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Intellectual disability

Gene: AP1B1

Amber List (moderate evidence)
AP1B1 (adaptor related protein complex 1 beta 1 subunit)
EnsemblGeneIds (GRCh38): ENSG00000100280
EnsemblGeneIds (GRCh37): ENSG00000100280
OMIM: 600157, Gene2Phenotype
AP1B1 is in 7 panels

3 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with global developmental delay from birth - including delayed motor milestones and delay in speech development. While the severe developmental delay in the neonatal period seems to mostly resolve in later childhood, it may be the first presenting symptom, alongside ichthyosis. Hence, this gene fits into the scope of the Intellectual disability panel, and should be promoted to Green at the next GMS update.
Created: 17 Oct 2025, 3:09 p.m. | Last Modified: 17 Oct 2025, 3:10 p.m.
Panel Version: 9.136
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).
Created: 17 Oct 2025, 2:42 p.m. | Last Modified: 17 Oct 2025, 4:28 p.m.
Panel Version: 9.136

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781

Publications

Created: 17 Oct 2025, 2:42 p.m.
Last Modified: 17 Oct 2025, 4:28 p.m.
Panel version: 9.136

Catherine Snow (Genomics England)

I don't know

AP1B1 identified by Konstantinos Varvagiannis as reported in Boyden et al. (2019 - PMID: 31630788) and Alsaif et al (2019 - PMID: 31630791)

AP1B1 is currently not in OMIM and is possible in Gene2Phenotype. Phenotype observed in all subjects included failure to thrive, ichthyosis (with variable palmoplantar keratoderma/erythroderma/abnormal hair) and hearing loss. However as DD/ID not consistent amongst all subjects AP1B1 will be rated as Amber.
Created: 27 Nov 2019, 2:02 p.m. | Last Modified: 27 Nov 2019, 2:02 p.m.
Panel Version: 2.1123

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Created: 27 Nov 2019, 2:02 p.m.
Last Modified: 27 Nov 2019, 2:02 p.m.
Panel version: 2.1123

Konstantinos Varvagiannis (Other)

I don't know

Boyden et al. (2019 - PMID: 31630788) and Alsaif et al (2019 - PMID: 31630791) report on the phenotype related to biallelic AP1B1 mutations.

Common features included failure to thrive, ichthyosis (with variable palmoplantar keratoderma/erythroderma/abnormal hair) and hearing loss. Each study focused on different additional features eg. thrombocytopenia or photophobia in all individuals reported by Boyden et al, while Alsaif et al. focused on abnormal copper metabolism (low plasma copper and ceruloplasmin) observed in all 3 affected individuals and enteropathy/hepatopathy observed in 2 sibs.

DD was observed in all 3 individuals (2 families) reported by Alsaif et al. and patient 424 reported by Boyden et al. ID was noted in all individuals of relevant age (2 from 2 families) in the study by Alsaif. Boyden commented that ID is not part of the phenotype. The adult (424) - despite his early DD - was noted to have normal intellect and had graduated college. The other patient (1325) was last followed up at 11 months (still DD was not reported).

AP1B1 encodes one of the large subunits (β1) of the adaptor protein complex 1. Each of the AP complexes is a heterotetramer composed of two large (one of γ, α, δ, ε and β1-β4 for AP-1 to AP-4 respectively), one medium (μ1-μ4) and one small (σ1-σ4) adaptin subunit. The complex is involved in vesicle-mediated transport.

Variants were confirmed in probands and carrier parents (NM_001127.3):
Boyden Pat424 (33y) : c.430T>C (p.Cys144Arg) in trans with c.2335delC (p.Leu779Serfs*26)
Boyden Pat1325 (11m) [consanguineous Ashkenazi Jewish family] : homozygosity for c.2374G>T (p.Glu792*)
Alsaif sibs P1,P2 (4y4m, 1y5m) [consanguineous - Pakistani origin] : homozygous for a chr22 75 kb deletion spanning only the promoter and ex1-2 of AP1B1
Alsaif P3 (4y6m) [consanguineous - Saudi origin] : homozygous for a c.38-1G>A

Variant / additional studies :
22q 75-kb deletion: PCR deletion mapping and Sanger delineated the breakpoints of the 22q12.2 del to chr22:29758984-29815476 (hg?). Complete absence of transcript upon RT-PCR (mRNA from fibrolasts).
Splicing variant (c.38-1G>A): RT-PCR confirmed replacement of the normal transcript by an aberrant harboring a 1 bp deletion (r.40del).
Stopgain variant (c.2374G>T): Western blot demonstrated loss of AP1B1 (and marked reduction also for AP1G1) in cultured keratinocytes of the homozygous patient.

Loss-of-function is the effect predicted by variants. Vesicular defects were observed in keratinocytes of an affected individual (homozygous for the nonsense variant). Rescue of these vesicular defects upon transduction with wt AP1B1 lentiviral construct confirmed the LoF effect. [Boyden et al.]

ATP7A and ATP7B, two copper transporters, have been shown to depend on AP-1 for their trafficking. Similar to MEDNIK syndrome, caused by mutations in AP1S1 and having an overlapping phenotype with AP1B1 (also including hypocupremia and hypoceruloplasminemia), fibroblasts from 2 affected individuals (from different families) demonstrated abnormal ATP7A trafficking. [Alsaif et al.]

Proteomic analysis of clathrin coated vesicles (2 ind from 2 fam) demonstrated that AP1B1 was the only AP1/AP2 CCV component consistently reduced in 2 individuals (from 2 families). [Alsaif et al.]

Boyden et al. provided evidence for abnormal differentiation and proliferation in skin from an affected individual. In addition E-cadherin and β-catenin were shown to be mislocalized in keratinocytes from this affected individual.

Loss of ap1b1 in zebrafish is not lethal but lead to auditory defects (/vestibular deficits). The inner ears appear to develop normally, although there is progressive degeneration of ear epithelia. There are no behavioral/neurological phenotypes listed for mouse models. [ http://www.informatics.jax.org/marker/MGI:1096368 ].

AP1B1 is not associated with any phenotype in OMIM/G2P/SysID.

Overall this gene could be considered for inclusion in the ID panel probably with amber rating.
Sources: Literature
Created: 11 Nov 2019, 4:19 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability

Publications

Created: 11 Nov 2019, 4:19 p.m.

Panel version: 2.1098

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150
  • KID syndrome, MONDO:0018781
Tags
Q3_25_promote_green
OMIM
600157
Clinvar variants
Variants in AP1B1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

20 Oct 2025, Gel status: 2

Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q3_25_promote_green tag was added to gene: AP1B1.

20 Oct 2025, Gel status: 2

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: AP1B1 were set to 31630788; 31630791

20 Oct 2025, Gel status: 2

Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

Phenotypes for gene: AP1B1 were changed from Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781

27 Nov 2019, Gel status: 2

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: ap1b1 has been classified as Amber List (Moderate Evidence).

11 Nov 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: AP1B1 was added gene: AP1B1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP1B1 were set to 31630788; 31630791 Phenotypes for gene: AP1B1 were set to Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability Penetrance for gene: AP1B1 were set to Complete Review for gene: AP1B1 was set to AMBER