title: Evidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome.
abstract: 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.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Matteo
authors: M
authors: Vatta
authors: Zhiyv
authors: Z
authors: Niu
authors: James R
authors: JR
authors: Lupski
authors: Philip
authors: P
authors: Putnam
authors: Katherine G
authors: KG
authors: Spoonamore
authors: Ping
authors: P
authors: Fang
authors: Christine M
authors: CM
authors: Eng
authors: Alecia S
authors: AS
authors: Willis
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D058747:CHARGE Syndrome / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D004265:DNA Helicases / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D017353:Gene Deletion; D057895:Haploinsufficiency; D006801:Humans; D009154:Mutation
chemical_list: D004268:DNA-Binding Proteins; D004265:DNA Helicases; C491434:CHD7 protein, human
keywords: CHARGE syndrome; CHD7; FoSTeS/MMBIR; MLPA
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