NF1 Microdeletion Syndrome: Refined FISH Characterization of Sporadic and Familial Deletions with Locus-Specific Probes

Abstract

Two familial and seven sporadic patients with neurofibromatosis 1-who showed dysmorphism, learning disabilities/mental retardation, and additional signs and carried deletions of the NF1 gene-were investigated by use of a two-step FISH approach to characterize the deletions. With FISH of YAC clones belonging to a 7-Mb 17q11.2 contig, we estimated the extension of all of the deletions and identified the genomic regions harboring the breakpoints. Mosaicism accounted for the mild phenotype in two patients. In subsequent FISH experiments, performed with locus-specific probes generated from the same YACs by means of a novel procedure, we identified the smallest region of overlapping (SRO), mapped the deletion breakpoints, and identified the genes that map to each deletion interval. From centromere to telomere, the approximately 0.8-Mb SRO includes sequence-tagged site 64381, the SUPT6H gene (encoding a transcription factor involved in chromatin structure), and NF1. Extending telomerically from the SRO, two additional genes-BLMH, encoding a hydrolase involved in bleomycin resistance, and ACCN1, encoding an amiloride-sensitive cation channel expressed in the CNS-were located in the deleted intervals of seven and three patients, respectively. An apparently common centromeric deletion breakpoint was shared by all of the patients, whereas a different telomeric breakpoint defined a deletion interval of 0.8-3 Mb. There was no apparent correlation between the extent of the deletion and the phenotype. This characterization of gross NF1 deletions provides the premise for addressing correctly any genotype-phenotype correlation in the subset of patients with NF1 deletions.

Novel and recurrent mutations in theNF1 gene in Italian patients with neurofibromatosis type 1

“…However, the DHPLC protocol used here might have failed to detect some mutations, since no technique is 100% sensitive. Large deletions, comprising the whole NF1 gene or a major part of it, multiexon deletions, large duplications or inversions, which together represent more than 15-25% of the total spectrum of NF1 mutations, would have escaped the DHPLC scanning (Cowley et al, 1998;Riva et al, 2000). Incomplete assessment of intronic and regulatory sequences may account for other unidentified mutations.…”

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

“…The array comprised a total of 14,207 oligonucleotide probes spanning the whole of chromosome 17, including 12 314 probes spanning a ~8 Mb interval surrounding the NF1 locus (~300 kb). This 8-Mb interval spanned the NF1 gene region and included the largest NF1 atypical microdeletions described in the literature (Riva P et al, 2000;Kehrer-Sawatzki et al, 2003;Venturin et al, 2004a;Pasmant et al, 2008). Details of the microarray design, including the 14,207 oligonucleotide probe chromosome locations, has been deposited in NCBI's GEO (Edgar et al, 2002) and are accessible through the GEO accession number GSE19730.…”

“…The typical type-2 microdeletion is smaller (1.2 Mb) and has breakpoints located in the SUZ12 gene (suppressor of zeste 12 homolog; NM_015355) and its pseudogene SUZ12P (Petek et al, 2003;KehrerSawatzki et al, 2004;Steinmann et al, 2007;Roehl et al, 2010). Even less frequent, atypical NF1 microdeletions with non-recurring breakpoints have also been reported (Riva et al, 2000;Kehrer-Sawatzki et al, 2003Venturin et al, 2004a;Mantripragada et al, 2006;Pasmant et al, 2008).…”

“…A more severe clinical phenotype has been reported in NF1 patients carrying genomic microdeletions that involve the entire NF1 gene, compare to patients with intragenic NF1 mutations. This contiguous gene syndrome does appear to include dysmorphic features (Upadhyaya et al, 1998;López Correa et al, 1999, 2000Streubel et al, 1999;Riva et al, 2000;Castle et al, 2003;Venturin et al, 2004b), learning disabilities (Tonsgard et al, 1997;Upadhyaya et al, 1998;Korf et al, 1999;López Correa et al, 1999, 2000Streubel et al, 1999;Riva et al, 2000;Castle et al, 2003;Descheemaeker et al, 2004;Venturin et al, 2004b), cardiovascular malformations (Riva et al, 2000;Venturin et al, 2004bVenturin et al, , 2005Mensink et al, 2006), childhood overgrowth (Spiegel et al, 2005), a higher tumour burden and earlier onset of benign neurofibromas (Leppig et al, 1997;López Correa et al, 2000;Castle et al, 2003), and probably, a higher incidence of MPNSTs (De Raedt et al, 2003) and other malignancies (López Correa et al, 2000). While many reports of NF1 microdeleted patients (currently > 150 cases) (Mensink et al, 2006) have been published since the initial study in 1992 (Kayes et al, 1992), to date, little is known about this genotype-phenotype correlation.…”

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

“…1 Hence, various microdeletion and duplication syndromes on chromosome 17 have been reported. [2][3][4][5][6][7] Deletions of chromosome band 17q24.2 are, however, rare. So far, only nine cases have been reported and five of these were large terminal aberrations ranging from 17q21.3 to qter.…”