EPCO-22. DEEP PHENOTYPING IDENTIFIES TRUNCATING MUTATIONS IN THE NF2 LINKER DOMAIN ASSOCIATED WITH DISEASE SEVERITY IN NEUROFIBROMATOSIS TYPE II

Abstract INTRODUCTION Neurofibromatosis type 2 (NF2) is an autosomal dominant tumor syndrome with protean presentation and variable penetrance. Our objective was to perform deep phenotypic and genetic analysis of a diverse NF2 population to identify predictors of worse clinical outcome. METHODS We evaluated 167 patients with NF2 and followed them for a mean duration of 4.5 years. Detailed clinical and radiographic characteristics were collected on each patient, and Karnofsky performance scale (KPS) scores and within-study mortality were monitored. CLIA certified genotyping was supplemented with a custom sequencing panel targeting NF2 and other schwannomatosis-related genes. Outcome predictors were assessed using multivariable linear or logistic regression. RESULTS Germline mutations (nonsense 36%, splice-site 16%, and large deletions 16%) were grouped by predicted protein effect (truncating 41%, non-truncating 27%, and mosaic 33%) and mapped to the NF2chromosomal locus. Patients with truncating NF2 mutations had lower mean age of diagnosis (19.9 versus 25.7, P = 0.01) and faster tumor growth rates (2.4% versus 1.1% for all tumors, P = 0.01). Patients whose truncating mutations occurred within the NF2 linker domain (exons 8, 11 and 12) had more total tumors (adjusted coefficient 15.0, 95% CI 0.8 – 29.0, P = 0.04), and specifically more schwannomas (adjusted coefficient 7.0, 95% CI 0.2 – 13.9, P = 0.04). Presence of a-helical domain mutations predicted higher within-study mortality (adjusted OR 4.3, 95% CI 1.1 – 16.2, P = 0.03). CONCLUSIONS The NF2 linker domain functions a hinge, facilitating binding between the tail domain and the LATS binding site within the FERM domain. In our study, truncating mutations in the NF2 linker domain were associated with higher tumor burden and over four-fold within-study mortality. The linker domain may constitute a novel therapeutic target in patients with NF2.