An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy

BackgroundEvidence 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. MethodsThe 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. ResultsSixty-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). ConclusionsWith 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. CLINICAL PERSPECTIVEO_ST_ABSWhats new?C_ST_ABSO_LIThe Clinical Genome Resource (ClinGen) Dilated Cardiomyopathy (DCM) Gene Curation Expert Panel reconvened to update the evidence for genes in DCM using the ClinGen clinical validity framework. C_LIO_LIA total of 35 genes were classified into clinically actionable, high evidence categories of Definitive, Strong, or Moderate evidence, an increase of 16 from the 2019-2020 curation. C_LIO_LIOf the 16 newly classified high evidence curations, 11 (69%) had an autosomal recessive mode of inheritance and were observed primarily in pediatric DCM. C_LI What are the clinical implications?O_LIThis update has substantially expanded the complex and diverse genetic architecture of DCM spanning 18 gene ontologies (8 new) identified in both adult and pediatric patients. C_LIO_LIThe 19 genes classified as high evidence in the 2019-2020 curations were adopted by the clinical genetics community as the key genes for clinical genetic testing and care for DCM patients and families. The 35 high evidence curations from the current assessment are recommended to be used as an updated list for clinical genetics care for DCM. C_LIO_LIDCM gene curation will require ongoing reassessments due to the continuing expansion of high-quality research data. C_LI