callosum abnormalities, congenital abnormalities, Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929:Attention deficit-hyperactivity disorder 8 , MIM# 619957; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.152 PLXNA1 Zornitza Stark Phenotypes for gene: PLXNA1 were changed from Neurodevelopmental disorder with cerebral and eye anomalies to Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Mendeliome v1.151 PLXNA1 Zornitza Stark edited their review of gene: PLXNA1: Changed phenotypes: Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Mendeliome v1.151 TBP Zornitza Stark Tag STR tag was added to gene: TBP.
Mendeliome v1.151 KITLG Zornitza Stark Phenotypes for gene: KITLG were changed from Deafness, autosomal dominant 69, unilateral or asymmetric, MIM# 616697 to Deafness, autosomal dominant 69, unilateral or asymmetric, MIM# 616697; deafness; heterochromia iridis; hypopigmentation of the skin; hyperpigmentation of the skin; Waardenburg syndrome,MONDO:0018094, KITLG-related
Mendeliome v1.150 KITLG Zornitza Stark Publications for gene: KITLG were set to 26522471
Mendeliome v1.149 KITLG Zornitza Stark Classified gene: KITLG as Green List (high evidence)
Mendeliome v1.149 KITLG Zornitza Stark Gene: kitlg has been classified as Green List (High Evidence).
Mendeliome v1.148 CLDN5 Zornitza Stark Marked gene: CLDN5 as ready
Mendeliome v1.148 CLDN5 Zornitza Stark Gene: cldn5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.148 CLDN5 Zornitza Stark Classified gene: CLDN5 as Amber List (moderate evidence)
Mendeliome v1.148 CLDN5 Zornitza Stark Gene: cldn5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.147 CLDN5 Zornitza Stark gene: CLDN5 was added
gene: CLDN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN5 were set to 35714222
Phenotypes for gene: CLDN5 were set to alternating hemiplegia, MONDO:0016210, CLDN5-related
Mode of pathogenicity for gene: CLDN5 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: CLDN5 was set to AMBER
Added comment: PMID: 35714222; Hashimoto, Y. et al. (2022): Two unrelated cases (early-onset) with alternating hemiplegia with microcephaly were shown to have the same de novo variant, NM_001363066.2:c.178G>A, p.(Gly60Arg).

One with Jewish / Tunisian ancestry: Onset was at 8 months, three episodes of febrile tonic-clonic 1 seizures of the four limbs, with eye rolling, loss of consciousness, transient left and right post-2 ictal hemiparesis and vomiting. The other with Asian / European ancestry: Onset was at 30 months with three iterative episodes of febrile and non-febrile hemiplegia and loss of 18 consciousness. The recurrent episodes alternatively involved the left-and 19 right-hand side, then generalised and were followed by post ictal hemiparesis.

CT scans of both showed brain calcifications and aberrant blood flow patterns. Transfected cell lines with this variant, c178G>A, showed higher chloride ion permeability and lower sodium ion permeability when compared to wildtype.
Sources: Literature
Mendeliome v1.146 PSMB9 Zornitza Stark Publications for gene: PSMB9 were set to 26524591
Mendeliome v1.145 PSMB9 Zornitza Stark Mode of inheritance for gene: PSMB9 was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.144 PSMB9 Zornitza Stark Classified gene: PSMB9 as Green List (high evidence)
Mendeliome v1.144 PSMB9 Zornitza Stark Gene: psmb9 has been classified as Green List (High Evidence).
Mendeliome v1.143 PSMB9 Zornitza Stark edited their review of gene: PSMB9: Added comment: Two additional individuals with neonatal onset autoinflammatory syndrome and a mouse model. De novo recurrent missense G156D.; Changed rating: GREEN; Changed publications: 26524591, 34819510; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.143 HCK Zornitza Stark Marked gene: HCK as ready
Mendeliome v1.143 HCK Zornitza Stark Gene: hck has been classified as Amber List (Moderate Evidence).
Mendeliome v1.143 HCK Zornitza Stark Classified gene: HCK as Amber List (moderate evidence)
Mendeliome v1.143 HCK Zornitza Stark Gene: hck has been classified as Amber List (Moderate Evidence).
Mendeliome v1.142 HCK Zornitza Stark gene: HCK was added
gene: HCK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HCK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HCK were set to 34536415
Phenotypes for gene: HCK were set to Autoinflammatory syndrome, MONDO:0019751, HCK-related
Mode of pathogenicity for gene: HCK was set to Other
Review for gene: HCK was set to AMBER
Added comment: Single patient with supportive functional data.
Sources: Literature
Mendeliome v1.141 TBX21 Zornitza Stark Classified gene: TBX21 as Amber List (moderate evidence)
Mendeliome v1.141 TBX21 Zornitza Stark Gene: tbx21 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.140 TBX21 Zornitza Stark changed review comment from: Single individual reported with disseminated disease following BCG vaccination, who subsequently developed severe persistent reactive airway disease and eosinophilia that responded to steroid treatment. Homozygous variant identified.

