An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy

Background: Evidence of the diverse genetic architecture of dilated cardiomyopathy (DCM) continues to emerge and requires reassessment of the clinical relevance of implicated disease genes. Building on the 2019-2020 Clinical Genome Resource (ClinGen) evaluation, the DCM Gene Curation Expert Panel (GCEP) reconvened in 2024-2025 to conduct a reassessment of genes in DCM. Methods: The ClinGen semi-quantitative clinical validity classification framework was applied with specifications to DCM to classify genes into categories based upon strength of published evidence for a DCM phenotype. Previously curated genes were reassessed and newly reported gene-disease-mode of inheritance (MOI) relationships, termed ?curations,? were evaluated. Results: Sixty-eight genes were evaluated, inclusive of 72 unique gene-disease-MOI relationships across 51 previously evaluated and 17 newly assessed genes. Thirty-five curations were classified as high evidence (16 Definitive, 10 Strong, 9 Moderate), increasing by 16 from the prior assessment. Nine newly assessed genes were classified as high evidence, including BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L. Twelve genes (11 newly appraised) were rated as high evidence with an autosomal recessive (AR) MOI. Five re-evaluated genes from 2019-2020 had clinically significant changes in classification. Except for JPH2, for which curation was modified to separate autosomal dominant (-AD) and -AR MOI curations, clinically significant changes involved upgrades from low to high evidence categories (PLEKHM2, PRDM16, TBX20, TNNI3K), demonstrating the robustness of the ClinGen gene curation process over time. An additional 29 gene-disease-MOI curations were classified as Limited, including six newly evaluated genes and one new MOI for a previously evaluated gene, MYBPC3-AR; four were classified as No Known Disease Relationship, and four remained Disputed. Four previously evaluated genes were curated for both AD and AR MOIs, including JPH2 (AD-Strong, AR-Limited), LDB3 (AD-Limited, AR-Strong), MYBPC3 (AD-Limited, AR-Limited), and TNNI3 (AD- and AR- Strong). Conclusions: With substantial new evidence, the genetic architecture of DCM has rapidly expanded. This updated assessment of genes reported in DCM yielded 35 high evidence curations, an increase from 19 only five years ago. The results of this evidence-based evaluation process informs clinical interpretation of genetic information in the care of DCM patients and families.