KCNQ1 and Long QT Syndrome in 1/45 Amish: The Road from Identification to Implementation of Culturally Appropriate Precision Medicine.

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 1st 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.