Association with asthma and nasal polyps pertains to promoter SNPs.; to: Single individual reported with disseminated disease following BCG vaccination, who subsequently developed severe persistent reactive airway disease and eosinophilia that responded to steroid treatment. Homozygous variant identified. Functional data.

Association with asthma and nasal polyps pertains to promoter SNPs.
Mendeliome v1.140 TBX21 Zornitza Stark edited their review of gene: TBX21: Changed rating: AMBER
Mendeliome v1.140 TTC25 Zornitza Stark Publications for gene: TTC25 were set to 27486780
Mendeliome v1.139 TTC25 Zornitza Stark Classified gene: TTC25 as Green List (high evidence)
Mendeliome v1.139 TTC25 Zornitza Stark Gene: ttc25 has been classified as Green List (High Evidence).
Mendeliome v1.138 KITLG Dean Phelan reviewed gene: KITLG: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 35543077, 28504826, 19375057, 21368769; Phenotypes: deafness, heterochromia iridis, hypopigmentation of the skin, hyperpigmentation of the skin, Waardenburg syndrome,MONDO:0018094, KITLG-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.138 NFATC2 Zornitza Stark Marked gene: NFATC2 as ready
Mendeliome v1.138 NFATC2 Zornitza Stark Gene: nfatc2 has been classified as Red List (Low Evidence).
Mendeliome v1.138 NFATC2 Zornitza Stark Classified gene: NFATC2 as Red List (low evidence)
Mendeliome v1.138 NFATC2 Zornitza Stark Gene: nfatc2 has been classified as Red List (Low Evidence).
Mendeliome v1.137 NFATC2 Paul De Fazio gene: NFATC2 was added
gene: NFATC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NFATC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC2 were set to 35789258
Phenotypes for gene: NFATC2 were set to Skeletal system disorder MONDO:0005172
Review for gene: NFATC2 was set to RED
gene: NFATC2 was marked as current diagnostic
Added comment: Patient born to consanguineous parents homozygous for a frameshift variant. No other (unaffected) members of the family were homozygous. Family history of recurrent childhood deaths.

After a healthy birth the patient developed painless decreased range of motion at 1.5yrs leading to difficulty with ambulation at 3yrs. Formal orthopedic assessment at age 15 years
demonstrated a neurodevelopmentally normal young man with marked bilateral fixed flexion contractures of knees, hips, and ankles. The main musculoskeletal findings were painless contractures of the large and small joints of the upper and lower limbs, osteochondromas, and osteopenia. Patient was diagnosed with B-cell lymphoma at age 18.

Patient CD8+ T-cells show impaired polyfunctionality, and the patient had an accumulation of non-functional memory CD4+ T-cells. TFH cell function was also impaired.
Sources: Literature
Mendeliome v1.137 PIK3C2B Zornitza Stark Marked gene: PIK3C2B as ready
Mendeliome v1.137 PIK3C2B Zornitza Stark Gene: pik3c2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.137 PIK3C2B Zornitza Stark Classified gene: PIK3C2B as Amber List (moderate evidence)
Mendeliome v1.137 PIK3C2B Zornitza Stark Gene: pik3c2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.136 CCDC155 Zornitza Stark Marked gene: CCDC155 as ready
Mendeliome v1.136 CCDC155 Zornitza Stark Gene: ccdc155 has been classified as Green List (High Evidence).
Mendeliome v1.136 CCDC155 Zornitza Stark Phenotypes for gene: CCDC155 were changed from Non-obstructive azoospermia; Premature ovarian insufficiency to Non-obstructive azoospermia; Premature ovarian insufficiency; Infertility disorder, MONDO:0005047, CCDC155-related