Modifying Mendel Redux: Unbiased Approaches Can Find Modifiers.

Abstract

Congenital heart disease (CHD) is one of the most common groups of birth defects,1 contributing to a major portion of mortality in early childhood and consuming large amounts of healthcare and family resources. They have a birth prevalence of 6 to 8/1000 live births, excluding late recognized defects, such as bicuspid aortic valve, which has a population frequency of 1% to 2%.1 See Article by Guo et al Genetic epidemiology studies and reports of multiple recurrences of CHDs within families demonstrate a strong genetic component. Familial clustering of CHDs is particularly apparent when grouped by developmental mechanism.2 A recent large study using hundreds of these multiplex families confirmed the concept of grouping CHD by developmental mechanism, and supporting animal data suggest that these groupings are because of perturbations of genetic networks important in cardiogenesis.3 Indeed, of all risk factors for CHD, a family history of CHD has the highest relative risk even over maternal diabetes mellitus or twinning.4 More formal segregation analyses have confirmed the strong genetic component, also noting that the inheritance pattern is likely complex and oligogenic.2 This evidence for the genetic basis of CHD spurred investigators to search for responsible loci and genes. A few early successes occurred using the traditional genetic approach of linkage, identifying pathogenic variants in NKX2-5 ,5 NOTCH1 ,6 and GATA4 7 among multiplex families with CHDs. Unfortunately, further successes have been scarce, with the exception of CHDs occurring as part of a syndrome (such as the RASopathies). Genome-wide association studies for specific groups of CHD have added a few more loci but with limited replications in a second study.8,9 Copy number variant studies have identified novel genomic disorders in as many as 20% of syndromic cases, a few percent of nonsyndromic …