Population Sampling and in vitro Modeling of a 25bp Deletion in MYBPC3 Associated With Hypertrophic Cardiomyopathy. A. B. Chowdry1, M. A. Mandegar2, G. M. Benton1, B. T. Naughton1, B. R. Conklin2 1) 23andMe Inc., Mountain View, CA; 2) The Gladstone Institute of Cardiovascular Disease, San Francisco, CA.
Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death (SCD) in young athletes. The prevalence of HCM has been estimated to be as high as 1 in 500 within the general population. However, due to cost and sensitivity problems, it is not screened for in the United States.
The majority of mutations leading to HCM have been identified in sarcomeric proteins, mainly the cardiac isoform of myosin-binding protein C (MYBPC3). Advances in DNA analysis could allow low-cost screening for high penetrance mutations in MYBPC3 and could inform selective echocardiograms. Of particular interest is a recently discovered 25bp deletion (rs36212066), known to have a high carrier frequency in South Asians, but previously unobserved in European populations.
23andMe has a database of over 150,000 genotyped individuals. This database contains over 160 carriers of the rs36212066 deletion, some of European ancestry, suggesting that this mutation has a broader distribution than initially reported. We are also able to observe homozygotes in the database, though at a reduced frequency consistent with previous studies. The large size of the 23andMe database uniquely positioned it to detect these individuals. We have performed an initial survey of these individuals to determine self-reported HCM status, but further follow up may be necessary.
While in vitro models of HCM have been created in human induced pluripotent stem (iPS) cells, none have been made so far for MYBPC3. We are using Transcription Activator-Like Effector Nuclease (TALEN)-directed homologous recombination to make an allelic series of MYBPC3 mutations in a common genetic background, including a heterozygous knockout. We are also engineering a FLAG epitope tag to reveal key binding partners of the of the ancestral and mutant forms of MYBPC3 via immunoprecipitation from iPS-derived cardiac myocytes.
Our work on the in vitro cellular phenotypes of iPS cells carrying this mutation can eventually be extended to population phenotyping using the 23andMe database. These studies will help explain the pathology and incomplete penetrance of rs36212066 and may provide targets for pharmaceutical therapy.
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