Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis

Louvrier, Camille; Pasmant, Éric; Briand-Suleau, Audrey; Cohen, Jérémy E.; Nitschké, Patrick; Nectoux, Juliette; Orhant, Lucie; Zordan, Cécile; Goizet, Cyril; Goutagny, Stéphane; Lallemand, Dominique; Vidaud, Michel; Vidaud, Dominique; Kalamaridès, Michel; Parfait, Béatrice

doi:10.1093/neuonc/noy009

Cited by 52 publications

(44 citation statements)

References 39 publications

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“…Patient 4 harbored c.764 T > G variant in exon 8 corresponding to the predicted missense p.(Leu255Arg). This patient’s variant was already reported [16]. This variant was not described in population databases and was predicted deleterious by several prediction softwares leading to a variant of unknown significance classification according to the American College of Medical Genetics recommendations [20].…”

Section: Resultsmentioning

confidence: 99%

“…DNA was isolated from peripheral blood leucocytes using the Maxwell® 16 system and Maxwell® 16 LEV Blood DNA Kit (Promega). NF2 , SMARCB1 and LZTR1 genes were investigated on the next-generation sequencing (NGS) facility of Cochin Hospital in Paris, France as already reported by Louvrier et al [16] Briefly, a custom Ampliseq panel targeting the coding sequences of these genes was designed using the Ampliseq Designer plugin [17]. Preparation of NGS libraries, amplification, purification, emulsion PCR, enrichment, loading on Ion 316™ chips, sequencing with an Ion Personal Genome Machine® (PGM™) System (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…Copy number variations (CNVs) analysis was also performed by using quantitative values (number of reads for each amplicon of each sample) of the Coverage Analysis plugin on the Ion Torrent Browser 5.0.4.0 (Life Technologies) [16].…”

Section: Methodsmentioning

confidence: 99%

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Segmental schwannomatosis: characteristics in 12 patients

Alaidarous

Parfait

Ferkal

et al. 2019

Orphanet J Rare Dis

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Background Segmental schwannomatosis is characterized by multiple schwannomas affecting one-limb or less than 5 contiguous segments of spine. Its characteristics are not well described in the literature. Our objective was to better describe the demographic and clinical characteristics of this condition. Methods This was a retrospective, bi-center study conducted in two French expert centers for neurofibromatosis and schwannomatosis. The clinical, radiographic, pathological and molecular aspects were extracted from patients’ clinical records. Results Twelve patients with segmental schwannomatosis were identified. Eight were female and 4 were male. The median age at initial symptom was 29 years (range: 6–60 years) and the median age at diagnosis was 34.5 years (range: 13–65 years). Pain was the initial symptom for the majority of patients (7 of 12). The number of tumors was variable with six patients having more than 10 tumors. Peripheral distribution was seen in all patients. Quality of life could be impaired (median Dermatology Life Quality Index score was 4.5 (range: 2–13). The median duration of follow up was 3 years (range: 1–26). Chronic pain was the main complication (9 of 12 patients). Surgical intervention to control chronic pain was performed for 9 patients of whom 5 experienced recurrence of tumors. Molecular investigations revealed heterozygous LZTR1 variants in 3 of 9 patients. Conclusion Segmental schwannomatosis is a rare condition that may start early in life and often remains undiagnosed for many years. Pain is the main symptom and consequently could impair the quality of life. Surgery seems to be effective, but recurrences are frequent. Some patients carried heterozygous LZTR1 variants. Further studies are needed to better understand this rare condition.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Segmental schwannomatosis: characteristics in 12 patients

Alaidarous

Parfait

Ferkal

et al. 2019

Orphanet J Rare Dis

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“…The most well-described genetic alteration is a mutation in the SMARCB1 gene or LZTR1 gene on chromosome 22q11.2. 13 In our case, these mutations were not present and instead a mutation in SOX10 was observed. While SOX10 has been used previously as an identifying marker for schwannomas, mutation of SOX10 as a contributor to the pathogenesis of schwannomatosis, to our knowledge, has not been previously reported.…”

Section: Discussionmentioning

confidence: 43%

Schwannomatosis of the Spinal Accessory Nerve: A Case Report

Morshed

Lee

et al. 2019

J Brachial Plex Peripher Nerve Inj

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Schwannomatosis is a distinct syndrome characterized by multiple peripheral nerve schwannomas that can be sporadic or familial in nature. Cases affecting the lower cranial nerves are infrequent. Here, the authors present a rare case of schwannomatosis affecting the left spinal accessory nerve. Upon genetic screening, an in-frame insertion at codon p.R177 of the Sox 10 gene was observed. There were no identifiable alterations in NF1, NF2, LZTR1, and SMARCB1. This case demonstrates a rare clinical presentation of schwannomatosis in addition to a genetic aberration that has not been previously reported in this disease context.

