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.

Position effect and of modifier Ras pathway genes in Neurofibromatosis type I microdeletion syndrome / P. Bettinaglio, V. Tritto, E. Mangano, R. Bordoni, C. Castronuovo, M. Volontè, C. Cesaretti, G.A. Cagnoli, C. Battaglia, V. Saletti, D. Bianchessi, F. Natacci, M. Eoli, P. Riva. - In: EUROPEAN JOURNAL OF HUMAN GENETICS. - ISSN 1018-4813. - 30:supplement 1(2022 Apr 07), pp. P11.087.A.352-P11.087.A.353. ((Intervento presentato al 54. convegno European Society of Human Genetics (ESHG) Conference tenutosi a virtual conference nel 2021.

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

V. Tritto
Secondo
;
C. Battaglia;P. Riva
Ultimo
2022

Abstract

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.
Settore BIO/13 - Biologia Applicata
https://www.nature.com/articles/s41431-021-01026-1
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/932184
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