Genomic Context Differs Between Human Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy

Area of Science:

• Genetics
• Cardiology
• Genomic Medicine

Background:

• Inherited cardiomyopathies exhibit variable penetrance and expression.
• Genetic factors contribute to the phenotypic variation observed in cardiomyopathies.
• Understanding genetic contributions is crucial for diagnosing and managing these conditions.

Purpose of the Study:

• To compare protein-coding genetic variations between hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).
• To evaluate the genetic contribution to variable expression and phenotypic differences in inherited cardiomyopathies.
• To identify potential modifier genes influencing cardiomyopathy development and severity.

Main Methods:

• Whole genome sequencing was performed on familial cases of HCM (n=56) and DCM (n=70).
• Nonsynonymous single-nucleotide variants (nsSNVs) in 102 cardiomyopathy-associated genes were identified and correlated with echocardiographic data.
• Statistical analyses, including principal component analysis and generalized linear models, were used to assess the relationship between nsSNVs and cardiomyopathy type/severity.

Main Results:

• Individuals with DCM had a significantly higher number of nsSNVs per person in cardiomyopathy genes compared to those with HCM.
• Increased nsSNVs in cardiomyopathy genes were associated with reduced left ventricular ejection fraction and increased left ventricular diameter in DCM patients.
• No significant correlation was found between nsSNV burden in cardiomyopathy genes and left ventricular measures in HCM patients.

Conclusions:

• A higher burden of nsSNVs in cardiomyopathy genes is associated with DCM, suggesting a genetic predisposition.
• Increased genetic variation in cardiomyopathy genes may contribute to DCM development and increased disease severity.
• The genetic background, specifically nsSNV burden, plays a differential role in the manifestation of HCM and DCM.