Objectives Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.
Methods Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups.
Results Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants.
Conclusions Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.
- genetic predisposition to disease
- genetic testing
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MJS and DGE are joint senior authors.
Contributors DGE designed the study. Patient data were compiled and analysed by KVS, DGE and MJS. Molecular testing was carried out by KVS, MJS, NLB, ST, CH, AJW and PTS. All other authors contributed data or individuals to the study. All authors reviewed the manuscript and approved the final version.
Funding We would like to acknowledge the NHS England funded highly specialised NF2 service. DGE is an NIHR Senior Investigator. This research was supported by the Manchester NIHR Biomedical Research Centre (IS-BRC1215-20007).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Ethical approval for use of anonymised samples from the Manchester Centre for Genomic Medicine archive was obtained from the North West-Greater Manchester Central Research Ethics Committee (reference 10/H1008/74).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Anonymised data from the study are available on request.
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