Pilot Project

Bruce D. Gelb,
Bruce D. Gelb, MD
Director Child Health and Development Institute
Professor Pediatrics, Cardiology
Professor Medicine, Genetics and Genomic Sciences
Mount Sinai School of Medicine

Exome Sequencing for Cardiovascular Traits

Two highly collaborative investigators with expertise in cardiovascular genetics and genomic informatics, respectively, propose to identify disease-causing mutations for four cardiovascular disorders inherited in Mendelian or near-Mendelian fashion: progressive familial heart block type I, Teebi hypertelorism syndrome, familial atrial septal defects, and familial fibromuscular dysplasia with arterial dissections. For Aim 1, we will address the hypothesis that point mutations or small insertion/deletions cause these traits. We will perform exome sequencing based on recently developed DNA capture and deep resequencing techniques for 3-4 members of kindreds inheriting these traits, using the limited overlapping variants to reduce candidate sequence variant numbers. Exome sequencing-specific informatics tools developed at Mount Sinai will be used to analyze the data for each subject and then compare findings within kindreds. Resequencing of surviving DNA variants in the broader kindreds will establish the true mutation. In Aim 2, we will address the hypothesis that larger genomic events, copy number variants (CNVs), underlie one or more of these cardiovascular disorders. Using the exome data generated in Aim 1, informatics tools will be used to re-analyze the sequence traces to detect these CNVs. Candidate CNVs will be analyzed in the larger kindreds using custom-designed quantitative PCR assays. Taken together, this pilot project will utilize state-of-the-art genomic technology, recently deployed at Mount Sinai, to drive gene discovery for four cardiovascular traits. Such problems have only become tractable in recent months and promises to advance this form of translational research at a pace once unimaginable. If successful, the findings will immediately enable clinical gene testing for these traits and provide the requisite preliminary data for competitive federal grant applications.