What we can learn from twins: congenital heart disease in the danish twin registry.

O ur understanding of the causes of congenital heart defects has benefited tremendously from state-of-the-art genetic and epigenetic tools. The rapid progress is due in part to the development of novel, high-throughput, cost-effective sequencing technology—so-called next-generation sequenc-ing—that has made it possible to sequence the entire genome or all genes (whole exome sequencing). However, to fully understand the causes of congenital heart disease, it has been important also to study population-based data that are available from large registries, which may take decades to establish. One such program has been in existence for >60 years and has provided novel insights into the genetic and environmental mechanisms of many diseases including congenital heart defects. The Danish Twin Registry is one of the oldest twin registries in the world, and it contains information about twins born in Denmark over the past 130 years. In the current study, Herskind et al 2 analyze data from the Danish Twin study, and the Danish National Patient Registry, as well, to examine the relationship of twin gestation to the development of congenital heart defects. Numerous investigators have suggested that twin gestation is associated with an increased risk of birth defects, including congenital heart disease. 3–5 In a large study of a California birth defects surveillance program, Hardin and colleagues 6 reported that the risk of congenital heart disease was significantly increased among twins for a variety of lesions. Lesions of the outflow tract had the strongest association with twin gestation. The present study confirms this association, demonstrating rather convincingly that twin gestation carries an increased risk for most forms of congenital heart disease. Twin studies have been particularly valuable in understanding the impact of genetic and environmental factors in the development of birth defects. When birth defects are more common among monozygotic twins than dizy-gotic twins, one would assume that vascular factors including the twin-twin transfusion syndrome play a critical role in teratogenesis. Alternatively, one might consider that the genetic factors that contribute to the process of monozygotic twinning might also contribute to the development of congenital heart disease. To date, there have been discrepant findings regarding the relationship of zygosity and the risk of developing congenital heart disease among twins. Most studies have suggested that birth defects are more common in monozygotic twins than in dizygotic twins. 6 Zygosity may not be easy to determine, especially in large public health data sets. Some investigators have sought to …