INNV-38 - Predicting the clinical phenotype in NF2 related Schwannomatosis patients

Background Different genetic scores have been proposed to predict the phenotype of NF2 related Schwannomatosis (NF2 -SCHW MIM # 101000) , a rare autosomal dominant familial cancer syndromes caused by pathogenic variants of the NF2 gene. The UK NF2 Reference Group proposed the Genetic Severity Score (GSS) based on the type and location of NF2 germline variant observed. Catasus et al. suggested a new score based also on a functional assay of Merlin and its downstream pathways (FGSS). Recently Teranish et al. used targeted deep sequencing to predict functional prognosis in those patients.Material and Methods 70 patients (median age 40) were identified by scanning the electronic NF2-SCHW patient database at Fondazione IRCCS C. Besta,. The median follow-up was 14 yrs. Clinical diagnosis was established following the Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis”. All patients underwent NF2, SMARCB1 and LZTR1 mutational screening by NGS and MPLA analysis using blood DNA or the tissue of two different tumors when available.NF2 gene germline pathogenic were found in 45 subjects (64%), in most cases NF2 point mutations, but in 4 cases and whole gene deletions was observed and in 2 a ring NF2 chromosome was identified, in four cases a mosaic NF2-SCH was identified and in 21 (30%) patients no pathogenic variant was found. We assessed NF2 clinical phenotype in relation to the UK GSS and FGSS to validate their use.Results The disease phenotype differed significantly depending both on clinicaland genetic factors.. GSS and FGSS showed significant correlation with several measures, allowing stratification of patients with severe and mild disease but not with moderate phenotype. Furthermore, we provided evidence on correlation between whole NF2 deletion extent and phenotype severity. Large cohorts of NF2-SCHW patients are needed to identify more accurate scores.