Biology subjects

Salem, J.-E.

Publications and source records attributed to Salem, J.-E..

2 recordsLinked to original sources

bioRxiv2025

Patient-derived Cellular Models of Polygenic Scores: Application to Long QT Syndrome

Polygenic scores (PGS) have emerged as important modifiers of disease risk, drug response, and rare variant penetrance, but the biological mechanisms underlying these associations remain poorly understood. To experimentally investigate these relationships, we derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from individuals at the 1st, 50th, and 99th percentiles of a genome-wide QT interval polygenic score (QT-PGS). We examined baseline repolarization, drug response to the hERG inhibitor E4031, and penetrance of two KCNH2 variants (p.Arg148Trp and p.Arg823Trp) in these cellular models. While baseline field potential durations (FPDs) did not differ across PGS levels, high-PGS iPSC-CMs showed exaggerated prolongation in response to E4031 and increased phenotypic expression of both KCNH2 variants. These findings provide the first experimental demonstration that polygenic background can shape cardiac electrophysiologic phenotypes and modulate the functional impact of both pharmacologic and genetic perturbations. This work establishes a scalable platform for mechanistic studies of polygenic risk.

genetics↗

bioRxiv2019

Deep Mutational Scan of a cardiac sodium channel voltage sensor

Variants in ion channel genes have classically been studied in low-throughput by patch clamping. Deep Mutational Scanning (DMS) is a complementary approach that can simultaneously assess function of thousands of variants. We have developed and validated a method to perform a DMS of variants in SCN5A, which encodes the major voltage-gated sodium channel in the heart. We created a library of nearly all possible variants in a 36 base region of SCN5A in the S4 voltage sensor of domain IV and stably integrated the library into HEK293T cells. In preliminary experiments, challenge with three drugs (veratridine, brevetoxin, and ouabain) could discriminate wildtype channels from gain and loss of function pathogenic variants. High-throughput sequencing of the pre- and post-drug challenge pools was used to count the prevalence of each variant and identify variants with abnormal function. The DMS scores identified 40 putative gain of function and 33 putative loss of function variants. For 8/9 variants, patch clamping data was consistent with the scores. These experiments demonstrate the accuracy of a high-throughput in vitro scan of SCN5A variant function, which can be used to identify deleterious variants in SCN5A and other ion channel genes.

genetics↗