KCNQ1 and Long QT Syndrome in 1/45 Amish

Abstract

Background - In population-based research exome sequencing (ES), the path from variant discovery to return of results (rROR) is not well established. Variants discovered by research ES have the potential to improve population health. Methods - Population-based ES and agnostic ExWAS were performed 5,521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a KCNQ1 variant from VUS to pathogenic. Results were returned to participants in a community setting. Results - A missense variant was identified in KCNQ1 (c.671C>T, p.T224M), a gene associated with long QT syndrome (LQTS) type 1 (LQT1), which can cause syncope and sudden cardiac death (SCD). The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248,566 in gnomAD) and was highly associated with QTc on EKG (p = 5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 non-carriers. There was stronger clinical evidence of LQTS in carriers (38.6% vs 5.5%, p = 0.0006), greater history of syncope (32% vs 17%, p = 0.020), and higher rate of SCD in 1 st degree relatives < age 30 (4.5% vs 0%, p = 0.026). Expression of p.T224M KCNQ1 in CHO cells showed near complete loss of protein function. Our clinical and functional data enabled reclassification of p.T224M from a variant of unknown significance (VUS) to pathogenic. Of the 88 carriers, 93% met criteria for beta-blocker treatment and 5/88 (5.7%) were on medications that may further prolong QTc. Carriers were provided a CLIA confirmed report, genetic counseling and treatment recommendations. Follow up care was coordinated with local physicians. Conclusions - This work provides a framework by which research ES can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.

Associations of genome-wide and regional autozygosity with 96 complex traits in old order Amish

“…In the Amish, the lead association was between higher autozygosity measurements and QTc interval. Because the Amish study population is enriched for a known, high effect size, KCNQ1 pathogenic variant, p.Thr244Met, that increases QTc intervals, [ 29 ] we removed the KCNQ1 genomic region from the analysis and re-assessed the association. The association, although not statistically significant after Bonferroni correction, was still present and did not diminish.…”

The burden of pathogenic variants in clinically actionable genes in a founder population

“…The seven variants present in the Amish population within the 78 genes on the panel that have been classified as disease-causing pathogenic testing is currently underway in the Amish community for the KCNQ1 p.T224M variant, which is associated with long QT syndrome (Streeten et al, 2020). Individuals harboring at least one copy of the APOB p.R3527Q variant have not been notified of their genetic results, but LDL-C levels were reported back to all study subjects with alerts to those with elevated levels, including APOB p.R3527Q carriers (Shen et al, 2010).…”

“…From these, 12 met criteria for P/LP, although 5 of these were suspicious due to Mendel errors and the number of apparent "de novo" mutations (Table S2). We performed Sanger sequencing on representative heterozygotes for each of the 12 variants except two that we have previously shown to be real (APOB p.R3527Q (Shen et al, 2010) and KCNQ1 p.T224M (Streeten et al, 2020)). The five variants showing poor evidence for Mendelian segregation were determined to be artifacts.…”

“…The APOB p.R3527Q variant, pathogenic for familial hypercholesterolemia (FH, MIM #144010), is strongly associated with elevated LDL-C levels and coronary artery calcification (Shen et al, 2010). We have recently reported the KCNQ1 p.T224M (carrier frequency 2.28% in Amish; 0.0009% in European) variant to be pathogenic for long QT syndrome and associated with longer QT interval and increased risk of unexplained sudden death (Streeten et al, 2020). In total, 14.7% of our study population harbored at least one of these seven clinically actionable pathogenic variants; the percentage is 1.7% if all individuals harboring at least one APOB p.…”

Return of Results in Genomic Research Using Large-Scale or Whole Genome Sequencing: Toward a New Normal

“…The NIH has funded multiple major research consortia incorporating and studying the return of genomic results, such as the CSER Consortium (44) and eMERGE Network (37,41,50,114). Even the NHLBI's large Trans-Omics for Precision Medicine (TOPMed) Program, which comprises more than 80 studies, includes studies returning results (38,55,104) and has posted draft guidance on gRoR from its Ethical, Legal, and Social Issues Committee (76). All of this is contributing to a shift in research practice toward return of results.…”