Gene discovery for cardiomyopathies

Summary

Cardiomyopathies are a group of heterogeneous cardiac muscle disorders. Cardiomyopathies are classified into different forms, including dilated, hypertrophic, restrictive, and arrhythmogenic, based on the structural and functional changes. Usually, these disorders are progressive and known to cause heart failure and sudden cardiac death. Many of these cardiomyopathies are monogenic. Notably, the occurrence and severity of these cardiac anomalies are highly variable and determined by the gene types and mutations. Mutations in genes encoding different components of the sarcomere are frequently identified in different forms of cardiomyopathies. Recent emerging evidence indicates that non-sarcomeric genetic variants induce cardiomyopathy through diverse molecular mechanisms involving RAS- MAPK and AKT-mTOR pathway modulations, cytoskeletal abnormalities, and defective cell migration. Still, around 50-60% of patients are negative for all known variants, suggesting novel genes and other important molecular mechanisms.

Therefore, for a comprehensive understanding of the genetic architecture of these disorders, we have sequenced various Indian patient samples and discovered novel gene variants showing a strong association with cardiomyopathy. Further, to infer the allele frequency of these variants in European population, we will carry out a replication analysis using genetic and phenotype data of cardiomyopathy patients available who are part of the NIHR Rare Diseases BioResource. Moreover, such genetic association studies in diverse ethnic populations will facilitate accurate identification of risk factors and developing tailor-made treatment strategies for cardiomyopathies. Additionally, this approach will have potential implications in developing novel therapies, which will significantly reduce the public health burden caused by this disease.