Genetic findings in people with schwannomas who do not meet clinical diagnostic criteria for <i>NF2</i>-related schwannomatosis.

Abstract

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 <i>NF2</i>-related schwannomatosis (SWN), but when BVS are absent, this can also indicate <i>SMARCB1</i>-related or <i>LZTR1</i>-related SWN. We assessed the variant detection rates for the three major SWN genes (<i>NF2</i>, <i>LZTR1</i> and <i>SMARCB1</i>) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for <i>NF2</i>-related SWN at the time of genetic testing. We found that 17 (11%) people from 13 families had a germline <i>SMARCB1</i> variant and 19 (12%) unrelated individuals had a germline <i>LZTR1</i> variant. 19 people had an <i>NF2</i> 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). There were similar proportions of <i>LZTR1</i>, <i>SMARCB1</i> or mosaic <i>NF2</i>. However, since an <i>NF2</i> 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.