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

Abstract

Background: In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health.

Methods: Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a KCNQ1 variant from variant of unknown significance 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 type 1, which can cause syncope and sudden cardiac death. 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 electro-cardiogram (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 noncarriers. There was stronger clinical evidence of long QT syndrome in carriers (38.6% versus 5.5%, P=0.0006), greater history of syncope (32% versus 17%, P=0.020), and higher rate of sudden cardiac death in first degree relatives<age 30 (4.5% versus 0%, P=0.026). Expression of p.T224M KCNQ1 in Chinese hamster ovary cells showed near complete loss of protein function. Our clinical and functional data enabled reclassification of p.T224M from a variant of unknown significance 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 Clinical Laboratory Improvement Amendments confirmed report, genetic counseling, and treatment recommendations. Follow-up care was coordinated with local physicians.

Conclusions: This work provides a framework by which research exome sequencing can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.

Keywords: exome; genetic counseling; human; population health; syncope.

Figure 1.

Exome-wide analysis of QTc in 5 521 Amish subjects.A, Manhattan plot, Q-Q plot (insert). The red dotted line represents the threshold for genomewide significance (P<5×10⁻⁸) and the blue dotted line represents a threshold of P <1×10⁻⁶. B, LocusZoom plot of KCNQ1 region on chromosome 11 showing all variants with P<5×10⁻⁸, for our study population. Peak association at p.T224M (rs199472706): Age and sex adjusted β=20.2 msec; P=5.53×10⁻²⁴. The red dotted line represents the threshold for genomewide significance (P<5×10⁻⁸), and the linkage disequilibrium values are computed from the Amish. Recombination rate data are obtained from HapMap and may not necessarily pertain to the Amish. C, Boxplot comparing unadjusted mean QTc between KCNQ1 p.T224M carriers (CT) vs noncarriers (CC).

Figure 2.

Recontact, clinical follow-up, and return of results for p.T224M KCNQ1 carriers. Of the124 carriers offered return of results, 88 (71% of those who received initial letter, 86% of those who responded) were enrolled. All 88 participants received their results with individualized clinical recommendations.

Figure 3.

Higher maximal QTc in KCNQ1 p.T224M variant carriers (black bars) vs noncarriers (white bars). Group, QTc max±SD and N are shown below bars. C=p.T224M carrier; NC=noncarrier of p.T224M. TOTAL=men and women. The normal QTc for men is <450 ms; for women <460 ms. P values for comparisons: *<0.0001, **0.34, and ***0.0005.

Figure 4.

Family history of unexplained sudden deaths in children, crib deaths, and stillborns in the families of carriers of the KCNQ1 p.T224M variant. None of the children who died were genotyped for this variant, and none was known to be deaf.

Figure 5.

KCNQ1 T224M loss of IKs function.A and B, IKs recorded in Chinese hamster ovary (CHO) cells in which wild-type (WT) KCNQ1 or T224M were co-expressed with KCNE1 (the I_Ks accessory subunit). C and D, Summarize activating and deactivating I_Ks in the 2 groups of cells. The mutant T224M channel had significantly reduced total activating and deactivating currents, with a marked positive shift in the voltage dependence of activation, by ≈26 mV (P<0.01). Current densities were expressed in pA/pF after normalization of current amplitude to cell capacitance. The voltage clamp protocol is shown in the inset.