Morphomechanic phenotypic variability of sarcomeric cardiomyopathies: A multifactorial polygenic perspective

Area of Science:

• Genetics
• Cardiology
• Bioinformatics

Background:

• Sarcomeric cardiomyopathies (CMs) are classified by morphology into hypertrophic (HCM) and dilated (DCM).
• Next-generation DNA sequencing (NGS) has improved CM diagnosis, management, and prognosis.
• Monogenic analyses overlook complex genetic interactions influencing CM phenotypes.

Purpose of the Study:

• To review the successes and challenges of genetic and genomic approaches in cardiomyopathies.
• To explore the impact of these approaches on current and future clinical care.
• To highlight the need for multifactorial variant models in understanding genotype-phenotype correlations.

Main Methods:

• Review of current literature on genetic and genomic studies in cardiomyopathies.
• Discussion of limitations of monogenic analyses and the role of complex genetic concepts (pleiotropy, heterogeneity, incomplete penetrance, variable expressivity).
• Exploration of modern genomics integrating electronic health records, genome-wide association studies, advanced imaging, and systems biology.

Main Results:

• NGS has significantly advanced CM diagnosis and management.
• Complex genetic interactions and multifactorial variant models are crucial for understanding CM phenotypes.
• Personalized medicine and novel therapeutic targets can be fostered through advanced genomic analyses.

Conclusions:

• Genetic and genomic approaches have transformed cardiomyopathies care.
• Future research must embrace multifactorial variant models and integrate diverse data sources for precise genotype-phenotype correlations.
• Personalized cardiology holds promise for improved patient outcomes in HCM and DCM.