The CISD2 gene was first associated with autosomal recessive Wolfram syndrome (WFS) in 2007 (Amr et al., PMID: 17846994). At least 6 unique variants (missense, splice-site, small deletion) have been reported in 9 probands in 7 publications (PMIDs: 17846994, 25056293, 25371195, 28335035, 27459537, 31391115, 31309279). At least two families have been identified in which a variant in CISD2 segregates with WFS in 8 family members (PMID: 17846994). Three mouse models, functional alteration studies and expression studies have been reported to show that LoF of the CISD2 gene leads to a phenotype similar to WFS or changes the behavior of the cells in which the variant protein is present (PMIDs: 19451219, 24833725, 28335035, 17846994, 31600780, 29237418. 33610659). In summary, there is definitive evidence to support the relationship between CISD2 and autosomal recessive Wolfram syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as Strong by the ClinGen Hearing Loss Working Group on 3/27/2018 as per SOP v6. It was reevaluated on 6/1/2023 as per SOP v9. As a result of this reevaluation, the classification increased from Strong to Definitive due to additional case level evidence (PMIDs: 27459537, 31391115, 31309279) as well as functional evidence (PMIDs: 17846994, 31600780, 29237418. 33610659).
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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