title: Characterization of a 7.6-Mb germline deletion encompassing the NF1 locus and about a hundred genes in an NF1 contiguous gene syndrome patient.
abstract: We describe a large germline deletion removing the NF1 locus, identified by heterozygosity mapping based on microsatellite markers, in an 8-year-old French girl with a particularly severe NF1 contiguous gene syndrome. We used gene-dose mapping with sequence-tagged site real-time PCR to locate the deletion end points, which were precisely characterized by means of long-range PCR and nucleotide sequencing. The deletion is located on chromosome arm 17q and is exactly 7 586 986 bp long. It encompasses the entire NF1 locus and about 100 other genes, including numerous chemokine genes, an attractive in silico-selected cerebrally expressed candidate gene (designated NUFIP2, for nuclear fragile X mental retardation protein interacting protein 2; NM_020772) and four microRNA genes. Interestingly, the centromeric breakpoint is located in intron 4 of the PIPOX gene (pipecolic acid oxidase; NM_016518) and the telomeric breakpoint in intron 5 of the GGNBP2 gene (gametogenetin binding protein 2; NM_024835) coding a transcription factor. As PIPOX and GGNBP2 have the same transcriptional orientation, we postulated, and then confirmed, the existence of a chimeric transcript. This transcript, and/or haploinsufficiency of one or several deleted genes, could explain the clinical severity of the syndrome in this patient.
authors.affiliation: UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France. eric.pasmant@etu.univ-paris5.fr
authors.forename: Eric
authors.initials: E
authors.lastname: Pasmant
authors.forename: Aurélie
authors.initials: A
authors.lastname: de Saint-Trivier
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.forename: Anne
authors.initials: A
authors.lastname: Dieux-Coeslier
authors.forename: Béatrice
authors.initials: B
authors.lastname: Parfait
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Dominique
authors.initials: D
authors.lastname: Vidaud
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
mesh_terms: D001483:Base Sequence; D002648:Child; D020451:Contig Mapping; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D023061:Gene Order; D016514:Genes, Neurofibromatosis 1; D018095:Germ-Line Mutation; D006801:Humans; D009456:Neurofibromatosis 1 / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome