Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

Jingfang Xu; Ying Zhang; Kun Zhu; Jiabin Li; Yuelin Guan; Xinyu He; Xuejing Jin; Guannan Bai; Lidan Hu

doi:10.3389/fgene.2022.991314

Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

Front Genet. 2022 Sep 28:13:991314. doi: 10.3389/fgene.2022.991314. eCollection 2022.

Authors

Jingfang Xu¹, Ying Zhang², Kun Zhu³, Jiabin Li⁴, Yuelin Guan⁵, Xinyu He⁵, Xuejing Jin⁶, Guannan Bai⁷, Lidan Hu⁵

Affiliations

¹ Department of Orthopaedics, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
² Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
³ Department of Pathology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
⁴ Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
⁵ The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
⁶ Centre for Evidence-based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
⁷ Department of Child Health Care, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.

Abstract

Congenital pseudarthrosis of the tibia (CPT) is a rare congenital bone malformation, which has a strong relationship with Neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant disease leading to multisystem disorders. Here, we presented the genotypic and phenotypic characteristics of one unique case of a five-generation Chinese family. The proband was CPT accompanied with NF1 due to NF1 mutation. The proband developed severe early-onset CPT combined with NF1 after birth. Appearance photos and X-ray images of the left limb of the proband showed significant bone malformation. Slit-lamp examination showed Lisch nodules in both eyes of the proband. Whole-exome sequencing (WES) and Sanger sequencing confirmed the truncation variant of NF1 (c.871G>T, p. E291^*). Sequence conservative and evolutionary conservation analysis indicated that the novel mutation (p.E291^*) was highly conserved. The truncated mutation led to the loss of functional domains, including CSRD, GRD, TBD, SEC14-PH, CTD, and NLS. It may explain why the mutation led to a severe clinical feature. Our report expands the genotypic spectrum of NF1 mutations and the phenotypic spectrum of CPT combined with NF1.

Keywords: bone deformity; congenital pseudarthrosis of the tibia; ferroptosis; genetic mutation; neurofibromatosis type 1.