CDC14A was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2016 (Delmaghani et al., PMID 27259055). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms. Therefore, the following disease entities have been split into two disease entities, hearing impairment and infertility in males syndrome (OMIM:608653) and autosomal recessive nonsyndromic hearing loss (OMIM:601071). The split curation for autosomal recessive hearing impairment and infertility in males syndrome (HIIMS) has been curated separately. For males, fertility is directly associated with the location of variants within this gene. Variants that preserve the function of the NM_033313.2 transcript result in nonsyndromic hearing loss instead of HIIMS, while variants that truncate this transcript are expected to result in HIIMS. Six homozygous variants (nonsense, missense, and frameshift) that have been reported in 18 probands in 5 publications (PMIDs: 29293958, 36056583, 33187236, 32231217, 27259055) are included in this curation. This gene-disease association is also supported by animal models (PMIDs: 29293958, 27259055) that demonstrate hearing loss associated with CDC14A heterozygotes. The models also indicate an effect on the length of the kinocilia in inner-ear hair cells, which can impact the differentiation of the auditory sensory cells’ hair bundles. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 2/26/2018. It was re-evaluated on 1/15/2025. As a result of this reevaluation, the classification changed from limited to definitive, due to the addition of genetic evidence and experimental evidence (PMIDs: 36056583, 33187236, 32231217, 27259055). In summary, CDC14A is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 1/15/2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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