The complex genetics of hypoplastic left heart syndrome
X Liu, H Yagi, S Saeed, AS Bais, GC Gabriel, Z Chen, M Ganapathiraju… The complex genetics of hypoplastic left heart syndrome, Nature Genetics, 2017, http://dx.doi.org/10.1038/ng.3870
Congenital heart disease (CHD) affects up to 1% of live births1. Although a genetic etiology is indicated by an increased recurrence risk2, 3, sporadic occurrence suggests that CHD genetics is complex4. Here, we show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heterogeneous. Using mouse forward genetics, we report what is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLHS. Mutations from seven HLHS mouse lines showed multigenic enrichment in ten human chromosome regions linked to HLHS5, 6, 7. Mutations in Sap130 and Pcdha9, genes not previously associated with CHD, were validated by CRISPR–Cas9 genome editing in mice as being digenic causes of HLHS. We also identified one subject with HLHS with SAP130 and PCDHA13 mutations. Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, whereas Pcdha9 increases penetrance of aortic valve abnormalities, both signature HLHS defects. These findings show that HLHS can arise genetically in a combinatorial fashion, thus providing a new paradigm for the complex genetics of CHD.
- The incidence of congenital heart disease. J. Am. Coll. Cardiol. 39, 1890–1900 (2002). & The incidence of congenital heart disease. J. Am. Coll. Cardiol. 39, 1890–1900 (2002). &
- Patterns of recurrence of congenital heart disease: an analysis of 6,640 consecutive pregnancies evaluated by detailed fetal echocardiography. J. Am. Coll. Cardiol. 42, 923–929 (2003) , , &
- Recurrence of congenital heart defects in families. Circulation 120, 295–301 (2009). et al.
- Genetics of hypoplastic left heart syndrome. J. Pediatr. 173, 25–31 (2016). , &
- Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. J. Am. Coll. Cardiol. 53, 1065–1071 (2009) et al.
- Linkage analysis of left ventricular outflow tract malformations (aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome). Eur. J. Hum. Genet. 17, 811–819 (2009). et al.
- Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Hum. Genet. 121, 275–284 (2007) et al.