CSRP3 was originally evaluated for DCM by the ClinGen DCM GCEP on 11/06/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 05/30/2025. As a result, the classification changed from limited to no known disease relationship. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.
CSRP3 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2002 (Knoll et al. 2002, PMID: 12507422). Human genetic evidence supporting this gene-disease relationship includes case-level and case-control data. At least four missense variants have been reported in humans with DCM (Mohapatra et al. 2003, PMID 14567970; Hershberger et al. 2008, PMID 19412328; Shakeel M et al. 2018, PMID 29776034; and Zimmerman et al. 2010, PMID 20474083). Two case-control studies did not find evidence of enrichment of the missense variant in cases, however, the confidence intervals were wide due to limited sample size (Mazzarotto et al. 2020, PMID 31983221; Walsh et al. 2017, PMID 27532257). In 2022, Trachoo et al. PMID 36166435 identified a missense variant in a cohort of DCM patients from Thailand. This gene-disease assertion is supported by experimental data from expression studies and animal, ex-vivo, and cell culture models. Arber et al. (1997, PMID 9039266) reported the phenotype of a transgenic homozygous CSRP3-null mouse, demonstrating defects of the cardiomyocyte cytoskeletal architecture with Z-disc misalignment and myofibrillar disarray. Knoll et al. (2002, PMID 12507422) demonstrated a defect in cardiomyocyte stretch-induced response. No further scorable variants were identified in the re-curation process. No convincing evidence for a causal role for CSRP3 and AD DCM has been reported. Although this gene-disease assertion is supported by experimental evidence, there is limited convincing genetic evidence that have directly implicated this gene in human disease. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 05/30/2025 (SOP Version 10).
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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