Identification of a Novel NF1 Frameshift Variant in a Chinese Family with Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) is a progressive neurocutaneous disorder in humans, mainly characterized by café-au-lait macules (CALMs) and neurofibromas. NF1 is caused by variants of the neurofibromin 1 gene (NF1), which encodes a Ras-GTPase-activating protein called neurofibromin. NF1 variants may result in loss of neurofibromin function and elevation of cell proliferation and tumor formation. In this study, a Chinese NF1 family with an autosomal dominant inheritance pattern was recruited. Exome sequencing and Sanger sequencing were performed to discover the causative variant responsible for the family, followed by molecular analysis of effect of the mutated NF1 protein on Ras activity. A novel frameshift variant c.541dupC (p.(Gln181Profs∗20)) in the NF1 gene was identified in all three affected family members. The variant cosegregated with the disease phenotypes in the pedigree and was absent in 100 healthy controls. Bioinformatic analysis showed that the variant c.541dupC (p.(Gln181Profs∗20)) was pathogenic. The further molecular analysis verified the cells expressing NF1 variant p.(Gln181Profs∗20) partially enhanced Ras activity and elevated cell proliferation and tumor formation due to loss of neurofibromin function caused by the variant. Taken together, the data strongly advocate the c.541dupC (p.(Gln181Profs∗20)) variant as the underlying genetic cause of the Chinese family with NF1. Moreover, our findings broaden the spectrum of NF1 variants and provide molecular insights into the pathogenesis of NF1.

Identifying a novel frameshift pathogenic variant in a Chinese family with neurofibromatosis type 1 and review of literature

“…A PN is a severe subtype of NF1 and can involve the eyelid, orbital, periorbital and facial structures [termed orbital-periorbital PN (OPPN)]. Less than 10% of NF1 cases develop PN [38] . Most OPPNs are distributed along the trigeminal nerve, and the most notable sign is blepharoptosis, which occurs in almost all cases, while congenital ptosis associated with NF1 has an incidence rate up to approximately 1% [39] and is usually unilateral.…”

Genotype–Phenotype Correlation of Novel NF1 Gene Variants Detected by NGS in Patients with Neurofibromatosis Type 1

“…It has been reported that splice site mutations are associated with the tendency to develop neoplasms consisting mostly of central nervous system gliomas and MPNSTs [39]. In the study of Xu et al, the frame shift mutation was detected in all three affected patients in a Chinese family [40]. Corsello et al reported the rate of nonsense mutations, splice mutations and missing mutations as 80% in their study [15].…”

Somatostatinoma: Beyond neurofibromatosis type 1 (Review)

“…The gene is difficult to be analysed because it is large and next-generation sequencing (NGS) seems promising to help the genetic diagnostic by covering the Ras-related signalling elements (66,67). Novel variants of NF1 gene such as p.(Gln181Profs*20) have been recently reported (68). Aggressive breast cancer in females with neurofibromatosis type 1 involves germline mutations of neurofibromin 1 in association with other somatic mutations of TP53 or KMT2c (69).…”