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Nat Genet. 2017 Jul;49(7):1152-1159. doi: 10.1038/ng.3870. Epub 2017 May 22.

The complex genetics of hypoplastic left heart syndrome.

Author information

1
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
2
The Jackson Laboratory, Bar Harbor, Maine, USA.
3
Pathology &Laboratory Medicine and the Electron Microscope Research Core, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
4
Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
5
Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
6
Division of Cardiology, Children's National Medical Center, Washington, D.C., USA.
7
Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
8
Department of Cell Biology, Center for Biological Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
9
Division of Cardiology, University of San Diego School of Medicine, San Diego, California, USA.
10
Department of Pediatrics, Division of Cardiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
11
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
12
Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Abstract

Congenital heart disease (CHD) affects up to 1% of live births. Although a genetic etiology is indicated by an increased recurrence risk, sporadic occurrence suggests that CHD genetics is complex. 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 HLHS. 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.

PMID:
28530678
PMCID:
PMC5737968
DOI:
10.1038/ng.3870
[Indexed for MEDLINE]
Free PMC Article

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