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Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis
  1. Kristen D Hadfield (kristen.hadfield{at}manchester.ac.uk)
  1. The University of Manchester, United Kingdom
    1. William G Newman (william.newman{at}cmmc.nhs.uk)
    1. The University of Manchester and Regional Genetics Service, United Kingdom
      1. Naomi L Bowers (naomi.bowers{at}cmmc.nhs.uk)
      1. University of Manchester and Regional Genetics Service, Manchester, United Kingdom
        1. Andrew Wallace (andreww{at}cmmc.nhs.uk)
        1. The Univeristy of Manchester and Regional Genetics Service, Manchester, United Kingdom
          1. Ciaran M Bolger (ciaran.bolger{at}beaumont.ie)
          1. Department of Neurosurgery, Beaumont Hospital, Dublin, Republic of Ireland
            1. Alison Colley (alison.colley{at}swsahs.nsw.gov.au)
            1. Department of Clinical Genetics, Liverpool Hospital, Sydney, Australia
              1. Emma McCann (emma.mccann{at}cd-tr.wales.nhs.uk)
              1. Department of Clinical Genetics, Glan Clwyd Hospital, Rhyl, United Kingdom
                1. Dorothy Trump (dorothy.trump{at}manchester.ac.uk)
                1. University of Manchester, United Kingdom
                  1. Trine Prescott (trine.prescott{at}rikshospitalet.no)
                  1. Department of Medical Genetics, Rikshospitalet University Medical Centre, Oslo, Norway
                    1. Gareth Evans (gareth.evans{at}cmmc.nhs.uk)
                    1. St Mary's Manchester, United Kingdom

                      Abstract

                      ABSTRACT

                      Background: Schwannomatosis is a rare condition characterised by multiple schwannomas and lack of involvement of the vestibular nerve. A recent report identified bi-allelic mutations in the SMARCB1/INI1 gene in a single family with schwannomatosis. We aimed to establish the contribution of the SMARCB1 and the NF2 genes to sporadic and familial schwannomatosis in our cohort.

                      Methods: We performed DNA sequence and dosage analysis of SMARCB1 and NF2 in 28 sporadic cases and 15 families with schwannomatosis.

                      Results: We identified germline mutations in SMARCB1 in 5 of 15 (33.3%) families with schwannomatosis and 2 of 28 (7.1%) individuals with sporadic schwannomatosis. In all individuals with a germline mutation in SMARCB1 in whom tumour tissue was available, we detected a second hit with loss of SMARCB1. In addition, in all affected individuals with SMARCB1 mutations and available tumour tissue, we detected bi-allelic somatic inactivation of the NF2 gene. SMARCB1 mutations were associated with a higher number of spinal tumours in patients with a positive family history (p=0.004).

                      Conclusion: In contrast to the recent report where no NF2 mutations were identified in a schwannomatosis family with SMARCB1 mutations, in our cohort, a four hit model with mutations in both SMARCB1 and NF2 define a subset of patients with schwannomatosis.

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