Zaidi et al are reporting in Nature the identification of several de novo mutations in genes in the H3K4me pathway in patients with Congenital Heart Disease (CHD). The genes were identified after comparing the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent–offspring trios. After selecting for damaging mutations (premature termination, frameshift, splice site) statistical analysis has identified the H3K4me pathway as the only gene set with significant enrichment in the patients versus controls. Consistent with this observation many of those genes showed higher expression in E14.5 mouse heart. Based on their results the authors have also estimated the total number of genes involved in CHD t0 401 (95% confidence interval, 197-813). Despite the significant findings of the study, the fraction of patients with de novo mutations accounted only for the 10% of the total number and the authors argue that additional rare non-coding mutations as well as rare and/or common transmitted variants in combination with environmental factors acting in critical developmental windows may contribute in the development of CHD.
Periklis Makrythanasis, MD, PhD