1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants

Abstract

Background The prevalence and genetic spectrum of cardiac channelopathies exhibit population-specific differences. We aimed to understand the spectrum of cardiac channelopathy-associated variations in India, which is characterised by a genetically diverse population and is largely understudied in the context of these disorders. Results We utilised the IndiGenomes dataset comprising 1029 whole genomes from self-declared healthy individuals as a template to filter variants in 36 genes known to cause cardiac channelopathies. Our analysis revealed 186,782 variants, of which we filtered 470 variants that were identified as possibly pathogenic (440 nonsynonymous, 30 high-confidence predicted loss of function ). About 26% (124 out of 470) of these variants were unique to the Indian population as they were not reported in the global population datasets and published literature. Classification of 470 variants by ACMG/AMP guidelines unveiled 13 pathogenic/likely pathogenic (P/LP) variants mapping to 19 out of the 1029 individuals. Further query of 53 probands in an independent cohort of cardiac channelopathy, using exome sequencing, revealed the presence of 3 out of the 13 P/LP variants. The identification of p.G179Sfs*62, p.R823W and c.420 + 2 T > C variants in KCNQ1, KCNH2 and CASQ2 genes, respectively, validate the significance of the P/LP variants in the context of clinical applicability as well as for large-scale population analysis. Conclusion A compendium of ACMG/AMP classified cardiac channelopathy variants in 1029 self-declared healthy Indian population was created. A conservative genotypic prevalence was estimated to be 0.9–1.8% which poses a huge public health burden for a country with large population size like India. In the majority of cases, these disorders are manageable and the risk of sudden cardiac death can be alleviated by appropriate lifestyle modifications as well as treatment regimens/clinical interventions. Clinical utility of the obtained variants was demonstrated using a cardiac channelopathy patient cohort. Our study emphasises the need for large-scale population screening to identify at-risk individuals and take preventive measures. However, we suggest cautious clinical interpretation to be exercised by taking other cardiac channelopathy risk factors into account.

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“…Many rare diseases are caused by genetic mutations. As another example, certain genetic mutations might be more common in specific populations due to ancestral heritage and geographic distributions of these populations (203)(204)(205)(206). Furthermore, cultural practices such as consanguineous marriage are associated with increased rates of certain inherited genetic conditions, particularly autosomal recessive conditions (207).…”

A Novel PINK1 p.F385S Loss‐of‐Function Mutation in an Indian Family with Parkinson's Disease

“…A publicly available database was used to search for putative variants in the control genomes ascertained from different regions of India. In brief, a total of 1029 self‐declared healthy individuals underwent whole‐genome sequencing to develop a comprehensive compendium of genetic variants in the Indian population 21,22 …”

“…In brief, a total of 1029 selfdeclared healthy individuals underwent whole-genome sequencing to develop a comprehensive compendium of genetic variants in the Indian population. 21,22…”