How Functional Genomics Can Keep Pace With VUS Identification

Abstract

Over the last two decades, an exponentially expanding number of genetic variants have been identified associated with inherited cardiac conditions. These tremendous gains also present challenges in deciphering the clinical relevance of unclassified variants or variants of uncertain significance (VUS). This review provides an overview of the advancements (and challenges) in functional and computational approaches to characterize variants and help keep pace with VUS identification related to inherited heart diseases.

Contribution of Inherited Variants to Hereditary Cancer Syndrome Predisposition

“…While one of these patients had paraganglioma, the other had pheochromocytoma. The other pathogenic variants were at TP53(4), CHEK2(3), MSH2(3), MUTYH(3), MMLH1 (2), VHL (2), BLM (1), BRCA2 (1), MRE11 (1),MSH6(1), PTCH1(1) and RAD51D(1) genes. One patient diagnosed with colon cancer had compound heterozygosity for MUTYH gene.…”

“…Forty patients (43%) had variants which were assessed as variant of unknown significant in our study. VUS were detected at NBN, PMS1 (2), BUB1B (2), CTNNA1, SDHD (2), 2), BRIP1, PMS2, BARD1, RAD51C and APC (2) genes. Two patients had two/three VUS in different genes.…”

Interpreting the molecular mechanisms of disease variants in human transmembrane proteins

“…Our observations underline the importance of stability and the loss thereof in disease-causing variants of membrane proteins and thereby show how computational tools can aid in interpreting molecular mechanisms that underlie disease. Such functional understanding may help address the substantial challenge of classifying VUS ( Anderson et al, 2022 ). Given the limited number of variants and proteins within this study, utilizing recent advantages like the large excess of experimental structures derived from electron microscopy or computational models from e.g.…”

Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes

“…Because most variants in rare diseases occur in a very small number of individuals it is often difficult to obtain sufficient clinical evidence to enable definitive evidence for pathogenicity on clinical data alone. Consequently, approximately half of all variants in genes implicated in cardiac diseases are classified as VUS ( Anderson et al, 2022 ). Functional assays hold great promise to help ease the burden of VUS and appropriately calibrated functional assays can provide up to strong functional evidence for variant classification ( Brnich et al, 2020 ).…”