Genetic findings in people with schwannomas who do not meet clinical diagnostic criteria forNF2-related schwannomatosis

Abstract

BackgroundMost 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 commonlyNF2-related schwannomatosis (SWN), but when BVS are absent, this can also indicateSMARCB1-related orLZTR1-related SWN.MethodsWe assessed the variant detection rates for the three major SWN genes (NF2,LZTR1andSMARCB1) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria forNF2-related SWN at the time of genetic testing.ResultsWe found that 17 (11%) people from 13 families had a germlineSMARCB1variant and 19 (12%) unrelated individuals had a germlineLZTR1variant. 19 people had anNF2variant, 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).ConclusionsThere were similar proportions ofLZTR1,SMARCB1or mosaicNF2. However, since anNF2variant 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.