Detecting Missing Heritability for Risk Stratification and Clinical Management of the Neurofibromatoses

Neurofibromatosis type 1 (NF1), NF2 and schwannomatosis are genetically distinct tumour predisposing conditions, with significant clinical overlap, but differing prognoses and clinical management requirements. NF2 was recently re-grouped with the schwannomatoses due to its clinical phenotype. We are using a range of genetic techniques to identify the missing heritable elements in our cohort with NF1 or NF2/schwannomatosis and to stratify their genetic risk. In our third year, we have published our genetic screen of schwannomatosis patients for potential causative genes. This study clarified that the candidate genes, COQ6, DGCR8 and CDKN2A/B, which have recently been associated with schwannomatosis, are very rare contributors to this disorder. We have also carried out a genotype-phenotype study of NF2 whole gene deletions and large intragenic deletions, duplications and rearrangements. We are currently working on some supporting functional work for this project prior to publication. In parallel, we have carried out long-read sequencing on a patient with a complex NF2 rearrangement to clarify the precise breakpoints and the overall level of complexity. We have also carried out deep sequencing on an initial cohort to assess the utility of our new gene panel design. Functional studies on untranslated SMARCB1 variants are also ongoing.