Submission Details

The AP1B1 gene was first reported in relation to autosomal recessive Keratitis-ichthyosis-deafness syndrome in 2019 (Alsaif, H S et al., PMID: 31630791). It is characterized by syndromic early-onset ichthyosis, alopecia, severe sensorineural hearing loss, as well as failure to thrive, mild developmental delay, and later-onset palmoplantar keratoderma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Autosomal Recessive Keratitis-ichthyosis-deafness Syndrome (KIDAR MIM #242150). Eleven variants (including missense, nonsense, frameshift, and large deletions involving exons 1-2 of the gene) have been reported in 10 probands in 7 publications (PMIDs: 31630791, 31630788, 33452671, 33349978, 35144013, 37657632, 32969855) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by functional characterization of fibroblasts derived from affected individuals and from animal models (zebrafish), which show abnormal ATP7A trafficking and auditory defects paralleling the hearing loss in our human subjects with AP1B1 mutations (PMIDs: 31630791, 23593334). In summary, there is definitive evidence supporting the relationship between AP1B1 and autosomal recessive Keratitis-ichthyosis-deafness syndrome. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen IEM GCEP on the meeting date August, 9, 2024. (SOP Version 10).