C73
Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis
Kristen Hadfield1, William Newman1, Naomi Bowers1, Andrew Wallace1, Ciaran Bolger2, Alison Colley3, Emma McCann4, Dorothy Trump1, Trine Prescott5, Gareth Evans1
1Academic Unit of Medical Genetics, University of Manchester and Regional Genetics Service, Manchester, UK, 2National Centre for Neurosurgery, Dublin, Ireland, 3Department of Clinical Genetics, Liverpool Hospital, Sydney, Australia, 4Department of Clinical genetics, Glan Clwyd Hospital, Rhyl, UK, 5Department of Medical Genetics, Rikshospitalet University Medical Centre, Oslo, Norway
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.
Method
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 3 of 28 (10%) 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.
