Article Text
Abstract
Background Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly NF2-related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1-related or LZTR1-related SWN.
Methods We assessed the variant detection rates for the three major SWN genes (NF2, LZTR1 and SMARCB1) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for NF2-related SWN at the time of genetic testing.
Results We found that 17 (11%) people from 13 families had a germline SMARCB1 variant and 19 (12%) unrelated individuals had a germline LZTR1 variant. 19 people had an NF2 variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS).
Conclusions There were similar proportions of LZTR1, SMARCB1 or mosaic NF2. However, since an NF2 variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification.
- Genetics
- Genetics, Medical
- Genetic Testing
- Germ-Line Mutation
- Loss of Function Mutation
Data availability statement
Data are available on reasonable request.
Statistics from Altmetric.com
Data availability statement
Data are available on reasonable request.
Footnotes
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Contributors Conception and design: MJS and GE. Acquisition of data: All authors. Analysis and interpretation of data MJS, GJB, SJW and MC. Drafting of the manuscript: MJS. Review and approval of final submission: All authors. MJS is responsible for the overall content and acts a guarantor.
Funding This study was supported by the USAMRAA CDMRP Neurofibromatosis Research Program, Investigator-Initiated Research Award (W81XWH1910334) and the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20007).
Competing interests GE has received consultancy fees from AstraZeneca, Springworks and Everything Genetic.
Provenance and peer review Not commissioned; externally peer reviewed.
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