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

Matteo Vatta, Zhiyv Niu, James R. Lupski, Philip Putnam, Katherine G. Spoonamore, Ping Fang, Christine M. Eng, Alecia S. Willis

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3182-3186
Number of pages5
JournalAmerican Journal of Medical Genetics, Part A
Issue number12
StatePublished - Dec 2013


  • CHARGE syndrome
  • CHD7
  • MLPA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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