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Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity
Sam Chai, … , Alfred L. George Jr., Isabelle Deschênes
Sam Chai, … , Alfred L. George Jr., Isabelle Deschênes
Published February 12, 2018
Citation Information: J Clin Invest. 2018;128(3):1043-1056. https://doi.org/10.1172/JCI94996.
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Research Article Cardiology Genetics

Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity

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Abstract

Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner. We found that iPSC-CMs recapitulated the clinical genotype-phenotype discordance in vitro. Importantly, iPSC-CMs derived from the severely affected LQT2 patients displayed prolonged action potentials compared with cells from mildly affected first-degree relatives. The iPSC-CMs derived from all patients with hERG R752W mutation displayed lower IKr amplitude. Interestingly, iPSC-CMs from severely affected mutation-positive individuals exhibited greater L-type Ca2+ current. Whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2, providing biologically plausible explanations for this variable expressivity. Genome editing to correct a REM2 variant reversed the enhanced L-type Ca2+ current and prolonged action potential observed in iPSC-CMs from severely affected individuals. Thus, our findings showcase the power of combining complementary physiological and genomic analyses to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. Furthermore, we propose that this strategy can be deployed to unravel myriad confounding pathologies displaying variable expressivity.

Authors

Sam Chai, Xiaoping Wan, Angelina Ramirez-Navarro, Paul J. Tesar, Elizabeth S. Kaufman, Eckhard Ficker, Alfred L. George Jr., Isabelle Deschênes

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Figure 1

Clinical details of carrier pairs in Cleveland LQT2 family.

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Clinical details of carrier pairs in Cleveland LQT2 family.
Zoomed-in sn...
Zoomed-in snapshot of the family pedigree that focuses on 5 individuals of the family we used to generate the carrier pairs along with their relevant patient history (see Methods for in-depth explanation of patient selection and phenotype binning criteria and Supplemental Table 2 for clinical details on all 26 R752W mutation–positive individuals). Individuals are referenced first by the generation number and then by the family member number, read from left to right (e.g., IV-3 is generation 4, family member 3). This reference system is used throughout the paper. The black square is the hERG mutation negative healthy male control. Blue circles and squares are females and males, respectively, who are mildly-affected-phenotype hERG R752W mutation–positive relatives. Red circles and squares are severely-affected-phenotype hERG R752W mutation–positive relatives. Hatched circles and squares are females and males, respectively, who are hERG R752W-carrying individuals who are not fully characterized in this study.
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