title: Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia.
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.
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA. mlongoni@mgh.harvard.edu.|Department of Surgery, Harvard Medical School, Boston, MA, USA. mlongoni@mgh.harvard.edu.
authors.forename: Mauro
authors.identifier: 0000-0001-9600-1160
authors.initials: M
authors.lastname: Longoni
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.|Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA.|Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Frances A
authors.initials: FA
authors.lastname: High
authors.affiliation: Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY, USA.|Department of Systems Biology, Columbia University, New York, NY, USA.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Qi
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Maliackal P
authors.initials: MP
authors.lastname: Joy
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Regis
authors.initials: R
authors.lastname: Hila
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Coletti
authors.affiliation: Departments of Pediatrics, Columbia University, New York, NY, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Wynn
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Loscertales
authors.affiliation: Departments of Pediatrics, Columbia University, New York, NY, USA.
authors.forename: Linshan
authors.initials: L
authors.lastname: Shan
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Bult
authors.affiliation: Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Jay M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, USA.|Department of Biomedical Informatics, Columbia University, New York, NY, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Departments of Pediatrics, Columbia University, New York, NY, USA.|Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
mesh_terms: D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D065630:Hernias, Diaphragmatic, Congenital / Q000235:genetics*; D006801:Humans; D011485:Protein Binding