Scientists at Northwestern and Case Western Reserve University School of Medicine have identified genes that can modify the intensity of congenital Long QT Syndrome, an inherited cardiac disorder that can cause heart arrhythmias and sudden cardiac death, according to a study published in the Journal of Clinical Investigation.
Alfred George, Jr., MD, chair and Magerstadt Professor of Pharmacology, was a co-author of the study, which according to the authors, could also serve as a paradigm for future investigations into inherited diseases.
Long QT Syndrome (LQTS) is a genetic disorder that affects the heart’s electrical cycle, elevating risk for arrhythmias and sudden cardiac death. Though it is a congenital disorder, the inheritance patterns for LQTS are complex and some people who carry disease-causing mutations remain asymptomatic, while other members of the same family experience symptoms, such as heart palpitations, fainting or cardiac arrest.
Investigating a large family from Cleveland with LQTS Type 2 caused by a known mutation in the gene KCNH2, the scientists sought possible genetic modifiers by looking for genetic variants in severely affected individuals that their mildly affected first-degree relatives lacked.
Using whole-exome sequencing coupled with patient-derived induced pluripotent stem cells (iPSC), the investigators eventually traced the symptomatic variability to differences in two genes: KCNK17 and REM2. Alone, a KCNK17 variant was observed to protect against LQTS, whereas the REM2 variant worsened the susceptibility to arrhythmia in the Cleveland family.
To confirm their findings, the scientists used gene editing to correct the REM2 variant in iPSCs and found that cardiac cell function became normal.
While LQTS is traditionally thought to be caused by a single gene, the compound effects of multiple gene variants — sometimes called a “double hit” — are well documented in LQTS and other cardiac diseases, and provide evidence that more genetic conditions might also have multiple drivers of disease. The authors note that their method — using iPSCs, next-generation exome sequencing and gene editing — might be useful to screen for genetic modifiers in populations at risk for other congenital diseases.
“The identification of modifier genes in human genetic disorders is very challenging,” said George, also director of the Center for Pharmacogenomics. “This study demonstrates successful integration of several state-of-the-art technologies that together enabled us to identify novel genetic modifiers of LQTS. We hope these results can be translated into strategies to better predict who is at highest risk for sudden death.”
This study was supported by NIH/NHLBI grant 1R01HL124245, American Heart Association Established Investigator Award 12EIA9300060, an American Heart Association Pre-Doctoral Fellowship from the Great Rivers Affiliate 15PRE25700037 and T32 Training Grant HL105338-01.
