SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis
© Rousseau et al; licensee BioMed Central Ltd. 2011
Received: 7 October 2010
Accepted: 24 January 2011
Published: 24 January 2011
Schwannomatosis is a disease characterized by multiple non-vestibular schwannomas. Although biallelic NF2 mutations are found in schwannomas, no germ line event is detected in schwannomatosis patients. In contrast, germline mutations of the SMARCB1 (INI1) tumor suppressor gene were described in familial and sporadic schwannomatosis patients.
To delineate the SMARCB1 gene contribution, the nine coding exons were sequenced in a series of 56 patients affected with a variable number of non-vestibular schwannomas.
Nine variants scattered along the sequence of SMARCB1 were identified. Five of them were classified as deleterious. All five patients carrying a SMARCB1 mutation had more multiple schwannomas, corresponding to 10.2% of patients with schwannomatosis. They were also diagnosed before 35 years of age.
These results suggest that patients with schwannomas have a significant probability of carrying a SMARCB1 mutation. Combined with data available from other studies, they confirm the clinical indications for genetic screening of the SMARCB1 gene.
Neurofibromatoses (NF) are an heterogeneous group of genetic disorders predisposing to various tumors of the nervous system, divided into two well recognized distinct clinical entities, NF1 and NF2. Patients with multiple non-vestibular schwannomas have been assembled into a particular category within neurofibromatoses called schwannomatosis . The SMARCB1 gene has been found to harbor germline alterations in both familial and sporadic schwannomatosis patients [2, 3], with a greater number of spinal schwannomas in familial cases and the presence of meningiomas  although this latter point remains debated . To improve the clinical indications for SMARCB1 molecular screening in medical genetics practice, we evaluated its implication in a series of patients exhibiting non-vestibular schwannomas and no NF2 germline alteration.
Primers used for the analysis of the 9 SMARCB1 coding exons
Point variations and phenotypic description of the patients exhibiting a SMARCB1 variation
11 non-vestibular schwannomas
c.34C > T
Multiple spinal schwannomas
c.[500+5G > T,505G > T]
1 facial nerve
7 spinal schwannomas
c.501-23T > G
2 spinal schwannomas
c.832C > T
Multiple schwannomas and meningiomas
Unilateral V-, VII-, spinal schwannomas
c.[897G > A;986+57_986+58dup;1119-41G > A]
Discussion and conclusions
Five mutations were identified through the analysis of the SMARCB1 gene for point mutations in a series of 56 NF2-negative patients affected with non-vestibular schwannomas. Patients carrying a mutation presented with multiple schwannomas at a young age, i.e. 10.2% in schwannomatosis patients  and 20% of patients diagnosed before 35 years of age, none with any family history of schwannomas. This proportion remains lower than that described in familial schwannomatosis [3, 7, 8]; however neither somatic mosaicisms nor genomic rearrangements were investigated [2, 7]. Tumor samples were not available thus precluding dosage analyses and the demonstration of SMARCB1 and/or NF2 somatic inactivation .
Review of the clinical description of SMARCB1 mutation patients affected with non-rhabdoid tumors
1 familial schwannomatosis
case report, initial description
28 sporadic + 15 familial non-vestibular schwannomatosis patients
2/28 + 5/15 mutations
1 familial schwannomatosis with multiple meningiomas
47 NF2-negative patients with multiple meningiomas
21 sporadic schwannomatosis patients
1 familial meningiomatosis
This work was supported by the French national cancer institute INCa through a grant dedicated to the PHRATries network (Prédispositions Héréditaires Rares Aux Tumeurs, Réseau d'Identification Et de Soins). We are grateful to the French clinicians who faithfully entrust our institution with molecular genetics tests of neurofibromatoses.
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- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/9/prepub
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