GJB2 was first reported in relation to autosomal dominant hearing loss with or without skin findings in 1998 (Richard et al., 9856479). At least 30 missense variants have been reported in humans. Association is seen in at least 11 probands in 11 publications (PMIDs: 11354642, 11912510, 15337980, 20937258, 21868108, 9856479, 9620796, 10369869, 10807696, 16226720, 28102197). Variants in this gene segregated with disease in 49 additional family members. Much more evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by animal models, expression studies, in vitro functional assays, and biochemical functional studies, which support a dominant-negative mechanism of disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern for AD nonsyndromic hearing loss, AD keratitis ichthyosis deafness (KID) and AD palmoplantar keratoderma (PPK) with deafness. It is possible that these phenotypes exist on a spectrum of disease. In summary, GJB2 is definitively associated with autosomal dominant Hearing Loss with or without Skin Findings. This classification was approved by the ClinGen Hearing Loss Working Group on 6/26/2018.
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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