Bs-452757-1 novel precision genetic approach improves diagnosis and risk stratification in long qt syndrome type 5

Type 5 long QT syndrome (LQT5) is a subtype of long QT syndrome caused by loss of function variants in KCNE1 encoding a key potassium channel function-modifying subunit. LQT5 cases are rare and incompletely penetrant, so it has been controversial whether KCNE1 variants are disease-causing or risk-modifying. We identified 9 local LQT5 probands carrying the D76N KCNE1 variant, the most common variant implicated in LQT5. To test the hypothesis that these probands shared a recent common ancestor and to identify other potential D76N carriers in BioVU, our biobank that links electronic health records to DNA data. We used dense genomic arrays and identity-by-descent (IBD)-based genotype inference to identify shared chromosomal segments in the 9 probands and 3 first-degree relatives, and across BioVU. We determined penetrance (QTc > 490 msec) and the relationship of penetrance to a 1.1 million SNP QT interval polygenic risk score (PRS) in all mutation carriers. IBD analysis identified large (>1 cM) shared chromosomal segments across 8 of the 9 probands, indicating a shared common ancestor approximately 4-5 generations ago. Interrogation of array data in 69,879 European ancestry subjects in BioVU identified a further 26 subjects sharing the same large chromosomal segment, and sequencing confirmed D76N carrier status in 22 subjects, all previously undiagnosed. One BioVU subject had a history of sotalol-induced Torsades de Pointes. We found that among the 34 D76N carriers, QT intervals were prolonged compared to >32,000 BioVU controls free of heart disease or QT prolonging drugs, and that penetrance for QTc>490 was 44%. Among carriers, the QTc PRS was associated with severe QT prolongation. Detection of large shared chromosomal segments around KCNE1 enabled us to define a local founder event, identify previously undiagnosed carriers, demonstrate the contribution of polygenic risk to monogenic disease penetrance, and to further establish LQT5 as a primary arrhythmia disorder. The analysis of distant relatedness is a promising new approach to identify undiagnosed cases of genetic diseases.