The Heritable Basis of Congenital Heart Disease

A heritable basis for congenital heart disease was probably first suggested more than a century ago by a report of 3 cyanotic siblings.1 In the early 1960s, Zetterqvist in Sweden and Pitt in Australia convincingly demonstrated autosomal dominant inheritance in 2 large, extended families who had atrial septal defects (ASDs) and tetralogy of Fallot, respectively.2,3 Of note, Pitt ascertained the diagnosis in 215 of 275 descendants of one man spanning 6 generations, many of whom he personally examined! In contrast, it took at least 2 dozen people to identify a missense mutation of α-cardiac actin ( ACTC1 ) as the cause of ASDs in the Swedish family.4 Their work, published in 2008, used linkage analysis, positional cloning, and Sanger DNA sequencing to diagnose one genetic mutation. Just 8 years later, White, Garg, and colleagues report in this issue their whole-exome sequencing (WES) analyses of 9 families. They identify the likely mutation in 3 families who had either ASDs or patent ductus arteriosus. Their stated goal was to demonstrate the clinical utility of WES in familial congenital heart disease.5 More broadly, their results highlight how far the field has come and how far it has to go in bringing genetics to pediatric cardiology.Article, see p 320 WES evaluates the ≈1% of the genome that encodes proteins. If a person’s disease is caused by a mutation in the exome, the sequence variant should be present in the WES output file of ≈3×107 nucleotides. A well-considered experimental design and bioinformatic pipeline are needed to filter the most plausible candidates from thousands of irrelevant variants. The investigators began by selecting families that demonstrate Mendelian patterns of a specific congenital heart defect, such as tetralogy of Fallot. Whether requiring the same defect in every affected family member increases the …