DNAJC7 was first reported in relation to amyotrophic lateral sclerosis (ALS) in 2019 (Farhan et al., PMID: 31768050). This seminal discovery reported a significant excess of rare protein-truncating variants in ALS using whole-exome sequencing data from cases (n=5,095) compared to controls (n=28,910) in a single-gene burden analysis (OR=96.9; P=2.5x10^-7). One additional protein truncating (nonsense) variant has since been reported in one sporadic ALS case (PMID: 33062890). The mechanism of pathogenicity is reported to be loss of function (LoF). This gene-disease association is also supported by experimental evidence from expression studies showing expression if DNAJC7 in the brain and specifically neurons (PMID: 25613900), as well as a physical protein interaction with the definitive ALS gene/protein FUS (PMID: 26344197).
In summary, to-date there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on the meeting date October 27, 2022 (SOP Version 9).
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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