Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia

J Med Genet. 2011 May;48(5):299-307. doi: 10.1136/jmg.2011.089680.

Abstract

Background: Congenital diaphragmatic hernia (CDH) is a life threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified.

Objective: To identify genomic alterations that contribute to the development of diaphragmatic defects.

Methods: A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations was screened for genomic alterations by array comparative genomic hybridisation or single nucleotide polymorphism based copy number analysis.

Results: Genomic alterations that were likely to have contributed to the development of CDH were identified in 8 patients. Inherited deletions of ZFPM2 were identified in 2 patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was identified in a patient with a partial pentalogy of Cantrell phenotype.

Conclusions: Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. These data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH related genes on chromosomes 16p11.2, 11q23-24 and 13q12, and suggest a possible role for FZD2 and Wnt signalling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Child, Preschool
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 1
  • Chromosomes, Human, Pair 11
  • Chromosomes, Human, Pair 16
  • Chromosomes, Human, Pair 17
  • Chromosomes, Human, Pair 8
  • Comparative Genomic Hybridization
  • DNA-Binding Proteins / genetics
  • Diaphragmatic Eventration / genetics
  • Female
  • Genome, Human / genetics*
  • Hernia, Diaphragmatic / diagnostic imaging
  • Hernia, Diaphragmatic / genetics
  • Hernias, Diaphragmatic, Congenital
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mutation / genetics
  • Radiography
  • Transcription Factors / genetics

Substances

  • DNA-Binding Proteins
  • Transcription Factors
  • ZFPM2 protein, human