Key result
Whole-exome sequencing identifies pathogenic variants in ~73% of patients with restrictive-phenotype cardiomyopathy.
Why the study?
Cardiomyopathy with a restrictive phenotype is uncommon, genetically heterogeneous, and difficult to distinguish from advanced hypertrophic or dilated cardiomyopathy, leaving the diagnostic yield and spectrum of pathogenic variants unclear.
What is the diagnostic yield and spectrum of pathogenic or likely pathogenic genetic variants in patients with cardiomyopathy exhibiting an echocardiographically defined restrictive phenotype, and how do genotypes associate with imaging features and survival?
Cohort (n=33)
No
What is the diagnostic yield and spectrum of pathogenic or likely pathogenic genetic variants in patients with cardiomyopathy exhibiting an echocardiographically defined restrictive phenotype, and how do genotypes associate with imaging features and survival?
Patients with cardiomyopathy exhibiting restrictive physiology have a high diagnostic yield (72.7%) of pathogenic or likely pathogenic variants on whole-exome sequencing, supporting integrated genetic and echocardiographic evaluation across morphological subtypes.
Supports genetic evaluation in restrictive-phenotype cardiomyopathy; leaves open prognostic and therapeutic implications pending prospective validation.
Background 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. Methods 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. Results 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. Conclusions 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.
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Zhou et al. (2026) conducted a cohort in Cardiomyopathy with an echocardiographically defined restrictive phenotype (n=33). Whole-exome sequencing and echocardiographic phenotyping (Pathogenic or likely pathogenic genetic variant carrier status) vs. Genotype-negative status (non-carriers of pathogenic or likely pathogenic variants) was evaluated on Diagnostic yield and spectrum of pathogenic or likely pathogenic (P/LP) variants. Whole-exome sequencing identified pathogenic or likely pathogenic variants in 72.7% (24/33) of patients with restrictive-phenotype cardiomyopathy, with an overall 5-year survival of 54.5%.
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