Neurofibromatosis type 1: from genotype to phenotype

Pasmant, Éric; Vidaud, Michel; Vidaud, Dominique; Wolkenstein, Pierre

doi:10.1136/jmedgenet-2012-100978

Cited by 135 publications

(108 citation statements)

References 67 publications

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“…café-au-lait spots, axillary and inguinal freckling, iris hematomas and optic gliomas (Basile et al 2010, Relles et al 2010, Pasmant et al 2012. The prevalence of NF1 is about 1 in 3000 individuals.…”

Section: :9mentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

111

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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Section: :9mentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

111

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“…12 These large NF1 locus deletions have been associated with a more severe phenotype including an elevated risk for MPNSTs. [13][14] For patients with intragenic NF1 mutations (more than 90% of all NF1 cases), no clear-cut allele-phenotype correlations have been established so far [15][16][17][18] with the exception of a 3-bp inframe deletion (c.2970_2972delAAT) in exon 22 of the NF1 gene that has been associated with the absence of cutaneous neurofibromas. 19 Screen for NF1 gene lesions routinely identify up to 95% of pathological mutations assumed to be present in patients presenting with typical NF1.…”

Section: Introductionmentioning

confidence: 99%

Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

et al. 2014

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Molecular diagnosis of neurofibromatosis type 1 (NF1) is challenging owing to the large size of the tumour suppressor gene NF1, and the lack of mutation hotspots. A somatic alteration of the wild-type NF1 allele is observed in NF1-associated tumours. Genetic heterogeneity in NF1 was confirmed in patients with SPRED1 mutations. Here, we present a targeted next-generation sequencing (NGS) of NF1 and SPRED1 using a multiplex PCR approach (230 amplicons of B150 bp) on a PGM sequencer. The chip capacity allowed mixing 48 bar-coded samples in a 4-day workflow. We validated the NGS approach by retrospectively testing 30 NF1-mutated samples, and then prospectively analysed 279 patients in routine diagnosis. On average, 98.5% of all targeted bases were covered by at least 20X and 96% by at least 100X. An NF1 or SPRED1 alteration was found in 246/279 (88%) and 10/279 (4%) patients, respectively. Genotyping throughput was increased over 10 times, as compared with Sanger, with B90h for consumables per sample. Interestingly, our targeted NGS approach also provided quantitative information based on sequencing depth allowing identification of multiexons deletion or duplication. We then addressed the NF1 somatic mutation detection sensitivity in mosaic NF1 patients and tumours.

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“…The biologic underpinnings of cognitive performance are difficult to identify given the complexity of NF1 phenotype 29 . However, findings of brain abnormalities such as reduced white matter integrity, macrocephaly, abnormal gamma-aminobutyric acid activity, among others have provided converging evidences for impaired communication between the neural regions, and early myelin dysfunction in NF1 has been hypothesized to underlie cognitive deficits.…”

Section: Nf1 Cognitive and Behavioral Featuresmentioning

confidence: 99%

Neurofibromatosis: part 2 – clinical management

Batista

Goloni-Bertollo

Costa

et al. 2015

Arq. Neuro-Psiquiatr.

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Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.Keywords: neurofibromatosis, neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis, Legius syndrome. resumo A primeira parte desta diretriz abordou o diagnóstico diferencial das neurofibromatoses (NF): neurofibromatose do tipo 1 (NF1), neurofibromatose do tipo 2 (NF2) e schwannomatose (SCH). As NF compartilham algumas características, como a origem neural dos tumores e sinais cutâneos, e afetam cerca de 80 mil brasileiros. O aumento do conhecimento científico sobre as NF tem permitido melhor manejo clínico e redução da morbidade das complicações, resultando em melhor qualidade de vida para os pacientes com NF. A maioria dos médicos é capaz de realizar o diagnóstico das NF, mas a variedade de manifestações clínicas e a dificuldade de se prever o surgimento e a gravidade de complicações, torna o manejo da NF um desafio para o clínico e envolve diferentes especialistas para o tratamento adequado e aconselhamento genético, especialmente a NF2 e a SCH. O presente texto sugere algumas orientações para o acompanhamento dos portadores de NF, com ênfase na NF1.Palavras-chave: neurofibromatoses, neurofibromatose 1, neurofibromatose 2, schwannomatose, síndrome de Legius. 532Arq Neuropsiquiatr 2015;73(6): [531][532][533][534][535][536][537][538][539][540][541][542][543] Part 1 of this guideline addressed differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH) 1 . This second part aims to offer some practical suggestions on the clinical management of NF.NF shares some features, such as the genetic origin of the neural tumors, cutaneous manifestations, heterogeneous phenotype and unpredictable and usually progressive natural course. However, they differ in age of onset, progression of the symptoms and prognosis. Moreover, NF clinical presentation and severity vary among patients and even between twins carrying the same NF gene mutation 2 . The wide range of NF clinical manifestations and the difficulties to predict the onset or the severity of new features, consequences, o...

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Neurofibromatosis type 1: from genotype to phenotype

Cited by 135 publications

References 67 publications

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

Neurofibromatosis: part 2 – clinical management

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