1School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore – 632014, Tamil Nadu, India
2Genotypic Technology Pvt Ltd., Bangalore – 560094, Karnataka, India
Cardiomyopathies are usually inherited heart muscle disorders which mostly cause sudden death in young and adults. Early screening and diagnosis in families with risk will enable taking measures to prevent the sudden cardiac death. Analysis of the genome Aggregation Database (gnomAD), consisting of both whole genome and whole Exome data from unrelated individuals for variants in 58 genes implicated in primary cardiomyopathies revealed several insights. The gnomAD consisted of two hundred and Eighty-three pathogenic variants reported in ClinVar. Twenty-two of the variants were present in South Asian population and ten of them were exclusive to this population. Majority of pathogenic variants were observed in hypertrophic cardiomyopathy related genes which is the highly prevalent phenotype in India. Unannotated variants form ClinVar were predicted for their pathogenicity using multiple predictive tools specific for the variant types. Fewer predicted pathogenic variants in key genes like MYBPC3, PKP2 and LMNA suggest, mutations in these genes might be intolerant and hence less represented in the gnomAD database. Analysis of data resulted in identification of inflated numbers of pathogenic alleles for each of the phenotypes. Analysis establishes the value of population database in assessing the pathogenic alleles. However higher number of pathogenic variants than the phenotype prevalence in the population suggests that some of these variants might be less penetrant or might have disease modifying effect in presence of other pathogenic variants rather than being causative of the phenotype. Availability of clinical phenotypes for these variants might also result in better interpretation and conclusion on variant’s pathogenicity.
Primary Cardiomyopathy, Gene, Allele frequency, Variants, Exome, Next generation sequencing
