The KCNQ4 gene has been associated with autosomal dominant nonsyndromic hearing loss in at least 35 probands in at least 15 publications. 25 unique missense variants, 2 in-frame deletions, and 6 truncating variants have been reported in humans, and there is segregation evidence in many families (PMID: 10369879, 28340560, 18941426, 25116015, 16596322, 26036578, 23717403, 24655070). KCNQ4 was first associated with this disease in humans in 1999 (Coucke et al.). More than enough genetic evidence is available in the literature to reach the maximum score (12 pts.). The hearing loss in patients is progressive and predominantly high-frequency, however the phenotypic spectrum may be variable. The mechanism for disease is either haploinsufficiency or dominant-negative, which is strongly supported by experimental evidence. This gene-disease association is also supported by multiple mouse models, expression evidence, and in vitro functional assays (PMID: 11042367, 24555524, 10025409, 23750663, 16437162). In summary, KCNQ4 is definitively associated with autosomal dominant 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 Working Group on 11/21/2017.
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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