WHRN was first reported in relation to autosomal recessive nonsyndromic genetic hearing loss in 2002 (Mustapha et al., PMID: 11973626). Three variants (nonsense and frameshift) that have been reported in 3 probands in 3 publications (PMIDs: 12833159, 29270100, 34194829) are included in this curation. Variants in this gene segregated with disease in 12 additional family members from 3 separate families. Many additional cases have been reported in the literature claiming autosomal recessive nonsyndromic hearing loss with WHRN variants; however, these variants were not scored due to a lack of convincing phenotyping to rule out late onset retinitis pigmentosa in the probands (i.e. patient is below age of RP onset for Usher type 2, age is not reported, eye examination is not reported) (PMIDs: 23767834, 24194196, 26561413, 26969326, 27344577, 27610647, 28600779, 30303587). The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by expression in the cochlea, and two separate mouse models phenocopying nonsyndromic genetic hearing loss in humans (PMID: 27117407). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on January 2, 2019. It was reevaluated on January 17, 2024. As a result of this reevaluation, the classification did not change.
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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