Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants

Abstract

The South Asian population, numbered at 1.8 billion, is estimated to comprise around 20% of the global population and 1% of the American population, and has one of the highest rates of cardiovascular disease. While South Asians show increased classical risk factors for developing heart failure, the role of population-specific genetic risk factors has not yet been examined for this group. Hypertrophic cardiomyopathy (HCM) is one of the major cardiac genetic disorders among South Asians, leading to contractile dysfunction, heart failure, and sudden cardiac death. This disease displays autosomal dominant inheritance, and it is associated with a large number of variants in both sarcomeric and non-sarcomeric proteins. The South Asians, a population with large ethnic diversity, potentially carries region-specific polymorphisms. There is high variability in disease penetrance and phenotypic expression of variants associated with HCM. Thus, extensive studies are required to decipher pathogenicity and the physiological mechanisms of these variants, as well as the contribution of modifier genes and environmental factors to disease phenotypes. Conducting genotype-phenotype correlation studies will lead to improved understanding of HCM and, consequently, improved treatment options for this high-risk population. The objective of this review is to report the history of cardiovascular disease and HCM in South Asians, present previously published pathogenic variants, and introduce current efforts to study HCM using induced pluripotent stem cell-derived cardiomyocytes, next-generation sequencing, and gene editing technologies. The authors ultimately hope that this review will stimulate further research, drive novel discoveries, and contribute to the development of personalized medicine with the aim of expanding therapeutic strategies for HCM.

Presence of Hypertrophic Cardiomyopathy Related Gene Mutations and Clinical Manifestations in Vietnamese Patients With Hypertrophic Cardiomyopathy

“…We found a high proportion of genotype-low prevalence in South Asian and Japanese people. 28,30 Because mutations in TPM1 are considered a very rare cause of HCM, its prevalence of 7.7% is an unusually high detection rate. 31 However, an HCM-causing mutation in TPM1, c.523G>A (p.Asp175Asn), was previously identified in a Finnish population with a similar prevalence (6.5%) as a founder mutation showing regional clustering.…”

“…TNNT2 (9.1%) and TNNI3 (4.5%) were identified as the next 2 most common causes of HCM after MYBPC3 and MYH7, in agreement with previous studies in several European and Asian populations. 23,26,28,30,33 Few mutations were found in non-sarcomeric genes. Except for P mutations identified in TCAP, the other variants were mostly classified as VUS, consistent with previous studies.…”

Genetic Polymorphisms that Playing Role in Development of Hypertrophic Cardiomyopathy

“…In another study performed by Ronkaratti et al, in the Italian population, it is found that the frequency of mutations determined in the MYH7 gene was found to be very low. Many factors, such as modifying genes, epigenetic factors, microRNAs, posttranslational protein modifications, and environmental factors, may affect the clinical course of HCM disease [1,10]. Genetic studies are required to understand the clinical and prognostic heterogeneity of HCM.…”

Recent Advances in Hypertrophic Cardiomyopathy: A System Review

“…Since the identiication of the irst locus for familial HCM and the irst mutation in MYH7-encoded beta-myosin heavy chain 20 years ago [25], over 1500 causal mutations associated with HCM encode sarcomeric proteins have been revealed [26]. According to gene susceptibility, HCM can be divided to "myoilament (sarcomeric) HCM," "Z-disk HCM," and "calcium-handling HCM," with "myoilament (sarcomeric) HCM" being the most common genetic form of HCM, account for 50% of all HCM cases [13]. Recently, large genotype-phenotype analysis correlation studies established implications for septal morphology, disease onset, and prognosis of certain sarcomeric genes, which may further facilitate commercialized genetic testing.…”

“…These mutations alter myocardial metabolism, resulting in increased wall thickness, cardiac storage abnormalities, and conduction irregularities second to multiple systematic disorders. The information of HCM susceptibility genes and HCM phenocopies are listed in Tables 2 and 3 [13,27,28].…”