Genetic Insights Into Cardiomyopathy With Restrictive Phenotype: Implications for Diagnosis and Personalized Care

Cardiomyopathy with a restrictive phenotype is uncommon, genetically heterogeneous, and difficult to distinguish from advanced hypertrophic or dilated cardiomyopathy. We aimed primarily to determine the diagnostic yield and spectrum of pathogenic or likely pathogenic variants among patients with an echocardiographically defined restrictive phenotype; genotype-imaging and survival comparisons were prespecified exploratory analyses.

We screened 568 patients with cardiomyopathy who underwent whole-exome sequencing and comprehensive echocardiography. Thirty-three met the operational definition of restrictive phenotype. Variants were classified. Genotype-imaging associations and survival were analyzed exploratorily.

Among the 568 patients, 33 exhibited a restrictive phenotype: 7 had restrictive cardiomyopathy (RCM), 20 had hypertrophic cardiomyopathy with a restrictive phenotype (HRCM), and 6 had dilated cardiomyopathy with a restrictive phenotype (HDRCM). Variant carriers had a smaller aortic sinus diameter. In addition, MYBPC3 variant carriers had greater ventricular wall thickness and more frequent septal hypertrophy. Both the HRCM and HDRCM groups showed hypertrophic features, with interventricular septal hypertrophy occurring more frequently in the HDRCM group. The estimated 5-year survival was 54.5%, and survival did not differ significantly according to genetic-variant status.

Pathogenic or likely pathogenic variants were frequent in this single-center cohort with restrictive physiology and were associated with selected imaging features. These exploratory findings support integrated genetic and echocardiographic evaluation.