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

Hum Genet
Authors
Keywords
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.

Year of Publication
2017
Journal
Hum Genet
Volume
136
Issue
6
Pages
679-691
Date Published
2017 Jun
ISSN
1432-1203
DOI
10.1007/s00439-017-1774-y
PubMed ID
28303347
PubMed Central ID
PMC5453716
Links
Grant list
HHSN268201100037C / HL / NHLBI NIH HHS / United States
P01 HD068250 / HD / NICHD NIH HHS / United States
R01 HD057036 / HD / NICHD NIH HHS / United States
UL1 RR024156 / RR / NCRR NIH HHS / United States