Revisiting the UK Genetic Severity Score for NF2: a proposal for adding functional information

BackgroundNeurofibromatosis Type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple schwannomas, particularly at vestibular nerves, and meningiomas. The UK NF2 Genetic Severity Score (GSS) helps predicting the disease course from germline NF2 pathogenic variants, optimizing the clinical follow-up and the genetic counselling offered to affected families. MethodsSpanish Reference Center patients were classified following the GSS and patients clinical severity was measured and compared between GSS groups. The GSS was reviewed considering phenotype quantification, genetic variant classification and functional assays of Merlin and its downstream pathways, studied by western blot in patients primary fibroblast. Principal component analysis and regression models were considered to evaluate the differences between severity and NF2 germline mutations. ResultsThe GSS was validated in the Spanish NF2 cohort. However, for some patients harboring mutations associated to mild and moderate phenotypes, GSS did not perform as well in predicting clinical outcomes as for pathogenic variants associated to severe phenotypes. We studied the possibility of modifying the mutation classification in GSS adding functional assays to evaluate the impact of pathogenic mutations on Merlins function. This revision help reducing variability within NF2 mutation classes and moderately enhances the correlation between patients phenotype and the different prognosis parameters analyzed. ConclusionsWe validated the UK NF2 GSS in a Spanish NF2 cohort although a significant phenotypic variability was identified. The revision of the GSS, named FGSS, could be an added value to the classification of mosaic patients and patients showing mild and moderate phenotypes.