The MYH9 gene definitively causes MYH9-Related Disorders, a class of autosomal dominant disorders characterized by congenital macrothrombocytopenia and variable leucocyte inclusion bodies, renal abnormalities, cataracts, and progressive sensorineural hearing loss. This association was assessed using the ClinGen Clinical Validity Framework as of 12/11/2017. Recent reviews report that missense variants are located at only 21 of the 1,960 amino acid residues of the protein (Balduini 2011, De Rocco 2013, Pecci 2014). Nonsense or frameshift variants of MYH9 have only been reported in the last exon of the gene. A genotype-phenotype correlation has been shown repeatedly (Dong 2005, Pecci 2008, Pecci 2014, Saposnik 2014). There are several reports of the p.Arg705His variant in MYH9 causing nonsyndromic hearing loss, DFNA17 (Lalwani 2000, Hildebrand 2006). However, no testing for the blood phenotype was reported in any affected individuals in these families, and at least two other individuals with the hematological features of MYH9-RD had the same variant (Verver 2015). These data suggest nonsyndromic hearing loss may not be a distinct entity from MYH9-RD. Hearing loss is not a fully penetrant feature of MYH9-RD; a review of cases indicated approximately 48% of patients have hearing loss (Pecci 2014). Individuals presenting with nonsyndromic hearing loss who are found to have a pathogenic variant in MYH9 should be tested for the other phenotypes of MYH9-RD. In vitro functional evidence indicates that disease-causing variants may act through different molecular mechanisms in different cell types (Franke 2005, Hu 2002, Pecci 2005), exhibiting a dominant-negative effect on wild-type protein in granulocytes and haploinsufficiency in megakaryocytes and platelets (Pecci 2005). Four knock-in mouse models harboring 3 different human variants in MYH9 fully recapitulated the human phenotype of MYH9-RD (Zhang 2012, Suzuki 2013). In summary, MYH9 is definitively associated with AD MYH9-RD. 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 2/20/2018.
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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