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Hum Genet. 2017 Jun;136(6):679-691. doi: 10.1007/s00439-017-1774-y. Epub 2017 Mar 16.

Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia.

Author information

1
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA. mlongoni@mgh.harvard.edu.
2
Department of Surgery, Harvard Medical School, Boston, MA, USA. mlongoni@mgh.harvard.edu.
3
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.
4
Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA.
5
Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
6
Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY, USA.
7
Department of Systems Biology, Columbia University, New York, NY, USA.
8
Department of Surgery, Harvard Medical School, Boston, MA, USA.
9
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
10
Departments of Pediatrics, Columbia University, New York, NY, USA.
11
The Jackson Laboratory, Bar Harbor, ME, USA.
12
Department of Biomedical Informatics, Columbia University, New York, NY, USA.
13
Department of Medicine, Columbia University, New York, NY, USA.

Abstract

Congenital Diaphragmatic Hernia (CDH) is a common and often lethal birth defect characterized by diaphragmatic structural defects and pulmonary hypoplasia. CDH is isolated in 60% of newborns, but may also be part of a complex phenotype with additional anomalies. We performed whole exome sequencing (WES) on 87 individuals with isolated or complex CDH and on their unaffected parents, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify new candidate genes. A combined analysis with 39 additional trios with complex CDH, previously published, revealed a significant genome-wide burden of de novo variants compared to background mutation rate and 900 control trios. We identified an increased burden of likely gene-disrupting (LGD, i.e. nonsense, frameshift, and canonical splice site) and predicted deleterious missense (D-mis) variants in complex and isolated CDH patients. Overall, an excess of predicted damaging de novo LGD and D-mis variants relative to the expected frequency contributed to 21% of complex cases and 12% of isolated CDH cases. The burden of de novo variants was higher in genes expressed in the developing mouse diaphragm and heart. Some overlap with genes responsible for congenital heart defects and neurodevelopmental disorders was observed in CDH patients within our cohorts. We propose that de novo variants contribute significantly to the development of CDH.

PMID:
28303347
PMCID:
PMC5453716
DOI:
10.1007/s00439-017-1774-y
[Indexed for MEDLINE]
Free PMC Article

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