Genetic Overlap Between Dilated Cardiomyopathy and Neurological Disorders: Insights from a Next-Generation Sequencing Study
TL;DR
Describing findings show that variants were most frequently observed in TTN, FLNC, and MYH6 and that several genes included in the ClinGen DCM curation framework have also been independently reported in neurological disorders.
Abstract
Background/Objectives: Dilated cardiomyopathy (DCM) is a genetically heterogeneous myocardial disorder. Emerging evidence suggests that some genes implicated in DCM may also be associated with neurological disorders, supporting the concept of genetic pleiotropy. This study explored the intersection between cardiac and neurological genetics, with the aim of identifying candidate genes that may contribute to shared pathogenic pathways linking these clinically distinct conditions. Methods: We performed exome sequencing in 149 patients with echocardiographically confirmed DCM and subsequently applied an in silico filter to a predefined list of 211 genes associated with inherited cardiomyopathies. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Genes with validated evidence for DCM according to the Clinical Genome Resource (ClinGen) were further investigated through the Human Gene Mutation Database (HGMD) and a focused literature review to identify reported associations with neurological disorders. Results: Genetic variants in DCM-associated genes were identified in 105 patients. Overall, 137 variants were detected, including pathogenic variants and variants of uncertain significance. The most frequently involved genes were TTN, FLNC, and MYH6. Several DCM-associated genes also showed reported associations with neurological disorders, including autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, epilepsy, and schizophrenia. Among them, TTN, FLNC, RYR2, and SCN5A displayed the broadest overlap between cardiac and neurological phenotypes. Conclusions: These descriptive findings show that variants were most frequently observed in TTN, FLNC, and MYH6 and that several genes included in the ClinGen DCM curation framework have also been independently reported in neurological disorders. Because most identified variants were VUS and no control group or systematic neurological phenotyping was available, the findings indicate gene-level co-annotation only and do not establish variant enrichment, shared pathogenic mechanisms, or clinical overlap.