The relationship between OTOA and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/10/2017. Variants in OTOA were first reported in humans with this disease as early as 2002 (Zwaenepoel et al.). At least 10 variants (e.g. missense, splice-site, large deletion, whole gene deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level, case-control, and experimental data. Variants in this gene have been reported in at least 9 probands in 6 publications (PMIDs: 11972037, 19888295, 23173898, 16460646, 26029705, 26969326). Variants in this gene segregated with disease in at least 17 additional family members. This gene-disease relationship has been studied in at least 1 case-control studies (PMID 25528277) at the aggregate variant level. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by a relevant expression studies as well as a knockout mouse model. OTOA also has a pseudogene, which could contaminate the sequencing of the gene. Caution should be used when assessing the missense variants reported in OTOA, because they could be in the pseudogene. In summary, OTOA is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 5/1/2018.
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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