Novel NF1 Variants and a First Reported Case of Neurofibromatosis Type 1 with Posterior Medullary Ischemic Degeneration: Genotype-Phenotype Analysis in NF1 Patients

Objective To investigate the mutations of NF1 and clinical phenotypes in patients with sporadic neurofibromatosis type 1 (NF1). This is aimed to evaluate the efficacy of high-throughput sequencing in diagnosing atypical cases, to expand the mutational spectrum of NF1, and to provide early diagnosis of NF1.Methods Clinical data from 11 sporadic NF1 patients without family history treated at the Fifth Affiliated Hospital of Sun Yat-sen University (2019–2023) were collected. NF1 gene variants were detected using whole-exome sequencing or chip-capture high-throughput sequencing, followed by bioinformatics analysis. Novel mutations were screened against normal population databases to exclude benign polymorphisms, and pathogenicity of the mutations was classified according to ACMG guidelines.Results Two novel frameshift mutations were identified: c.7904delA (p.Asp2635Valfs*9) and c.5122_5123del (p.Phe1708Hisfs*9). The patient carrying c.7904delA exhibited an undocumented phenotype of posterior medullary ischemic degeneration. Among the 11 NF1 patients,the types of mutations included frameshift (36.4%), nonsense (27.3%), intronic (18.2%), splicing (9.1%), and start codon variants (9.1%). Common phenotypes were café-au-lait macules (72.7%) and neurofibromas (54.5%), yet significant phenotypic heterogeneity existed among patients sharing identical mutations.Conclusion This study discovered two novel NF1 mutations and an unreported NF1-associated phenotype, expanding both the NF1 mutational and phenotypic spectra. High-throughput sequencing significantly enhances molecular diagnostic efficacy for atypical NF1, providing a critical basis for clinical NF1 diagnosis.