The POU4F3 gene has been associated with autosomal dominant nonsyndromic hearing loss DFNA15 in at least 18 probands in 18 publications. Missense, in-frame indel, nonsense, frameshift, large deletion variants have been reported in humans, and variants in this gene segregated with disease in over 60 additional family members. POU4F3 was first associated with this disease in humans in 1998 (Vahava et al.). The hearing loss in DFNA15 individuals is progressive, with a highly variable age of onset between the second and fifth decades of life. The mechanism for disease is likely haploinsufficiency, due to the wide variant spectrum, however mice require only one copy of the functional gene to retain hearing (Erkman 1997, Keithley 1999, Hertzano 2004). This gene-disease association is supported by multiple mouse models, expression studies, and in vitro functional assays. In summary, POU4F3 is definitively associated with autosomal dominant nonsyndromic sensorineural 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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