ORIGINAL ARTICLES

Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis

K D Hadfield¹, W G Newman¹, N L Bowers¹, A Wallace¹, C Bolger², A Colley³, E McCann⁴, D Trump¹, T Prescott⁵, D G R Evans¹

¹ Academic Unit of Medical Genetics, University of Manchester and Regional Genetics Service, Manchester, UK
² National Centre for Neurosurgery, Dublin, Republic of Ireland
³ Department of Clinical Genetics, Liverpool Hospital, Sydney, Australia
⁴ Department of Clinical Genetics, Glan Clwyd Hospital, Rhyl, Denbighshire, UK
⁵ Department of Medical Genetics, Rikshospitalet University Medical Centre, Oslo, Norway

Professor G Evans, Department of Clinical Genetics, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, UK; gareth.evans{at}cmmc.nhs.uk

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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