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

TitleEvidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome.
Publication TypeJournal Article
Year of Publication2013
AuthorsVatta, M, Niu, Z, Lupski, JR, Putnam, P, Spoonamore, KG, Fang, P, Eng, CM, Willis, AS
JournalAm J Med Genet A
Date Published2013 Dec
KeywordsAbnormalities, Multiple, CHARGE Syndrome, Child, DNA Helicases, DNA Replication, DNA-Binding Proteins, Exons, Female, Gene Deletion, Haploinsufficiency, Humans, Mutation

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.

Alternate JournalAm. J. Med. Genet. A
PubMed ID23956205
PubMed Central IDPMC3926511
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States