An autosomal dominant cardiac arrhythmia syndrome, ST Depression Syndrome, is caused by thede novocreation of a cardiomyocyte enhancer

Abstract

AbstractA substantial proportion of mutations underlying rare Mendelian diseases remain unknown, potentially because they lie in the non-coding genome. Here, we report the mapping of the causal mutation of an autosomal dominant cardiac arrhythmia syndrome, ST Depression Syndrome, which is associated with widespread ST-depression on the electrocardiogram together with risk of sudden death and heart failure, to the non-coding region of theKCNB1locus. Using genetic linkage analysis, we narrowed the associated region to 1cM of the genome and then with a genome editing approach, we show that the mutation, a small complex insertion-deletion, generates ade novogain-of-function enhancer that drives higher expression ofKCNB1in cardiomyocytes. This is the first report of a gain ofde novoenhancer function causing Mendelian disease. Critically, the tissue-specific gain-of-function regulatory change could be predicted using a deep neural network. Application of a similar framework will enable identification of causal non-coding mutations and affected genes in other rare diseases.