Dilated cardiomyopathy with a MYH6 variant of uncertain significance (c.2894A > C, p.K965 T): a 13-year longitudinal follow-up case report
TL;DR
This case suggests that a MYH6 VUS may be associated with a severe and rapidly progressive DCM phenotype in specific clinical contexts, and long-term multimodality imaging follow-up and assessment of device therapy response are critical for individualized management of VUS carriers.
Abstract
Background Genetic evaluation has become a routine component of clinical practice for dilated cardiomyopathy (DCM). However, a substantial proportion of test results return as variants of uncertain significance (VUS), posing considerable challenges for clinical decision-making and genetic counseling. The MYH6 gene encodes the cardiac α-myosin heavy chain, and although its association with DCM has been established, related case reports remain scarce, and the genotype–phenotype correlation is poorly defined. Case report We report a 41-year-old Han Chinese male carrying a heterozygous MYH6 variant (c.2894A > C, p.K965 T), classified as VUS in ClinVar, who presented with a progressive DCM phenotype. Despite 13 years of guideline-directed medical therapy, the patient demonstrated relentless left ventricular enlargement (left ventricular end-diastolic diameter increasing from 71 mm to 98 mm), persistent severe systolic dysfunction (left ventricular ejection fraction consistently ≤17%), and suffered an out-of-hospital cardiac arrest in the 12th year of his disease course. Cardiac magnetic resonance (CMR) revealed extensive transmural septal fibrosis. Sanger sequencing of family members showed that his healthy mother carried the identical variant, whereas his affected father and elder brother did not, forming a classic “genotype–phenotype non-segregation” paradox. Following the cardiac arrest, the patient received a cardiac resynchronization therapy defibrillator (CRT-D), but exhibited no left ventricular reverse remodeling at 12 months post-implantation and is currently undergoing pre-transplant evaluation for heart transplantation. Conclusion This case suggests that a MYH6 VUS may be associated with a severe and rapidly progressive DCM phenotype in specific clinical contexts. However, the non-segregation within the family implies that this variant may act merely as a disease modifier or may require synergistic genetic or environmental co-factors to manifest pathogenicity. Long-term multimodality imaging follow-up and assessment of device therapy response are critical for individualized management of VUS carriers.