An autosomal dominant cardiac arrhythmia syndrome, ST Depression Syndrome, is caused by the de novo creation of a cardiomyocyte enhancer

A 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 the KCNB1 locus. 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 a de novo gain-of-function enhancer that drives higher expression of KCNB1 in cardiomyocytes. This is the first report of a gain of de novo enhancer 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.