I型神经纤维瘤患者12例的临床特征及NF1基因变异分析

Analysis of clinical features and variants of NF1 gene in 12 patients with Neurofibromatosis type 1

目的探讨I型神经纤维瘤(NF1)患者NF1基因的变异类型和临床特征。方法回顾性分析2019年12月至2022年5月宁波市妇女儿童医院确诊的12例NF1患者的临床资料,对先证者及其家系成员进行高通量测序,并用Sanger测序和染色体微阵列分析对候选变异进行验证。结果12例NF1患者就诊年龄为4个月~27岁,男女比例为2:1。所有患者均存在牛奶咖啡斑,83.3%伴腋窝或腹股沟雀斑,58.3%伴神经纤维瘤,16.7%伴有先天性胫骨假关节。在12例患者中共发现5种NF1基因变异。5例为无义变异,4例为移码变异,1例为错义变异,1例为剪接变异,1例为涉及整个基因的大片段杂合缺失,其中6例为新发变异,2例遗传自亲代,4例未接受亲代验证。c.3379del(p.Thr1127Glnfs*15)和c.6628_6629del(p.Glu2210Thrfs*10)变异查询文献和数据库均未见报道和收录。结论NF1患者早期多表现为牛奶咖啡斑,是由NF1基因的变异所致。高通量测序能够高效检测NF1基因的致病性变异,有助于确诊。

Objective To explore the types of NF1 gene variants and clinical characteristics among patients with Neurofibromatosis type I(NF1).Methods Clinical data of 12 patients diagnosed at Ningbo Women and Children′s Hospital between December 2019 and May 2022 were retrospectively analyzed.The probands and their family members were subjected to high-throughput sequencing,and candidate variants were verified by Sanger sequencing and chromosome microarray analysis.Results The 12 patients had ranged from 4 months to 27 years old,with a male-to-female ratio of 2:1.Cafè-au-lait spots were found in all patients.83.3%of them also had axillary and/or inguinal freckling,58.3%had neurofibromas,and 16.7%had congenital pseudarthrosis of the tibia.Five types of NF1 gene variants were identified in the patients,including 5 nonsense variants,4 frameshift variants,1 missense variant,1 splice variant,1 large deletion involving the whole gene.Six patients were found to harbor de novo variants,2 had inherited the variants from their parents,and 4 were not verified for their parental origin.The c.3379del(p.Thr1127Glnfs*15)and c.6628_6629del(p.Glu2210Thrfs*10)variants were unreported in literature and databases.Conclusion Most NF1 patients may present with Cafè-au-lait spots initially and are due to pathogenic variant of the NF1 gene.High-throughput sequencing can efficiently identify such variants among the patients and enable the definite diagnosis.