Analysis of inframe indels in cardiovascular disease-associated proteins

Aim. To describe the prevalence, location, pathogenicity, and penetrance of inframe indels in clinically significant genes associated with cardiovascular diseases (CVD). Material and methods. We used the ClinVar and dbSNP databases, as well as sequencing data from samples from various Russian cohorts. Genome variant annotation was performed using the ENSEMBL VEP program. Results. Forty-two genes associated with 22 CVDs were selected, and indels in the genes from this sample, described in the ClinVar database, were analyzed. A wide range of indel numbers and their distribution by type of clinical significance was observed. Indels are significantly less common, but are more pathogenic than non-synonymous variants (missenses). Indels, as causal variants, are the rarest in cardiomyopathies, myopathies, and vascular diseases, while they are more common in arrhythmias and hypercholesterolemia. Pathogenic indels were shown to be rarely observed in sequence repeats or low-complexity regions, while benign indels were less frequently observed in sequence regions annotated as Pfam functional domains. Based on the analysis of >6800 sequenced samples from various Russian cohorts, we revealed that the studied pathogenic indels have a relatively high penetrance. Examples of pathogenic indels potentially specific to the Russian population are described. Conclusion. For the first time, the characteristics of a certain type of genomic variant (inframe indels) in key CVD genes have been systematically described. The obtained results highlight the clinical importance of causality and penetrance of protein indels, despite their lower prevalence compared to nonsynonymous variants.