A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.

Huson, Susan M.; Compston, D. A. S.; Clark, Peggy; Harper, Peter S.

doi:10.1136/jmg.26.11.704

Cited by 481 publications

(319 citation statements)

References 22 publications

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“…Complications occur in some patients and include learning difficulties or mental retardation, focal neurological deficits, dysplastic skeletal lesions, hypertension, and, rarely, malignancy (Huson SM and Hughes R, 1994). The disease is fully penetrant and exhibits a mutation rate some 10-fold higher than that reported for most other disease genes (Huson et al, 1989). As a consequence, a high number of sporadic cases (up to 50%) is observed (Upadhyaya and Cooper, 1998).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, affecting 1 in 3500 individuals. NF1 is a fully penetrant exhibiting a mutation rate some 10-fold higher compared to most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of NF1 gene, the presence of pseudogenes and the great variety of lesions. In the present study we attempted to delineate the NF1 mutational spectrum in the Italian population reporting four-year experience with the direct analysis of the whole NF1 coding region in 110 unrelated subjects affected by NF1. For each patient, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, most often, by denaturing high performance liquid chromatography (DHPLC). Mutations were identified in 75 (68%) patients. Twenty-two mutations were found to be novel. The detection rate for the different methods was 7/18 (39%) for PTT, and 68/103 (66%) for DHPLC. The mutations were evenly distributed along the NF1 coding sequence. Thirty-two of the 75 unrelated NF1 patients in which germline mutations were identified (32/75, 43%) harbour 23 different recurrent mutations. Fifteen sequence variants likely to represent nonpathogenic polymorphisms were observed at the NF1 locus. Genotype-phenotype analysis was unable to detect any obvious correlation.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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“…Relative risks were calculated by dividing the observed numbers of cases of NF-I among patients with each type of leukaemia or lymphoma by the expected number, assuming the childhood population prevalence of NF-I of 1:2,558, which was estimated by Huson et al (1989) (Bader & Milkr, 1978;Narod et al, 1991). From (Sieff et al, 1981).…”

Section: Methodsmentioning

confidence: 99%

Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study

Stiller

Chessells²,

Fitchett³

1994

Br J Cancer

259

119

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Sm_mary There is a well-known raised risk of leukaemia in children with neurofibromatosis type 1 (NF-1).We carried out the first detailed population-based study of leukaemia and non-Hodgkin lymphoma (NHL) associated with NF-I in order to estimate the risk and elucidate the relationship between these conditions. Over the 17 year study period there were five cases of chronic myelomonocytic leukaemia (CMML) in patients with NF-1 (relative risk 221; 95% CI 71-514), 12 cases of acute lymphoblastic leukaemia (ALL) (relative nrsk 5.4; 95% CI 2.8-9.4) and five cases of NHL (relative risk 10.0; 95% CI 3.3-23.4). Marrow cytogenetics could be reviewed for seven patients. Specific abnormalities found were monosomy 21 in a child with CMML and 7p+, 17p-in a child with ALL. No abnormalities were reported of 17q, which includes the NFI gene. CMML occurred predominantly in boys, who also had a family history of NF-1. ALL and NHL were more often found in children with no previous family history.

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“…NF1 gene product, neurofibromin, is a 250 KDa hydrophilic protein comprising 2818 amino acids [Cawthon et al, 1990b]. The central region of neurofibromin displays marked homology with Ras-GTPase activation proteins (GAPs) that are involved in the negative regulation of RAS-mediated signal transduction pathways [Cichowski and Jacks, 2001].The mutation rate at the NF1 gene is estimated to be ~1x10 -4 /gamete/generation making it one of the highest of any human disease genes [Huson et al, 1989;Upadhyaya and Cooper, 1998]. Mutations encompass both single nucleotide substitutions and large genomic deletions [Stenson et al, 2003].…”

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Identification of forty-five novel and twenty-three knownNF1 mutations in Chinese patients with neurofibromatosis type 1

Lee

You

et al. 2006

Hum. Mutat.

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Neurofibromatosis type 1 (NF1), characterized by skin neurofibromas and an excess of café-au-lait spots, is due to mutations in the neurofibromin (NF1) gene. Identifying the genetic defect in individuals with the disease represents a significant challenge because the gene is extremely large with a high incidence of sporadic mutations across the entire gene ranging from single nucleotide substitutes to large deletions. In the present study, we have used a combination of techniques (heteroduplex analysis, sequencing, loss of heterozygosity and quantification of gene dosage) to define the genetic defect in 68 individuals from a cohort of 107 NF1 Taiwanese patients of Chinese origin. Fifty-eight were initially identified using heteroduplex analytical techniques and confirmed by sequence analysis. A further five were identified by direct sequence analysis alone. The reminders were shown to carry large deletions in the NF1 gene by demonstrating loss of heterozygosity that was confirmed by gene dosage measurements using quantitative-PCR techniques. Mis-sense, non-sense, frameshift or splice-site mutations were identified across the entire gene of which the majority (45/68) were novel in nature. The detection rate with the various analytical techniques and the types of mutation detected are consistent with published data involving both individuals and large cohort studies from other ethnic backgrounds. INTRODUCTIONWith a frequency of 1/3000 live births, Neurofibromatosis type 1 (NF1; MIM# 162200) is one of the most common autosomal dominant disorders involving the human nervous system [Friedman, 1999]. The clinical features of the disease include: café-au-lait spots, cutaneous or subcutaneous neurofibromas, large plexiform neurofibromas, Lisch nodules and skin freckling. Other features such as scoliosis, macrocephaly, pseudoarthrosis, short stature, mental sub-normality and malignancies are present in a minority of patients 1997]. Except for the discoloration of the skin (Café-au-lait macules), which can be identified at a very young age, most of the other clinical features usually occur insidiously after puberty.The NF1 gene (NM_000267.1), which spans approximately 350Kb of genomic sequence on chromosome 17q11.2, is composed of 60 exons coding an 8.9Kb mRNA [Cawthon et al., 1990a;Wallace et al., 1990]. NF1 gene product, neurofibromin, is a 250 KDa hydrophilic protein comprising 2818 amino acids [Cawthon et al., 1990b]. The central region of neurofibromin displays marked homology with Ras-GTPase activation proteins (GAPs) that are involved in the negative regulation of RAS-mediated signal transduction pathways [Cichowski and Jacks, 2001].The mutation rate at the NF1 gene is estimated to be ~1x10 -4 /gamete/generation making it one of the highest of any human disease genes [Huson et al., 1989;Upadhyaya and Cooper, 1998]. Mutations encompass both single nucleotide substitutions and large genomic deletions [Stenson et al., 2003]. Approximately a half of all mutations arise de novo and do not appear to be clustered within...

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A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.

Cited by 481 publications

References 22 publications

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

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

Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study

Identification of forty-five novel and twenty-three knownNF1 mutations in Chinese patients with neurofibromatosis type 1

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