De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.

Science. 2015 Dec 4;350(6265):1262-6. doi: 10.1126/science.aac9396.

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.

Homsy J1Zaidi S2Shen Y3Ware JS4Samocha KE5Karczewski KJ5DePalma SR6McKean D7Wakimoto H7Gorham J7Jin SC2Deanfield J8Giardini A8Porter GA Jr9Kim R10Bilguvar K11López-Giráldez F12Tikhonova I12Mane S12Romano-Adesman A13Qi H14Vardarajan B15Ma L16Daly M5,

Comment by Benjamin Landis


Our understanding of the genetic basis of congenital heart disease (CHD) was recently advanced in a major way by this recent publication by Homsy and colleagues from the Pediatric Cardiac Genetics Consortium and Pediatric Heart Network.  In an effort of unprecedented scale, 1213 CHD trios (each consisting of a proband with CHD and parents without known CHD) underwent whole exome sequencing to identify de novo variants (nonsense, frameshift, splice site, or predicted damaging missense variants) in the proband.  None of the subjects included was known to have a genetic syndrome associated with CHD.  In broad terms, there was a significantly higher number of damaging de novo variants in CHD cases than expected statistically, particularly among those with an extracardiac anomaly and/or neurodevelopmental delay (NDD).  Many of the genes containing de novo damaging variants were highly expressed during heart development.  Across the entire cohort, there were 21 genes containing more than 1 de novo damaging variant.  For the majority of these genes (16 of 21), the associated CHD phenotypes were heterogeneous between cases, highlighting variable expression.  Among these 21 genes, 7 were known CHD genes such as KMT2D (found in 6 cases) and PTPN11 (4 cases), which illustrates that genes classically associated with syndromes (Kabuki and Noonan syndromes, respectively) may cause CHD in the absence of recognized features.  Enrichment analysis of de novo damaging variants together reproduced the Consortium’s previous report that chromatin-modifying genes contribute to some cases of CHD.  The authors also hypothesize an important role for genes impacting RNA splicing such as RBFOX2 (3 cases).  Finally, a striking degree of overlap of de novo damaging variant genes was observed between the CHD cases with NDD and previously published findings in non-CHD NDD cohorts.  Many of these genes are expressed in both developing heart and brain, indicating shared genetic mechanisms between CHD and NDD.  Taken together, this study has identified a multitude of directions for future mechanistic study.  It is increasingly clear that disrupted gene regulation significantly contributes to CHD, and therefore the study of regulatory regions of the genome through whole genome sequencing will likely further elucidate the genetic basis of CHD.  Clinically, the compelling link between the genetic etiologies of CHD and NDD may facilitate genetic screening at a young age, implementation of early developmental interventions, and improved long term outcomes.