From Single Variants to Protein Cascades

Abstract

Understanding the role of genetics in disease has become a central part of medical research. Non-synonymous single nucleotide variants (nsSNVs) in coding regions of human genes frequently lead to pathological phenotypes. Beyond single variations, the individual combination of nsSNVs may add to pathogenic processes. We developed a multiscale pipeline to systematically analyze the existence of quantitative effects of multiple nsSNVs and gene combinations in single individuals on pathogenicity. Based on this pipeline, we detected in a data set of 842 nsSNVs discovered in 76 genes related to cardiomyopathies, associated nsSNV combinations in seven genes present in at least 70% of all 639 patient samples, but not in a control cohort of healthy humans. Structural analyses of these revealed primarily an influence on the protein stability. For amino acid substitutions located at the protein surface, we generally observed a proximity to putative binding pockets. To computationally analyze cumulative effects and their impact, pathogenicity methods are currently being developed. Our approach supports this process, as shown on the example of a cardiac phenotype but can be likewise applied to other diseases such as cancer.

Association of Variants in BAG3 With Cardiomyopathy Outcomes in African American Individuals

“…The finding that each of these is pathogenic when evaluated in a biologic system emphasizes the lack of specificity of in silico pathogenicity prediction algorithms and the use of enhanced software and computational predictions in determining pathogenicity and providing annotation for SNVs. 42 The variants identified in the present study have not been recognized previously in cohorts of probands with familial DCM. This is likely because of the paucity of African American individuals in genetic studies of HF.…”