Characterization of a 7.6-Mb germline deletion encompassing the NF1 locus and about a hundred genes in an NF1 contiguous gene syndrome patient.

European Journal of Human Genetics, 2008

Characterization of a 7.6-Mb germline deletion encompassing the NF1 locus and about a hundred genes in an NF1 contiguous gene syndrome patient.
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.
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.European Journal of Human Genetics advance online publication, 23 July 2008; doi:10.1038/ejhg.2008.134.