The relationship between DNAJB6 and autosomal dominant limb-girdle muscular dystrophy (LGMD type 1D included), has been evaluated using the ClinGen Clinical Validity Framework as of March, 2022. This association was made using case-level, segregation, and experimental data. The DNAJB6 gene is located on chromosome 7q36.3 . The shorter transcript (DNAJB6b) referred to in the literature (NM_005494.3) is 1571 bp long encoding a 241-amino acid protein. Thirteen pathogenic and likely pathogenic variants reported in humans with autosomal dominant limb girdle muscular dystrophy (AD-LGMD) are recorded in ClinVar, all of them being gain of function variants such as missense variants. Patients with AD-LGMD due to DNAJB6 variants show proximal muscle weakness with an age of onset ranging from second to fifth decade, difficulty in walking and running with loss of ambulation in some, foot drop, mild to severe respiratory issues, increased serum creatine kinase levels, and a muscle biopsy showing dystrophic changes. DNAJB6 was first reported as an LGMD disease causing gene by Harms et al (PMID: 22334415). Summary of Case Level Data (12 points): The association is seen in at least 17 probands in 5 publications (PMID: 22366786, 22334415, 26338452, 26205529, 23394708). Variants in the gene segregated with the disease. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is gain of function. Summary of Experimental Data (3 points): This gene-disease relationship is supported by animal models and functional assays. DNAJB6 encodes for a protein that acts as a molecular chaperone by stimulating ATPase activity. Sarparanta et al. 2012 (PMID: 22366786) studied DNAJB6 variants in vivo and in vitro showing that the mutations in vivo show a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. While in vitro studies demonstrated that the mutations increase the half-life of DNAJB6 and reduce its protective anti-aggregation effect. In summary, this gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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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