Elucidating Genotype-Phenotype Relationship of Polygenic Dilated Cardiomyopathies: Administrative Supplement (INCLUDE)

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PROJECT SUMMARY Down syndrome (DS) is the most common chromosomal abnormality affecting one in every 700 live births. Up to 50% of individuals born with DS, also known as trisomy 21 (T21), are born with a congenital heart disease (CHD). Despite the high frequency of DS-CHD, the exact mechanisms of DS-related CHD remain unknown. In this Supplement to the Parent R01 HL130020-5, we propose to leverage our established iPSC-based experimental models to understand the genetic basis of DS-CHD. We hypothesize that an interaction of genes between T21 and non-T21 mutations causes CHD in DS. Patients. In Aim 1, we will perform whole genome- sequencing (WGS) in DS patients with or without CHD to identify single nucleotide variants (SNV) associated with DS-CHD. In Aim 2, we will validate the pathogenicity of SNVs on development of CHDs in the presence of T21. We will use CRISPR/Cas9 to correct or insert the SNVs to iPSCs from control and DS patients to establish a genotype-phenotype relationship between SNVs and CHDs. Completing the aims of this supplement will likely increase our understanding of DS-related CHD as well as broaden the overall impact of the parent R01 award. In summary, this INCLUDE Administrative Supplement proposal will create novel opportunities to build a massive functional and sequencing database as well as iPSC biorepository that will be broadly shared with multi- disciplinary investigators. The combination of deep clinical phenotyping, the use of iPSC, CRISPR/Cas9 and multi-omic approaches will undoubtedly help to move this field forward and better understand DS-related cardiac pathologies.