Molecular Pathology of Cardiomyopathies: Bridging Morphology, Genomics, and Clinical Phenotypes

TL;DR

This review explores how molecular genetics and pathology help understand and diagnose different types of cardiomyopathies, linking genetic causes to clinical outcomes.

Contribution

The paper provides an updated synthesis of molecular pathology in cardiomyopathies, emphasizing genotype–phenotype correlations and multidisciplinary approaches.

Findings

Up to 60% of cardiomyopathies have an identifiable genetic basis.

Desmosomal, sarcomeric, and cytoskeletal protein mutations disrupt myocardial function.

Molecular autopsy is emerging as a key tool in unexplained sudden cardiac death cases.

Abstract

Cardiomyopathies represent a heterogeneous group of myocardial diseases that share overlapping clinical and genetic profiles but distinct morphological and molecular signatures. Advances in molecular genetics and next-generation sequencing have revolutionized the diagnostic landscape, revealing that up to 60% of cardiomyopathies have an identifiable genetic basis. From a pathologist’s perspective, integrating histopathological findings with molecular data is crucial for understanding genotype–phenotype correlations and for guiding precision medicine. This review provides an updated overview of the molecular pathology of major cardiomyopathy subtypes, including dilated, hypertrophic, restrictive, arrhythmogenic, and non-compaction forms. For each entity, we discuss morphologic hallmarks, genetic mechanisms, and their impact on disease progression and sudden cardiac death. Special emphasis is placed on the role of desmosomal, sarcomeric, and cytoskeletal proteins in myocardial structure and function, and on how their mutations disrupt cardiomyocyte integrity and signaling pathways. Furthermore, we address the emerging role of molecular autopsy in unexplained sudden cardiac death, underscoring the importance of multidisciplinary collaboration among pathologists, geneticists, and clinicians. Finally, we highlight future directions in molecular diagnostics and targeted therapies, which are reshaping the classification and management of cardiomyopathies.