Abstract P1120: Project Singular: Building A Large-scale Genetics Dataset To Fuel Research Towards Curative Solutions For Single Ventricle Heart Disease

Abstract

Objective: Single ventricle (SV) heart disease is a set of rare conditions occurring in 5 out of 100,000 births. Forty years ago, such diagnoses were universally fatal, but surgical advances have enabled most patients to live into their thirties. However, SV patients face a lifetime of expensive, invasive clinical care for complications and co-morbidities and decreased life expectancy and quality of life. The cause of SV heart disease is still unknown; believed to be both Mendelian and non-Mendelian, multigenic and multifactorial. To date, four genes have been linked to SV disease; however, the penetrance is low, and none are causal. Project Singular aims to uncover the cause(s) of SV by sequencing at least 5,000 SV patients and immediate family members, in conjunction with collecting important medical data, creating the largest genetic dataset available to date in this disease community and make it available free of charge to all qualified researchers. Methods: Subjects will be recruited and consented virtually through an online portal and will receive a biospecimen collection kit (saliva or buccal) by mail to return to the Broad Institute of MIT and Harvard. Samples will be processed, quality-controlled, and whole genome-sequenced using Illumina HiSeq at 30X coverage, with methylation arrays conducted on a subset. Sequences will be aligned to the human genome, annotated, deidentified, and securely deposited into the Terra.bio platform. Participants will fill out a survey on demographics and medical history, and patients will provide medical records. Deidentified phenotypic and genotypic data will be made available for free to qualified researchers globally. Integration with other SV-related registries will be undertaken where possible to increase the power of the study. Conclusion: Project Singular is the first genetics sequencing initiative of its size and depth focused specifically on SV, the most complex of all congenital heart defects. By enabling patients and families to participate from their homes, Project Singular will reduce barriers of travel and cost to increase diversity of participants. Data democratization of the dataset will fuel discovery in single ventricle etiology and lead to new targeted treatments and potentially curative solutions.