SMARCA4-Associated Schwannomatosis

Abstract

Abstract Background Schwannomatosis is a disorder characterized by a predisposition to multiple benign spinal, peripheral and intracranial nerve sheath tumors (schwannomas (SWNs)). The molecular mechanism of schwannomatosis involves several genes located on chromosome 22q, SMARCB1, LZTR1, NF2 and more recently, DGCR8. Case Presentation: here, we present a family with SMARCA4-associated schwannomatosis - this is the first report of this association. The proband presented with a spinal SWN at age 30y whilst her mother (deceased) had had 4 peripheral SWNs (right and left arms) at age 50y followed by a glioblastoma (GBM) at age 54y. All the tumors, except for the GBM, showed loss of BRG1 (SMARCA4) in 80–90% of cells and loss of INI1 (SMARCB1) in the complementary 10–20% of cells. The GBM showed retention of BRG1 and INI1. Whole exome sequencing of the proband’s germline revealed a likely pathogenic (LP) variant, SMARCA4 (NM_001128844.2):c.1752_1755del, p.(Lys585Argfs*27) (ClinVar ID: 873514). Furthermore, we identified LOH at the SMARCA4 locus along with 12–23 Mb of chromosome 19p in all SWNs (acting as the second hits), but not in the GBM. No other pathogenic variants or allelic imbalance on Chromosome 22q were detected in the schwannomas. Additionally, from DNA methylation analyses, we observed that the SMARCA4- associated SWNs clustered together with other SWNs (mutated in SMARCB1 or LZTR1, or negative germline status) and away from rhabdoid tumours associated with SMARCA4 and SMARCB1 deficiency (small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and atypical teratoid rhabdoid tumour (ATRT)). Conclusion Taken together, our findings lead us to propose SMARCA4 as a new candidate schwannomatosis gene and that there might be other mechanisms by which SWNs are formed.