以动眼神经麻痹为表现的2型神经纤维瘤病患者1例的临床特点及遗传学分析

Clinical features and genetic analysis of a patient with Neurofibromatosis type 2 manifested as oculomotor nerve palsy

目的报告1例以动眼神经麻痹为首发症状的2型神经纤维瘤病(NF2)患者,并探讨其遗传学病因。方法选择2021年7月10日就诊于首都医科大学附属北京地坛医院的1例NF2患者作为研究对象。对患者及其父母进行全脑、全脊髓MRI检查,追溯其家族史,采集家系成员的外周血样,提取DNA并进行全外显子组测序。对候选变异进行Sanger测序家系验证。结果影像学检查显示患者存在双侧前庭神经鞘瘤、海绵窦区脑膜瘤、腘窝神经源性肿瘤、皮下多发结节等。基因测序证实其NF2基因第8外显子存在c.757A>T新发无义变异,导致第253位的赖氨酸替换为终止密码子,导致编码的Merlin蛋白从第253位以后的氨基酸丢失。该变异未见健康人群公共数据库收录,生物信息学软件预测其氨基酸序列高度保守。根据美国医学遗传学与基因组学学会(ACMG)相关指南判定为致病性变异(PVS1+PS2+PM2_Supporting+PP3+PP4)。结论该患者发病较早,症状不典型且较重,其遗传学病因为NF2基因c.757A>T(p.K253*)杂合无义变异。上述发现丰富了NF2基因的变异谱。

Objective To report on a rare case of Neurofibromatosis type 2(NF2)manifesting as oculomotor nerve palsy and explore its genetic basis.Methods A patient with NF2 who had presented at Beijing Ditan Hospital Affiliated to Capital Medical University on July 10,2021 was selected as the study subject.Cranial and spinal cord MRI was carried out on the patient and his parents.Peripheral blood samples were collected and subjected to whole exome sequencing.Candidate variant was verified by Sanger sequencing.Results MRI revealed bilateral vestibular Schwannomas,bilateral cavernous sinus meningiomas,popliteal neurogenic tumors,and multiple subcutaneous nodules in the patient.DNA sequencing revealed that he has harbored a de novo nonsense variant of the NF2 gene,namely c.757A>T,which has replaced a codon(AAG)encoding lysine(K)at position 253 with a stop codon(TAG).This has resulted in removal of the Merlin protein encoded by the NF2 gene from position 253 onwards.The variant was not found in public databases.Bioinformatic analysis suggested that the corresponding amino acid is highly conserved.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the variant was rated as pathogenic(PVS1+PS2+PM2_Supporting+PP3+PP4).Conclusion The heterozygous nonsense variant c.757A>T(p.K253*)of the NF2 gene probably underlay the disease in this patient with an early onset,atypical but severe phenotype.