Abstract BACKGROUND NF2 related Schwannomatosis (NF2 -SCHW MIM # 101000) is a rare autosomal dominant familial cancer syndromes caused by mutations in the NF2 gene, mainly due to NF2 point mutations or intragenic deletions. NF2 patients. In 95% of patients, bilateral vestibular schwannomas are present, but NF2 -SCHW patients can develop other tumors and show ophthalmic and dermatological signs. Several studies established a genotype-phenotype correlations; the UK NF2 Reference Group proposed a Genetic Severity Score (GSS) based on the type and location of NF2 germline variant observed. Catasus et al. after validation of the score in a Spanish cohort 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, where the patients had undergone full neurological, ophthalmic, and audiological assessment. 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-SCHW clinical phenotype in relation to the UK GSS and FGSS to validate their use as clinical and research tools, despite the significant phenotypic variability observed. RESULTS The disease outcome differed significantly depending both on clinicaland genetic factors. Among these factors,” Age of symptom onset” “Truncating”, “Mosaic”, and “whole gene deletion” had the most significant effects on functional disability. Conclusion 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, becoming useful tools for patient management.