Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 16, Issue 12, Pages 1459-1466Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2008.134
Keywords
neurofibromatosis type 1; microdeletion; contiguous gene syndrome
Funding
- Association Neurofibromatoses et Recklinghausen
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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.
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