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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).
DDG2P v3.12 TYRP1 Achchuthan Shanmugasundram reviewed gene: TYRP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 15996218, 8651291, 19533799, 16704458; Phenotypes: OCULOCUTANEOUS ALBINISM TYPE 3, OMIM:203290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v3.12 TYR Achchuthan Shanmugasundram reviewed gene: TYR: Rating: GREEN; Mode of pathogenicity: ; Publications: 30679655, 8477259, 1970634, 2511845, 3081286, 28667292; Phenotypes: OCULOCUTANEOUS ALBINISM TYPE 1, OMIM:203100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v3.12 TAT Achchuthan Shanmugasundram reviewed gene: TAT: Rating: GREEN; Mode of pathogenicity: ; Publications: 1357662; Phenotypes: TYROSINEMIA TYPE 2, OMIM:276600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v3.12 HSD17B10 Achchuthan Shanmugasundram reviewed gene: HSD17B10: Rating: GREEN; Mode of pathogenicity: ; Publications: 10521307, 12555940, 16148061, 12696021; Phenotypes: INTELLECTUAL DEVELOPMENTAL DISORDER SYNDROMIC X-LINKED TYPE 10, OMIM:300220, 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY, OMIM:300438; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
DDG2P v3.12 HPD Achchuthan Shanmugasundram reviewed gene: HPD: Rating: GREEN; Mode of pathogenicity: ; Publications: 10942115; Phenotypes: TYROSINEMIA TYPE 3, OMIM:276710, HAWKINSINURIA, OMIM:140350; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v3.12 FAH Achchuthan Shanmugasundram reviewed gene: FAH: Rating: GREEN; Mode of pathogenicity: ; Publications: 7977370, 8829657, 7757089, 1401056, 8364576, 8162054, 11196105, 8318997; Phenotypes: TYROSINEMIA TYPE 1, OMIM:276700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v3.11 TYRP1 Achchuthan Shanmugasundram Publications for gene: TYRP1 were updated from 8651291; 15996218; 19533799; 16704458 to 15996218; 8651291; 19533799; 16704458
DDG2P v3.11 TYR Achchuthan Shanmugasundram Publications for gene: TYR were updated from to 8477259; 30679655; 1970634; 2511845; 3081286; 28667292
DDG2P v0.2 TYRP1 Rebecca Foulger reviewed gene: TYRP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v0.2 TYR Rebecca Foulger reviewed gene: TYR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v0.1 TYRP1 Rebecca Foulger gene: TYRP1 was added
gene: TYRP1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: TYRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TYRP1 were set to 8651291; 15996218; 19533799; 16704458
Phenotypes for gene: TYRP1 were set to OCULOCUTANEOUS ALBINISM TYPE 3 203290
DDG2P v0.1 TYR Rebecca Foulger gene: TYR was added
gene: TYR was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: TYR was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TYR were set to OCULOCUTANEOUS ALBINISM TYPE 1 203100
DDG2P v0.1 TAT Rebecca Foulger gene: TAT was added
gene: TAT was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: TAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAT were set to 1357662
Phenotypes for gene: TAT were set to TYROSINEMIA TYPE 2 276600
DDG2P v0.1 HSD17B10 Rebecca Foulger gene: HSD17B10 was added
gene: HSD17B10 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: HSD17B10 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: HSD17B10 were set to 16148061; 12555940; 12696021
Phenotypes for gene: HSD17B10 were set to 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY 300438
DDG2P v0.1 HPD Rebecca Foulger Added phenotypes TYROSINEMIA TYPE 3 276710 for gene: HPD
Publications for gene HPD were changed from to 10942115
DDG2P v0.1 FAH Rebecca Foulger gene: FAH was added
gene: FAH was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: FAH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAH were set to 7977370; 11196105; 8829657; 7757089; 1401056; 8364576; 8162054; 8318997
Phenotypes for gene: FAH were set to TYROSINEMIA TYPE 1 276700