Evidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome

Am J Med Genet A. 2013 Dec;161A(12):3182-6. doi: 10.1002/ajmg.a.36178. Epub 2013 Aug 16.


Haploinsufficiency of CHD7 (OMIM# 608892) is known to cause CHARGE syndrome (OMIM# 214800). Molecular testing supports a definitive diagnosis in approximately 65-70% of cases. Most CHD7 mutations arise de novo, and no mutations affecting exon-7 have been reported to date. We report on an 8-year-old girl diagnosed with CHARGE syndrome that was referred to our laboratory for comprehensive CHD7 gene screening. Genomic DNA from the subject with a suspected diagnosis of CHARGE was isolated from peripheral blood lymphocytes and comprehensive Sanger sequencing, along with deletion/duplication analysis of the CHD7 gene using multiplex ligation-dependent probe amplification (MLPA), was performed. MLPA analysis identified a reduced single probe signal for exon-7 of the CHD7 gene consistent with potential heterozygous deletion. Long-range PCR breakpoint analysis identified a complex genomic rearrangement (CGR) leading to the deletion of exon-7 and breakpoints consistent with a replicative mechanism such as fork stalling and template switching (FoSTeS) or microhomology-mediated break-induced replication (MMBIR). Taken together this represents the first evidence for a CHD7 intragenic CGR in a patient with CHARGE syndrome leading to what appears to be also the first report of a mutation specifically disrupting exon-7. Although likely rare, CGR may represent an overlooked mechanism in subjects with CHARGE syndrome that can be missed by current sequencing and dosage assays.

Keywords: CHARGE syndrome; CHD7; FoSTeS/MMBIR; MLPA.

Publication types

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

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / physiopathology
  • CHARGE Syndrome / genetics*
  • CHARGE Syndrome / physiopathology
  • Child
  • DNA Helicases / genetics*
  • DNA Replication / genetics*
  • DNA-Binding Proteins / genetics*
  • Exons
  • Female
  • Gene Deletion
  • Haploinsufficiency
  • Humans
  • Mutation


  • DNA-Binding Proteins
  • DNA Helicases
  • CHD7 protein, human