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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.

SUBMITTER: Riva P

PROVIDER: S-EPMC1288315 | biostudies-literature | 2000 Jan

REPOSITORIES: biostudies-literature

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NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes.

Riva P P Corrado L L Natacci F F Castorina P P Wu B L BL Schneider G H GH Clementi M M Tenconi R R Korf B R BR Larizza L L

American journal of human genetics 20000101 1

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 pa ...[more]

PMID: 10631140

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Project description:BACKGROUND:17q11.2 microdeletions, which include the neurofibromatosis type 1 (NF1) gene region, are responsible for the NF1 microdeletion syndrome, observed in 4.2% of all NF1 patients. Large deletions of the NF1 gene and its flanking regions are associated with a more severe NF1 phenotype than the NF1 general population. CASE PRESENTATION:We hereby describe the clinical and molecular features of two girls (aged 2 and 4?years, respectively), with non-mosaic atypical deletions. Patient 1 showed fifteen café-au-lait spots and axillary freckling, as well as a Lisch nodule in the left eye, strabismus, high-arched palate, malocclusion, severe kyphoscoliosis, bilateral calcaneovalgus foot, mild generalized hypotonia, hyperactivity and deficits of speech-related abilities. NF1 genomic rearrangements through multiplex ligation-dependent probe amplification (MLPA) detected an heterozygous deletion of the whole NF1 gene. Array comparative genomic hybridization (a-CGH) analysis defined a 17q11.2 deletion of about 1?Mb (breakpoints at positions 29,124,299 and 30,151,654), which involved different genes (partially CRLF3, ATAD5, TEFM, ADAP2, RNF135, OMG, EVI2B, EVI2A, RAB11FIP4), including NF1. Patient 2 showed growth and developmental delay, supravalvular pulmonary stenosis, twenty-five café-au-lait spots, axillary freckling, craniofacial dysmorphic features, short neck with pterygium, limb abnormalities and foci of neural dysplasia on brain magnetic resonance imaging (MRI). MLPA detected an heterozygous deletion of NF1, which was detailed by a-CGH indicating the positions 29,124,299 and 30,326,958 as its breakpoints, and which included aside from the genes deleted in Patient 1 also COPRS, UTP6 and partially SUZ12. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletions in both cases. CONCLUSIONS:The present report will likely provide further insights and a better characterization of NF1 microdeletion syndrome.

Project description:Background: Cognitive impairment is the most common neurological manifestation in NF1 and occurs in 30-70% of NF1 cases. The onset and severity of each specific cognitive deficit varies greatly from child to child, with no apparent external causes. The wide variability of phenotype is the most complex aspect in terms of management and care. Despite multiple research, the mechanism underlying the high heterogeneity in NF1 has not yet been elucidated. While many studies have focused on the effects of specific and precise genetic mutations on the NF1 phenotype, little has been done on the impact of NF1 transmission (sporadic vs. familial cases). We used a complete neuropsychological evaluation designed to assess five large cognitive areas: general cognitive functions (WISC-IV and EVIP); reading skills ("L'Alouette," ODEDYS-2 and Lobrot French reading tests); phonological process (ODEDYS-2 test); visual perceptual skills (JLO, Thurstone and Corsi block tests) and attention (CPT-II), as well as psychosocial adjustments (CBCL) to explore the impact of NF1 transmission on cognitive disease manifestation in 96 children affected by NF1 [55 sporadic cases (29♀, 26♂); 41 familial cases (24♀, 17♂)]. Results: Familial and Sporadic form of NF1 only differ in IQ expression. The families' socioeconomic status (SES) impacts IQ performance but not differently between sporadic and familial variants. However, SES is lower in familial variants than in the sporadic variant of NF1. No other cognitive differences emerge between sporadic and familial NF1. Conclusions: Inheritance in NF1 failed to explain the phenotype variability in its entirety. IQ differences between groups seems in part linked to the environment where the child grows up. Children with NF1, and especially those that have early diagnoses (most often in inherited cases), must obtain careful monitoring from their early childhood, at home to strengthen investment in education and in school to early detect emerging academic problems and to quickly place them into care. Trial Registration: IDRCB, IDRCB2008-A01444-51. Registered 19 January 2009.

Dataset Information

NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes.

Publications

NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes.

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