Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants

Hutter, Sonja; Piro, Rosario M.; Reuß, David; Hovestadt, Volker; Sahm, Felix; Farschtschi, Said; Kehrer‐Sawatzki, Hildegard; Wolf, Stephan; Lichter, Peter; Deimling, Andreas von; Schuhmann, Martin U.; Pfister, Stefan M.; Jones, David; Mautner, Victor

doi:10.1007/s00401-014-1311-1

Cited by 36 publications

(32 citation statements)

References 12 publications

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“…In the original publication, Pitrowski et al claimed that LZTR1 germline mutations could be found in 80% of schwannomatosis patients lacking germline mutations in SMARCB1 [47]. These numbers have been challenged by two independent groups claiming that LZTR1 are responsible for approximately 20% of the sporadic cases [41,51]. Hence, it is likely that there are additional schwannomatosis causing genes on chromosome 22q.…”

Section: Lztr1mentioning

confidence: 99%

Recent developments in brain tumor predisposing syndromes

2015

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Section: Lztr1mentioning

confidence: 99%

Recent developments in brain tumor predisposing syndromes

2015

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“…A combination of linkage analysis in affected families and mutation screening of the NF2 gene in schwannomas indicated that schwannomatosis is not due to germline mutations in the NF2 gene (Jacoby et al 1997; Kaufman et al 2003; MacCollin et al 2003). However, instead of constitutional (germline) NF2 mutations, independent somatic mutations affecting both NF2 alleles are frequently found in schwannomas of patients with schwannomatosis (Jacoby et al 1997; Kaufman et al 2003; Boyd et al 2008; Hadfield et al 2008; Sestini et al 2008; Hutter et al 2014; Paganini et al 2015a; Piotrowski et al 2014; Smith et al 2015, 2016). …”

Section: Introductionmentioning

confidence: 99%

“…So far, two schwannomatosis predisposition genes have been identified, SMARCB1 and LZTR1 (Hulsebos et al 2007; Sestini et al 2008; Hadfield et al 2008; Smith et al 2012b; Hutter et al 2014; Piotrowski et al 2014; Smith et al 2015). Further schwannomatosis predisposition genes may well exist, but they still remain to be discovered.…”

Section: Introductionmentioning

confidence: 99%

The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis

et al. 2016

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Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. Despite the clinical overlap with neurofibromatosis type 2 (NF2), schwannomatosis is not caused by germline NF2 gene mutations. Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. In contrast to patients with rhabdoid tumours, which are due to complete loss-of-function SMARCB1 mutations, individuals with schwannomatosis harbour predominantly hypomorphic SMARCB1 mutations which give rise to the synthesis of mutant proteins with residual function that do not cause rhabdoid tumours. Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2. Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes. This review provides an overview of current models of tumorigenesis and mutational patterns underlying schwannomatosis that will ultimately help to explain the complex clinical presentation of this rare disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1753-8) contains supplementary material, which is available to authorized users.

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“…The sporadic origin in this case is consistent with the approximately 90% of de novo mutations seen in schwannomatosis. 8,21 This specific mutation, c.93G>A in exon 1 has not previously been described (Fig. 8).…”

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confidence: 68%

“…8 Zhang et al reported that perhaps mutations in COQ6 play a role in schwannomatosis development. 24 …”

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confidence: 99%

An unusual case of schwannomatosis with bilateral maxillary sinus schwannomas and a novel SMARCB1 gene mutation

Toms¹,

Harrison²,

Richard³

et al. 2016

SPI

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Schwannomas are benign tumors that arise from Schwann cells in the peripheral nervous system. Patients with multiple schwannomas without signs and symptoms of neurofibromatosis Type 1 or 2 have the rare disease schwannomatosis. Tumors in these patients occur along peripheral nerves throughout the body. Mutations of the SMARCB1 gene have been described as one of the predisposing genetic factors in the development of this disease. This report describes a patient who was observed for 6 years after having undergone removal of 7 schwannomas, including bilateral maxillary sinus schwannomas, a tumor that has not been previously reported. Genetic analysis revealed a novel mutation of c.93G>A in exon 1 of the SMARCB1 gene.

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Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants

Cited by 36 publications

References 12 publications

Recent developments in brain tumor predisposing syndromes

Recent developments in brain tumor predisposing syndromes

The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis

An unusual case of schwannomatosis with bilateral maxillary sinus schwannomas and a novel SMARCB1 gene mutation

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