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| DDG2P v6.8 | AP1B1 |
Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019 Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings. Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome. PMID: 33452671 Vornweg et al., 2021 Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin. PMID: 33349978 Ito et al., 2021 Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels. PMID: 32969855 Meriç et al., 2021 11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits. PMID: 35144013 Faghihi et al., 2022 Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions. AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025). This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024). |
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| DDG2P v6.5 | TSPAN7 | Ida Ertmanska changed review comment from: Comment on list classification: There are at least 7 unrelated individuals reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene should be rated Amber for Intellectual disability.; to: Comment on list classification: There are at least 7 unrelated individuals reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, we decided to demote this gene to Amber for Intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v6.1 | PDE1B |
Sarah Dixon gene: PDE1B was added gene: PDE1B was added to DDG2P. Sources: Literature Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE1B were set to PMID: 40492975 Phenotypes for gene: PDE1B were set to hypotonia; ataxia; dystonia; developmental delay; intellectual disability Penetrance for gene: PDE1B were set to unknown Review for gene: PDE1B was set to GREEN Added comment: PMID: 40492975 Biallelic LOF variants in PDE1B identified in seven individuals from five different families Disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability Sources: Literature |
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| DDG2P v3.12 | IDUA | Achchuthan Shanmugasundram reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: ; Publications: 8328452, 7951228, 10466419, 4221470, 10735634, 6821579, 7550232, 9391892, 8664897; Phenotypes: MUCOPOLYSACCHARIDOSIS TYPE 1S, OMIM:607016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v3.11 | IDUA | Achchuthan Shanmugasundram Publications for gene: IDUA were updated from 8328452; 6821579; 7951228; 8664897; 10735634 to 8328452; 7951228; 10466419; 10735634; 4221470; 6821579; 7550232; 9391892; 8664897 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v3.7 | SLC22A5 | Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v3.6 | MAP4K4 |
Irina Ziravecka gene: MAP4K4 was added gene: MAP4K4 was added to DDG2P. Sources: Literature Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAP4K4 were set to PMID: 37126546 Phenotypes for gene: MAP4K4 were set to neurodevelopmental differences; multiple congenital anomalies Mode of pathogenicity for gene: MAP4K4 was set to Other Review for gene: MAP4K4 was set to GREEN Added comment: PMID: 37126546 - "a cohort of 26 affected individuals from 21 unrelated families with neurodevelopmental differences, cardiac issues, and CFAs who share a phenotype overlap with RASopathies and harbor a series of rare variants in MAP4K4. Functional studies in zebrafish showed that MAP4K4 variants caused hypomorphic, LOF, or DN effects." Sources: Literature |
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| DDG2P v2.55 | TPP2 |
Dmitrijs Rots gene: TPP2 was added gene: TPP2 was added to DDG2P. Sources: Literature Mode of inheritance for gene: TPP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TPP2 were set to PMID: 25414442 Phenotypes for gene: TPP2 were set to Developmental delay; immunodefficiency; autoimmunity Review for gene: TPP2 was set to GREEN Added comment: 14 individuals with "TRIANGLE" (TPPII-related immunodeficiency, autoimmunity, and neurodevelopmental delay with impaired glycolysis and lysosomal expansion) syndrome are summarized in 25414442, where in 9/14 DD was present, which seems to be a common feature. Sources: Literature |
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| DDG2P v2.53 | PBX1 |
Dmitrijs Rots gene: PBX1 was added gene: PBX1 was added to DDG2P. Sources: Literature Mode of inheritance for gene: PBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PBX1 were set to Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay Review for gene: PBX1 was set to GREEN Added comment: Syndromic gene. Most of the individuals present with developmental delay, according to OMIM. Sources: Literature |
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| DDG2P v2.50 | ATG7 |
Dmitrijs Rots gene: ATG7 was added gene: ATG7 was added to DDG2P. Sources: Literature Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATG7 were set to PMID:34161705 Phenotypes for gene: ATG7 were set to developmental delay; ataxia Review for gene: ATG7 was set to GREEN Added comment: Zornitsa Stark wrote for this gene in Ataxia panel: "12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk. Functional data including mouse model. " Should be also on ID panel. Sources: Literature |
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| DDG2P v1.9 | TTN | Rebecca Foulger commented on gene: TTN: PMID:28040389 (Fernández-Marmiesse et al 2017) report a newborn boy, first child of non-consanguineous parents with arthrogryposis multiplex congenita and severe axial hypotonia without cardiac involvement. The individual had a novel homozygous truncating variant c.38661_38665del in TTN, which is expressed only in the fetal skeletal isoform. A fetal ultrasound reported Clubfoot. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v1.9 | TTN | Rebecca Foulger commented on gene: TTN: PMID:29575618 (Chervinsky et al 2018) evaluate a consanguineous family of Moslem Bedouin origin with lethal congenital contracture syndrome and a homozygous c.36122delC (p. P12041Lfs*20) variant in TTN. 8 affected individuals (newborns and fetuses) were studied. Six of the affecteds were diagnosed prenatally by fetal ultrasound and two were diagnosed at birth. One pregnancy was complicated with fetal hydrops, and polyhydramnios was noted in at least three affecteds. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v0.2 | IDUA | Rebecca Foulger reviewed gene: IDUA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v0.1 | IDUA |
Rebecca Foulger Added phenotypes MUCOPOLYSACCHARIDOSIS TYPE 1H 607014 for gene: IDUA Publications for gene IDUA were changed from 10735634; 10466419; 8664897; 7550232; 9391892 to 8328452; 6821579; 7951228; 8664897; 10735634 |
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| DDG2P v0.1 | IDUA |
Rebecca Foulger Added phenotypes MUCOPOLYSACCHARIDOSIS TYPE 1H/S 607015 for gene: IDUA Publications for gene IDUA were changed from 7550232; 4221470 to 10735634; 10466419; 8664897; 7550232; 9391892 |
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| DDG2P v0.1 | IDUA |
Rebecca Foulger gene: IDUA was added gene: IDUA was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IDUA were set to 7550232; 4221470 Phenotypes for gene: IDUA were set to MUCOPOLYSACCHARIDOSIS TYPE 1S 607016 |
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