The relationship between DFNB59 (aka PJVK) and autosomal recessive nonsyndromic genetic deafness was evaluated using the ClinGen Clinical Validity Framework as of 11/17/2017. Variants in PJVK were first reported in humans with this disease as early as 2006 (Delmaghani et al., PMID 16804542). At least 8 unique variants (missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, animal models, and expression studies that help elucidate the role of PJVK in the peroxisomes of inner ear hair cells and neurons (PMIDs: 16804542, 26166082, 22617256, 28964305, 17373699, 25631766). Variants in this gene have been reported in at least 8 probands in 14 publications. Variants in this gene segregated with disease in more than 33 additional family members.More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is hypothesized to be that the PJVK gene is critical to the "regulation of peroxisomal dynamics and the antioxidant defense triggered by noise exposure in hair cells and auditory neurons of the inner ear"(PMID: 26544930). In summary, DFNB59 is definitively associated with ARNSHL. 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 12/19/2017.
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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