title: De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia.
abstract: COUP-TFII (NR2F2) is mapped to the 15q26 deletion hotspot associated with the common and highly morbid congenital diaphragmatic hernia (CDH). Conditional homozygous deletions of COUP-TFII in mice result in diaphragmatic defects analogous to the human Bochdalek-type hernia phenotype. Despite evidence from animal models however, mutations in the coding sequence of COUP-TFII have not been reported in patients, prompting the speculation that additional coding or non-coding sequences in the 15q26 locus are necessary for diaphragmatic hernias to develop. In this report, we describe a case of a patient with a heterozygous de novo COUP-TFII frameshift mutation, presenting with CDH and an atrial septal defect. The p.Pro33AlafsTer77 mutation specifically disrupts protein isoform 1 which contains the DNA binding domain. In addition, we review other COUP-TFII sequence variations and deletions that have been described in cases of CDH. We conclude that COUP-TFII mutations can cause diaphragmatic hernias, and should be included in the differential diagnosis of CDH patients, particularly those with comorbid congenital heart defects. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts.|Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Department of Surgery, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Frances A
authors.initials: FA
authors.lastname: High
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Pooja
authors.initials: P
authors.lastname: Bhayani
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Surgery, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Jay M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Bult
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Mauro
authors.initials: M
authors.lastname: Longoni
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D000483:Alleles; D051837:COUP Transcription Factor II / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D005838:Genotype; D065630:Hernias, Diaphragmatic, Congenital / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D051837:COUP Transcription Factor II; C095569:NR2F2 protein, human
keywords: 15q26; COUP-TFII; NR2F2; atrial septal defect; congenital diaphragmatic hernia; de novo; pleuroperitoneal folds; trio