Prevalence of NF1 missense mutations and candidate modifier genes in 12 familial and 15 sporadic spinal neurofibromatosis patients

Spinal Neurofibromatosis (SNF) is a specific form of Neurofibromatosis type 1 (NF1) characterized by bilateral neurofibromas involving all spinal roots. This feature allows to specifically distinguish SNF from Neurofibromatosis type 1 (NF1), and Multiple Neurofibromas Few Spinal Root (MNFSR), presenting single/few isolated spinal neurofi- bromas. While the clinical phenotype of SNF, MNSFR and classical NF1 can be revealed by spinal MRI, little is known on the molecular basis underlying these conditions. We investigated 12 NF1 families with at least one SNF patient, 15 sporadic SNF/MNSFR patients, diagnosed by Spinal MRI. We applied Targeted NGS using a panel consisting of 139 genes encoding RAS pathway effectors, neurofibromin interactors and genes mapping at 17q11.2 region. On identified 26 NF1 variants, 36,6% were missense mutations, indicating an increased prevalence in our cohort versus 27,7% missense/nonsense mutations reported in Italian (PMID: 26740943) and in a British (PMID:28637487) NF1 population. Furthermore, we evaluated rare variants with damaging predictors in genes of RAS pathway and neuro- fibromin interactors. In more than one sporadic case pos- sible pathogenic variants were found in LIMK2, RASAL1, RASAL3, SOS1, A2ML1, MAP3K1, while in more than one SNF family were detected RASAL1, RASAL3, MAP3K1 genes variations. Our results confirm the high frequency of missense mutations in SNF as reported (PMID: 26740943, PMID:25211147), indicating neurofi- bromin gain-of-function variants as associated to SNF. In some patients, the co-occurrence of potential pathogenic variants in NF1 related genes are detected with severe phenotypes, suggesting that they might be modifier genes and promising pharmacological targets. Italian Ministry of Health RF-2016-02361293.