DOI: 10.60645/bdc-ja3r-5cmj
title: PCGC Study - CMG Collaboration

description: 
This substudy phs001843 PCGC Study - CMG Collaboration contains whole genome sequences. Summary level phenotypes for the PCGC Cohort study participants can be viewed at the top-level study page [phs001194](./study.cgi?study_id=phs001194) PCGC Cohort. Individual level phenotype data and molecular data for all PCGC top-level study and substudies are available by requesting Authorized Access to the PCGC Cohort study [phs001194](./study.cgi?study_id=phs001194).

Mendelian cardiovascular disorders provide crucial insights into the genetic susceptibility to more common forms of cardiovascular disease. While Mendelian cardiovascular disorders are individually rare, collectively they impose a significant public health burden. This proposal focuses on 2 specific categories of cardiovascular disease for which we have extensive research expertise and existing cohorts, congenital heart disease (CHD) and inherited arrhythmia syndromes. The tremendous burden on the health care system and on families with these Mendelian cardiovascular disorders underscore the urgency to understand their genomic bases, in order to design improved strategies for risk stratification, surveillance and medical intervention. Emerging evidence supports the use of whole-genome sequencing (WGS) over whole-exome sequencing (WES) for detecting coding variants in discovery projects, in addition to the obvious advantages of detecting features invisible to WES: structural variants (SV) and non-coding variants. We believe the way forward lies in widening the scope for discovery to include the patient&#39;s entire genome - and all types of variants. While family-based studies are crucial for genomic discovery, obtaining a sufficient number of high-risk pedigrees to achieve meaningful conclusions remains a challenge for most research institutions. For this proposal, we will leverage 2 powerful resources for the identification, ascertainment and recruitment of high-risk cardiovascular disease pedigrees: (1) the NHLBI-sponsored Pediatric Cardiac Genomics Consortium (PCGC) and (2) the Utah Population Database (UPDB). We propose to perform WGS on PCGC and UPDB cohorts with autosomal dominant disease to achieve the following Specific Aims: Aim 1) Identify the genomic basis for CHD in high-risk pedigrees derived from the PCGC and UPDB; and Aim 2) Identify the genomic basis for inherited arrhythmia disorders, using extended pedigrees derived from the UPDB. Aim 2 focuses on familial forms of AF, undiagnosed Long QT Syndrome, Wolff-Parkinson White syndrome and progressive conduction disorders.

A WGS approach in high-risk pedigrees coupled with our validated bioinformatics pipeline, will allow the identification and prioritization of disease-causing SVs and sequence variants in coding and non-coding regulatory elements. These variants will be functionally characterized and validated in downstream experiments (heterologous expression systems, zebrafish cardiac assays, induced pluripotent stem cell-derived cardiomyocytes) that are beyond the scope of this X01. For this proposal, we have assembled the right combination of clinical expertise, resources for patient recruitment and computational know-how to enable these game-changing methodologies and to apply them to the challenge of cardiovascular Mendelian disease-gene discovery.