Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Diverse genetic backgrounds cause varied cardiomyopathy (CMP) phenotypes.
• Previous studies often analyzed single phenotypes, limiting understanding of genotype-phenotype prognostic features.
• Diagnostic and prognostic implications of CMP genotypes across different phenotypic expressions are poorly understood.

Purpose of the Study:

• To compare the predictive accuracy of genotype versus phenotype for patient outcomes in cardiomyopathies.
• To analyze differences in outcome prediction when stratifying patients by phenotype at presentation versus by genotype.
• To enhance risk stratification for patients with cardiomyopathies and positive genetic testing.

Main Methods:

• Examined dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, and other CMP variants.
• Included 281 patients with pathogenic or likely pathogenic variants (80% DCM).
• Assessed outcomes: all-cause mortality/heart transplant, sudden cardiac death/major ventricular arrhythmias, and heart failure death/transplant/LVAD.

Main Results:

• Sudden cardiac death/major ventricular arrhythmias were more frequent in non-DCM phenotypes and carriers of DSP, PKP2, LMNA, and FLNC variants.
• Genotype-based classification, unlike phenotype-based, predicted sudden cardiac death/major ventricular arrhythmias after age/sex adjustment.
• LMNA variants showed the poorest outcomes for mortality/transplant and heart failure death/transplant/LVAD.

Conclusions:

• Genotypes are linked to significant phenotypic heterogeneity in genetic cardiomyopathies.
• Genotypic classification demonstrated superior precision in predicting patient outcomes compared to phenotypic classification.
• Findings improve understanding of inherited CMPs and aid risk stratification in genetically tested patients.