Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants

Abstract

Background: Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. Methods and Results:We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed race/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic/likely pathogenic variants in cardiac actionable genes (2%) and found evidence for clinical correlates in the electronic health record. African ancestry participants had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size, corrected for body surface area, from approximately 400 biobank participants (1,723 patient years) correlated with genetic findings. The presence of one or more uncertain variants in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance. Conclusions:These data indicate a subset of uncertain variants may confer risk and should not be considered benign.

Copy number variants and placental abnormalities in stillborn fetuses: a secondary analysis of the Stillbirth Collaborative Research Network study

“…22 Since VOUS CNVs should not be considered benign, we classified CNVs into two groups: abnormal CNVs (abnormal CNVs), defined as pathogenic CNVs (including aneuploidy) or VOUS, and normal CNVs (normal CNVs), defined as no CNVs > 500 kb or benign CNVs. [23][24][25] . As such, the abnormal CNVs and normal CNVs groups were compared in statistical analysis.…”

Analysis of missense variants in the human genome reveals widespread gene-specific clustering and improves prediction of pathogenicity

“…Achieving this goal relies critically on developing the capability to recognize the one or a few mutations that have a clinical impact among the hundreds of thousands of benign variants which are normally present in an individual's genome. 18,19 Next generation sequencing (NGS) is now being applied routinely in clinical diagnostic settings, 20 making the prediction of pathogenic DNA variants, and particularly of missense variants, a crucial element not only for medical research, but also in the context of patient diagnosis and disease management. The American College of Medical Genetics and Genomics (ACMG) has provided guidelines for the classification of variants into five categories: pathogenic, likely pathogenic, variants of uncertain significance (VUSs), likely benign, and benign, thereby establishing a terminology that has been widely adopted by the molecular genetics community.…”

Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

“…Analysis of cardiomyopathy testing at the Laboratory for Molecular Medicine revealed a lower likelihood of detecting a likely pathogenic or pathogenic variant—and a higher likelihood of a VUS—in individuals of African ancestry [ 75 ]. Furthermore, in individuals of African and Latino ancestry, VUSs in medically actionable cardiomyopathy genes are associated with clinical findings such as increased left ventricular diameter in systole and diastole [ 76 ]. As described above in a single DCM referral center, TTN truncating variants were enriched in individuals of European ancestry but not in individuals of African ancestry; reasons for this unexpected observation require further study [ 47 ].…”