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“…It has been shown that 48% of familial and 9.8% of sporadic patients with schwannomatosis exhibit germline SMARCB1 mutations (Boyd et al, 2008;Hadfield et al, 2008;Hulsebos et al, 2007;Rousseau, Noguchi, Bourdon, Sobol, & Olschwang, 2011;Sestini, Bacci, Provenzano, Genuardi, & Papi, 2008;Smith, Wallace, Bowers, Eaton, & Evans, 2014;Smith et al, 2012). Genetic heterogeneity is observed in schwannomatosis since germline mutations in LZTR1 have also been identified in patients with the disease (Hutter et al, 2014;Louvrier et al, 2018;Paganini et al, 2015;Piotrowski et al, 2012;Smith et al, 2015). Furthermore schwannomatosis predisposition genes are likely to exist since germline mutations in SMARCB1 or LZTR1 are not detectable in at least 50% of sporadic patients with schwannomatosis (Kehrer-Sawatzki, Farschtschi, Mautner, & Cooper, 2017).…”

Section: Introductionmentioning

confidence: 99%

Co‐occurrence of schwannomatosis and rhabdoid tumor predisposition syndrome 1

Kehrer‐Sawatzki

Kordes

Seiffert

et al. 2018

Molec Gen & Gen Med

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BackgroundThe clinical phenotype associated with germline SMARCB1 mutations has as yet not been fully documented. It is known that germline SMARCB1 mutations may cause rhabdoid tumor predisposition syndrome (RTPS1) or schwannomatosis. However, the co‐occurrence of rhabdoid tumor and schwannomas in the same patient has not so far been reported.MethodsWe investigated a family with members harboring a germline SMARCB1 deletion by means of whole‐body MRI as well as high‐resolution microstructural magnetic resonance neurography (MRN). Breakpoint‐spanning PCRs were performed to characterize the SMARCB1 deletion and its segregation in the family.ResultsThe index patient of this family was in complete continuous remission for an atypical teratoid/rhabdoid tumor (AT/RT) treated at the age of 2 years. However, at the age of 21 years, she exhibited paraparesis of her legs and MRI investigations revealed multiple intrathoracic and spinal schwannomas. Breakpoint‐spanning PCRs indicated that the germline deletion segregating in the family encompasses 6.4‐kb and includes parts of SMARCB1 intron 7, exons 8–9 and 3.3‐kb located telomeric to exon 9 including the SMARCB1 3′ UTR. The analysis of sequences at the deletion breakpoints showed that the deletion has been caused by replication errors including template‐switching. The patient had inherited the deletion from her 56‐year‐old healthy mother who did not exhibit schwannomas or other tumors as determined by whole‐body MRI. However, MRN of the peripheral nerves of the mother's extremities revealed multiple fascicular microlesions which have been previously identified as indicative of schwannomatosis‐associated subclinical peripheral nerve pathology.ConclusionThe occurrence of schwannomatosis‐associated clinical symptoms independent of the AT/RT as the primary disease should be considered in long‐term survivors of AT/RT. Furthermore, our investigations indicate that germline SMARCB1 mutation carriers not presenting RTs or schwannomatosis‐associated clinical symptoms may nevertheless exhibit peripheral nerve pathology as revealed by MRN.

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Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis

Cited by 52 publications

References 39 publications

Segmental schwannomatosis: characteristics in 12 patients

Segmental schwannomatosis: characteristics in 12 patients

Schwannomatosis of the Spinal Accessory Nerve: A Case Report

Co‐occurrence of schwannomatosis and rhabdoid tumor predisposition syndrome 1

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