The Germline Mutational Spectrum in Neurofibromatosis Type 1 and Genotype–Phenotype Correlations

Cooper, David Neil; Upadhyaya, Meena

doi:10.1007/978-3-642-32864-0_10

Cited by 7 publications

(6 citation statements)

References 116 publications

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“…NF1 may be caused by many different loss‐of‐function mutations of the NF1 gene . In about 5% of NF1 patients, microdeletions of the entire NF1 gene and surrounding genomic region are responsible for the disorder.…”

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confidence: 99%

Growth in neurofibromatosis 1 microdeletion patients

et al. 2015

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Microdeletions of the entire NF1 gene and surrounding genomic region occur in about 5% of patients with neurofibromatosis 1 (NF1). NF1 microdeletion patients usually have more cutaneous and plexiform neurofibromas and a higher risk of developing malignant peripheral nerve sheath tumors than other people with NF1. Somatic overgrowth has also been observed in NF1 microdeletion patients, an observation that is remarkable because most NF1 patients are smaller than average for age and sex. We studied longitudinal measurements of height, weight, and head circumference in 56 patients with NF1 microdeletions and 226 NF1 patients with other kinds of mutations. Although children with NF1 microdeletions were much taller than non-deletion NF1 patients at all ages after 2 years, the lengths of deletion and nondeletion NF1 patients were similar in early infancy. NF1 microdeletion patients tended to be heavier than other NF1 patients, but height or weight more than 3 standard deviations above the mean for age and sex was infrequent in children with NF1 microdeletions. Head circumference and age of puberty were similar in deletion and non-deletion NF1 patients. The pattern of growth differs substantially in deletion and non-deletion NF1 patients, but the pathogenic basis for this difference is unknown.

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confidence: 99%

Growth in neurofibromatosis 1 microdeletion patients

et al. 2015

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“…The mutation rate at the NF1 locus is one of the highest reported in any human disorder [8]; almost 50% of all NF1 patients exhibit a de novo NF1 mutation. The NF1 mutational spectrum is shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment [9]. Nearly 1,300 different inherited mutations of the NF1 gene have been reported as a cause of NF1; these vary in size from deletions spanning more than a megabase to subtle single base-pair substitutions that alter an encoded amino acid or the function of a splice junction [9].…”

Section: Introductionmentioning

confidence: 99%

“…The NF1 mutational spectrum is shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment [9]. Nearly 1,300 different inherited mutations of the NF1 gene have been reported as a cause of NF1; these vary in size from deletions spanning more than a megabase to subtle single base-pair substitutions that alter an encoded amino acid or the function of a splice junction [9]. In classical NF1 patients, NF1 gene mutations are detectable in 50% to 95% of individuals depending upon the mutation detection techniques employed and the source of tissue used for analysis [2,10].…”

Section: Introductionmentioning

confidence: 99%

Screening in silico predicted remotely acting NF1gene regulatory elements for mutations in patients with neurofibromatosis type 1

et al. 2013

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Neurofibromatosis type 1 (NF1), a neuroectodermal disorder, is caused by germline mutations in the NF1 gene. NF1 affects approximately 1/3,000 individuals worldwide, with about 50% of cases representing de novo mutations. Although the NF1 gene was identified in 1990, the underlying gene mutations still remain undetected in a small but obdurate minority of NF1 patients. We postulated that in these patients, hitherto undetected pathogenic mutations might occur in regulatory elements far upstream of the NF1 gene. In an attempt to identify such remotely acting regulatory elements, we reasoned that some of them might reside within DNA sequences that (1) have the potential to interact at distance with the NF1 gene and (2) lie within a histone H3K27ac-enriched region, a characteristic of active enhancers. Combining Hi-C data, obtained by means of the chromosome conformation capture technique, with data on the location and level of histone H3K27ac enrichment upstream of the NF1 gene, we predicted in silico the presence of two remotely acting regulatory regions, located, respectively, approximately 600 kb and approximately 42 kb upstream of the NF1 gene. These regions were then sequenced in 47 NF1 patients in whom no mutations had been found in either the NF1 or SPRED1 gene regions. Five patients were found to harbour DNA sequence variants in the distal H3K27ac-enriched region. Although these variants are of uncertain pathological significance and still remain to be functionally characterized, this approach promises to be of general utility for the detection of mutations underlying other inherited disorders that may be caused by mutations in remotely acting regulatory elements.

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“…The type 2 microdeletion spanning 1.2 Mb and type 3 spanning 1.0 Mb are less frequent (3)(4)(5)(6). Chromosomal rearrangements affecting one or several exons have also been observed (7). In addition, the human genome contains NF1 pseudogenes in chromosomes 2, 12, 14, 15, 18, 21 and 22 (8-12), which interfere with gDNA-based sequencing methods.…”

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confidence: 96%

Neurofibromatosis Type 1 Gene Mutation Analysis Using Sequence Capture and High-throughput Sequencing

Uusitalo¹,

Hammais²,

Palonen³

et al. 2014

Acta Derm Venerol

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Neurofibromatosis type 1 syndrome (NF1) is caused by mutations in the NF1 gene. Availability of new sequencing technology prompted us to search for an alternative method for NF1 mutation analysis. Genomic DNA was isolated from saliva avoiding invasive sampling. The NF1 exons with an additional 50bp of flanking intronic sequences were captured and enriched using the SeqCap EZ Choice Library protocol. The captured DNA was sequenced with the Roche/454 GS Junior system. The mean coverages of the targeted regions were 41x and 74x in 2 separate sets of samples. An NF1 mutation was discovered in 10 out of 16 separate patient samples. Our study provides proof of principle that the sequence capture methodology combined with high-throughput sequencing is applicable to NF1 mutation analysis. Deep intronic mutations may however remain undetectable, and change at the DNA level may not predict the outcome at the mRNA or protein levels.

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The Germline Mutational Spectrum in Neurofibromatosis Type 1 and Genotype–Phenotype Correlations

Cited by 7 publications

References 116 publications

Growth in neurofibromatosis 1 microdeletion patients

Growth in neurofibromatosis 1 microdeletion patients

Screening in silico predicted remotely acting NF1gene regulatory elements for mutations in patients with neurofibromatosis type 1

Neurofibromatosis Type 1 Gene Mutation Analysis Using Sequence Capture and High-throughput Sequencing

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