WP3 objectives: 1) Improve variant classification and identify novel pathogenic variant classes affecting gene expression for established DCM genes. 2) Identify novel loci (GWAS) and genes (WGS) that will provide new substrate for target identification strategies. 3) Generate improved and more informative polygenic scores (PGS) from the GWAS and assess how they modify penetrance and disease severity.
Genomics studies for DCM-NEXT will use three data modalities. Taking advantage of the unprecedented size of existing clinical genetic gene panel datasets from the five centres, we will develop approaches to enhance variant interpretation and resolve genes of uncertain significance. SNP genotyping data will be completed for all samples and GWAS will be performed to identify significantly associated loci/genes for insights into disease pathophysiology and the identification of potential novel targets. From the GWAS datasets, we will explore the role of polygenic scores in influencing disease penetrance and expressivity. Genome sequencing will be applied to a large subset of the patients to identify novel genetic associations for DCM, including novel disease genes and rare and low frequency non-coding variation.