Position effect and of modifier Ras pathway genes in Neurofibromatosis type I microdeletion syndrome

Introduction: Neurofibromatosis type1(NF1) microdeletion syn- drome (MD)accounting for 5-11% of NF1 patients is characterized by a severe phenotype.70% of patients show the 1.4 Mb type1 deletion and variable expressivity of the phenotype suggesting the involvement of different mechanisms. Materials-And-Methods: We studied 19 NF1-type1-MD patients by targeted-NGS analysis with a panel of RAS/MAPK pathway genes, genes within and flanking the 17q11.2 micro- deletion, to investigate pseudo-dominance and genetic modifier effect.We assayed position effect of deleted region by gene expression analysis of 10 genes flanking the deletion by RT-PCR on RNA from peripheral blood comparing a subgroup of 15 NF1-MD patients with 15 patients with an NF1 gene mutation.Haploinsuf- ficiency was established by evaluating the probability of LoF intolerance. Results: We identified 14rare variants(Table1) and classified “likely pathogenic”two variants in Ras pathway genes RAF1 and RASA1.The RAF1 variant is present in a patient with a cerebro- vascular pathology while the RASA1 in a patient with an uncommon glioma of the brainstem developed during infancy. Expression analysis showed five hypo-expressed(IFT20,SSH2, RHOT1,ZNF207,PSMD11) and two over-expressed genes(ABHD15, BLMH) in NF1-MD patients compared to classical NF1 patients,with a statistical significance of p < 0.05.Furthermore,we found that ATAD5,NF1,OMG,RAB11FIP4,andSUZ12 genes are intolerant to haploinsufficiency. Conclusions: Besides haploinsufficiency,position effect of NF1 microdeletion and possible modifier gene variants of Ras pathway could have a role in phenotype severity.Further genetic and functional studies in a larger cohort of NF1-type1-MD will be performed to improve genotype-phenotype correlation.