目的

探讨Ⅰ型神经纤维瘤病（NF1）的家系中患者的临床表型特征、确定致病基因及其突变位点。

方法

收集两个临床诊断为NF1家系的临床资料和遗传学资料，包括对患者及参与研究的亲属询问病史并进行详细的眼科检查。抽取患者及部分家属的外周静脉血提取脱氧核糖核酸（DNA），采用全外显子捕获测序技术（WES），筛选致病基因及突变位点；使用Ugene软件评估其在物种中的保守度，使用Polyphen 2和Mutation Taster软件评估突变的危害性；使用Sanger测序进行家系共分离验证，并结合其临床表型及发病特点给予不同的治疗方案。

结果

家系1中，包含2名患者与3名正常的家族成员；家系2中，包含1名患者及1名正常的家庭成员。经眼科检查，发现家系1先证者及家系2先证者均存在咖啡牛奶斑、虹膜Lisch结节以及眼眶-眶周丛状神经纤维瘤。测序数据结果显示NF1基因为两个家系患者的致病基因，在NF1基因上检出致病突变。家系1先证者（F1-Ш1）及其患病的弟弟（F1-Ш2）在NF1基因上均存在c.7240-7241delAG（p.Ser2414Argfs*12）杂合移码突变。家系2先证者（F2-Ш1）在NF1基因上发现c.2570del（p.Asn857llefs*21）杂合移码突变。Ugene软件结果显示两种突变均在多种物种中高度保守，polyphen 2和Mutation Taster软件结果显示两个突变均具有较强的致病性。结合先证者1的病情并与其家属充分沟通后暂未对患者行特殊治疗仅对此患者进行长期随访。先证者2经手术治疗后外观较前明显改善，半年后肿瘤未复发。

结论

NF1基因突变是导致I型神经纤维瘤病的主要致病原因，NF1基因突变所致疾病具有典型遗传异质性与临床异质性，不同突变会导致患者表现出不同的临床表型，多样的疾病表型需要为患者提供个体化的治疗方案。本研究通过全外显子测序检测出2个家系均在NF1基因上存在杂合移码突变；其中，c.2570del（p.Asn857llefs*21）为首次报道，并在基因水平上进一步明确了临床诊断。同时本研究方法也可为此两个家系未来产前诊断、遗传咨询及分析基因型与表型的相关性提供参考。

Objective

To investigate the clinical phenotypic characteristics，pathogenic genes and mutation sites of patients with neurofibromatosis typeⅠ（NF1）in a family.

Methods

The clinical and genetic data of two families with clinical diagnosis of NF1 were collected，including the patient and relatives who participated in the study were asked for medical history and detailed ophthalmic examination.Deoxyribonucleic acid（DNA）was extracted from peripheral venous blood of patients and some family members.The pathogenic genes and mutation sites were screened by whole exon capture sequencing（WES）.The degree of conservation in species was evaluated by using ugene software，and the harmfulness of mutation was evaluated by using polyphen 2 and mutation taster software.Sanger sequencing was used for family co separation verification，and different treatment schemes were given according to the clinical phenotype andpathogenesis characteristics.

Results

Family 1 included 2 patients and 3 normal family members.Family 2 contains one patient and one normal family member.After ophthalmic examination，the proband of family 1 and family 2 were found to have coffee milk spots，iris Lisch nodules and orbital periorbital plexiform neurofibroma（oppn）.Sequencing data showed that the NF1 gene was the pathogenic gene of patients in two families，and pathogenic mutations were detected in the NF1 gene.A heterozygous frameshift mutation of c.7240-7241delAG（p.Ser2414Argfs*12）was found in the NF1 gene of the proband of family 1（f1-Ш 1）and his sick brother（f1-Ш 2）.A c.2570del（p.Asn857llefs*21）heterozygous frameshift mutation was found in the NF1 gene of the proband of family 2（F2-Ш 1）.The results of Ugene software showed that the two mutations were highly conserved in many species，and the results of polyphen 2 and mutation taster software showed that the two mutations were highly pathogenic.In combination with the condition of proband 1 and full communication with his family members，the patient was not given special treatment for the time being，and only the patient was followed up for a long time.The appearance of proband 2 was significantly improved after surgical treatment，and the tumor did not recur six months later.

Conclusions

NF1 gene mutation is the main cause of type I neurofibromatosis.The disease caused by NF1 gene mutation has typical genetic heterogeneity and clinical heterogeneity.Different mutations will lead to different clinical phenotypes of patients.The diversity of disease phenotypes needs to provide individualized treatment for patients.In this study，heterozygous frameshift mutations in NF1 gene were detected in both families by full exon sequencing；Among them，c.2570del（p.Asn857llefs*21）was reported for the first time and further confirmed the clinical diagnosis at the gene level.At the same time，this research method can also provide reference for prenatal diagnosis，genetic counseling and analysis of the correlation between genotype and phenotype of the two families in the future.