De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia

Am J Med Genet A. 2016 Sep;170(9):2457-61. doi: 10.1002/ajmg.a.37830. Epub 2016 Jul 1.

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.

Keywords: 15q26; COUP-TFII; NR2F2; atrial septal defect; congenital diaphragmatic hernia; de novo; pleuroperitoneal folds; trio.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics
  • Alleles
  • COUP Transcription Factor II / genetics*
  • DNA Mutational Analysis
  • Female
  • Frameshift Mutation*
  • Genetic Association Studies*
  • Genotype
  • Hernias, Diaphragmatic, Congenital / diagnosis*
  • Hernias, Diaphragmatic, Congenital / genetics*
  • Humans
  • Infant, Newborn
  • Male
  • Pedigree
  • Phenotype*
  • Polymorphism, Single Nucleotide

Substances

  • COUP Transcription Factor II
  • NR2F2 protein, human