Sudden cardiac death is a major source of mortality in developed nations with an incidence rate of >300,000 persons/year. Mutations in KCNH2 (also referred to human Ether-a-go-go Related gene; hERG), the gene encoding for the pore forming subunit of the cardiac rapid acting inward rectifying potassium channel (IKr), cause Long QT Syndrome 2 (LQT2), which increases susceptibility to ventricular arrhythmias. Most often, a mutation in KCNH2 results in nonfunctioning potassium channels and a consequent reduction in potassium currents. As commonly observed in many cardiac channelopathies, even though LQTS is inherited in an autosomal dominant fashion, the pattern of inheritance and clinical phenotypes of these patients are complex and often display incomplete penetrance where disease-causing mutation carriers are asymptomatic. The causes for this variable clinical expressivity are currently not well understood, but as previously demonstrated by the sponsor, disease modifying genes are one of the potential explanations. Over many years the sponsor's group has studied clinically as well as in vitro a large LQT2 family carrying hERG R752W. Out of the 101 family members studied, 26 individuals carried the hERG R752W mutation. Syncope occurred in only 4 of the genetically affected family members displaying the incomplete penetrance of the disease. We hypothesize that the presence of disease modifying genes can explain the genotype-phenotype discordance observed in this LQT2 family. In this proposal, the applicant will elucidate the mechanisms of incomplete penetrance in this LQT2 family using cardiomyocytes differentiated from patient derived induced pluripotent stem cells (iPS) and exome sequencing. Based on our previous work, we hypothesize that patient-derived iPS differentiated cardiomyocytes (iPS-CM) faithfully recapitulate the arrythmogenic pathology and that heretofore unknown candidate genes revealed by exome sequencing account for variable phenotypic penetrance. The aims of this proposal are: 1. Demonstrate the electrophysiological variability of human cardiomyocytes derived from gene carriers in a large LQT2 family. 2. Identify through exome sequencing disease modifying genes underlying incomplete penetrance in a large LQT2 family. We will perform electrophysiological characterization and exome sequencing from iPS-CM derived from closely related LQT2 hERG R752W carrier pairs (father/son and sib pair) but displaying discordant clinical phenotype.
|Program type||Predoctoral Fellowship|
|Effective start/end date||07/01/2015 → 06/30/2017|