STMP identifies a likely functional regulatory variant in a novel candidate disease gene for neonatal ventricular arrhythmia.
A) Pedigree (left) and representative neonatal ECG from a proband with ventricular fibrillation (right). B) UCSC Genome Browser screenshot showing ENCODE regulatory tracks surrounding a novel variant in the 5’ UTR, rs4600103 (red box), found in cis with a nonsense variant in ATP2B4, as well as linked variant (r2 = 0.87) rs4951276 (green box). Tracks for chromatin accessibility, including DNaseI hypersensitivity, and promoter histone modification (H3K4M3) ChIP-seq data are shown for human cardiac myocytes (HCM), human cardiac fibroblasts (HCF) and heart tissue. DNaseI hypersensitivity clusters, transcription factor ChIP-seq and active histone modification (H3K27Ac) ChIP-seq data are shown for multiple ENCODE cell lines. C) Functional validation of common variants using allele-specific reporter assays. Common variants at ATP2B4, rs4600103 and rs4951276 were evaluated in luciferase reporter assays in HEK293 and H9c2. Values are expressed as relative fold change versus empty vector (pLuc) and represent mean ± SEM of triplicates from three independent experiments.