Congenital Heart Disease
Entering a New Era of Human Genetics
De Novo Mutations in Histone-Modifying Genes in Congenital Heart Disease
Zaidi et al
Congenital heart disease (CHD) remains a leading cause of morbidity and mortality in childhood and is the most common human birth defect, affecting nearly 1% of all live births worldwide. The morphogenetic events that are disrupted during cardiogenesis that lead to CHD are now partially understood, as are many of the molecular networks that guide normal heart development.1–4 Studies of rare Mendelian forms of familial CHD, as well as CHD associated with stereotypic syndromes, have revealed numerous single-gene mutations that cause CHD.1–5 However, mutations in these genes are infrequent in the more common sporadic form of CHD. Despite epidemiological evidence for an inherited component in sporadic CHD, the contribution of inherited variants or de novo mutations in the setting of CHD has been unclear. A recent landmark article in Nature6 begins to tackle this question by using modern genetic approaches and suggests that roughly 10% of sporadic CHD cases have de novo mutations that contribute significantly to the disease process.
The ability to perform DNA sequencing at a reasonable cost now allows the interrogation of rare, as well as common, variants in large populations. Although many complex traits have been studied using whole-genome or exome sequencing, a rate-limiting step in the CHD field has been acquisition of sufficient numbers of cases for meaningful statistical analysis. To address this, a National Heart, Lung, and Blood Institute–funded consortium of centers was established to recruit patients and parents into common studies to reveal the genetic underpinnings of CHD (Pediatric Cardiac Genomics Consortium).7 In the first report from this group, Zaidi et al6 sequenced the entire protein-coding exome from 362 trios of patients with a …