NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

Pasmant, Éric; Sabbagh, Audrey; Spurlock, Gillian; Laurendeau, Ingrid; Grillo, Elisa; Hamel, Marie-José; Martin, Ludovic; Barbarot, S.; Leheup, Bruno; Rodriguez, Diana; Lacombe, Didier; Dollfus, Hélène; Pasquier, Laurent; Isidor, Bertrand; Ferkal, Salah; Soulier, Jean; Sanson, Marc; Dieux-Coëslier, Anne; Bièche, Ivan; Parfait, Béatrice; Vidaud, Michel; Wolkenstein, Pierre; Upadhyaya, Meena; Vidaud, Dominique

doi:10.1002/humu.21271

Cited by 212 publications

(205 citation statements)

References 42 publications

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…2010; Pasmant et al. 2010). Such patients have a higher incidence of intellectual disability (mental retardation), developmental delay, dysmorphic facial features, the earlier appearance of cutaneous neurofibromas, and connective tissue abnormalities.…”

Section: Discussionmentioning

confidence: 99%

126 novel mutations in Italian patients with neurofibromatosis type 1

Bianchessi¹,

Morosini²,

Saletti³

et al. 2015

Molec Gen & Gen Med

View full text Add to dashboard Cite

Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation‐dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970_2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA‐based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients.

show abstract

Section: Discussionmentioning

confidence: 99%

126 novel mutations in Italian patients with neurofibromatosis type 1

Bianchessi¹,

Morosini²,

Saletti³

et al. 2015

Molec Gen & Gen Med

View full text Add to dashboard Cite

show abstract

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…4 Individuals with NF1 microdeletion syndrome have a more severe phenotype than those with NF1 due to intragenic mutations, with the microdeletion syndrome characterized by facial dysmorphisms, developmental delay (DD), intellectual disability (ID), and excessive neurofibromas. 5,6 The NF1 microdeletions are caused by nonallelic homologous recombination (NAHR) between the low-copy repeats (LCRs) that flank this region. 7 The deletions may be 1.0-1.4 Mb in size depending on the specific LCR mediating the deletion and are classified as types 1-3.…”

Section: Introductionmentioning

confidence: 99%

“…7 The deletions may be 1.0-1.4 Mb in size depending on the specific LCR mediating the deletion and are classified as types 1-3. [6][7][8][9][10][11] The most common NF1 microdeletion, type 1, is a 1.4-Mb deletion mediated by LCRs NF1-repeat (-REP) A and NF1-REP C (Figure 1) and is hypothesized to preferentially arise during meiotic NAHR. 8 Type 2 microdeletions have predominantly been seen as a result of mitotic NAHR and are 1.2 Mb in size with breakpoints within SUZ12 and its pseudogene SUZ12P adjacent to NF1-REP C and NF1-REP A, respectively (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] The 1.0-Mb type 3 NF1 microdeletions are the smallest of the three, mediated by LCRs NF1-REP B and NF1-REP C (Figure 1). 6,11 NAHR between LCRs, such as NF1-REPs A, B, and C, lead to both deletion and duplication of the intervening sequence. 15 For many of the recurrent microdeletion syndromes caused by NAHR, reciprocal microduplications have been identified and 16 has a reciprocal microduplication that is also characterized by variable phenotypes (OMIM 611936).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

Moles

Gowans

Gedela

et al. 2012

Genetics in Medicine

View full text Add to dashboard Cite

Purpose: Neurofibromatosis, type 1 (NF1) is an autosomal dominant disorder caused by mutations of the neurofibromin 1 (NF1) gene at 17q11.2. Approximately 5% of individuals with NF1 have a 1.4-Mb heterozygous 17q11.2 deletion encompassing NF1, formed through nonallelic homologous recombination (NAHR) between the low-copy repeats that flank this region. NF1 microdeletion syndrome is more severe than NF1 caused by gene mutations, with individuals exhibiting facial dysmorphisms, developmental delay (DD), intellectual disability (ID), and excessive neurofibromas. Although NAHR can also cause reciprocal microduplications, reciprocal NF1 duplications have been previously reported in just one multigenerational family and a second unrelated proband. methods:We analyzed the clinical features in seven individuals with NF1 microduplications, identified among 48,817 probands tested in our laboratory by array-based comparative genomic hybridization. Results:The only clinical features present in more than one individual were variable DD/ID, facial dysmorphisms, and seizures. No neurofibromas were present. Three sets of parents were tested: one duplication was apparently de novo, one inherited from an affected mother, and one inherited from a clinically normal father.conclusion: This is the first report comparing the phenotypes of nonrelated individuals with NF1 microduplications. This comparison will allow for further definition of this emerging microduplication syndrome.Genet Med 2012:14(5):508-514

show abstract

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

Cited by 212 publications

References 42 publications

126 novel mutations in Italian patients with neurofibromatosis type 1

126 novel mutations in Italian patients with neurofibromatosis type 1

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

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

Contact Info

Product

Resources

About