Abstract：
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 magnetic resonance imaging (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).
CONCLUSIONS: 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.
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 magnetic resonance imaging (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).
CONCLUSIONS: 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.
摘要：
目的：报道1例2型神经纤维瘤病（NF2）表现为动眼神经麻痹的罕见病例，并探讨其遗传基础。
方法：选择2021年7月10日在首都医科大学附属北京地坛医院就诊的NF2患者作为研究对象。对患者及其父母进行了颅骨和脊髓磁共振成像（MRI）。收集外周血样品并进行全外显子组测序。通过Sanger测序验证候选变体。
结果：MRI显示双侧前庭神经鞘瘤，双侧海绵窦脑膜瘤，pop神经源性肿瘤，和患者的多个皮下结节。DNA测序显示他有一个NF2基因的从头无意义变体,即c.757A>T，其已经用终止密码子(TAG)替换了253位编码赖氨酸(K)的密码子(AAG)。这导致由NF2基因编码的Merlin蛋白从位置253开始被去除。在公共数据库中找不到该变体。生物信息学分析表明，相应的氨基酸是高度保守的。根据美国医学遗传学和基因组学学院（ACMG）的指南，该变体被评为致病性(PVS1+PS2+PM2_支持+PP3+PP4)。
结论：杂合无义变体c.757A>T（p。NF2基因的K253*）可能是该早发性患者的疾病基础，非典型但严重的表型。
方法：选择2021年7月10日在首都医科大学附属北京地坛医院就诊的NF2患者作为研究对象。对患者及其父母进行了颅骨和脊髓磁共振成像（MRI）。收集外周血样品并进行全外显子组测序。通过Sanger测序验证候选变体。
结果：MRI显示双侧前庭神经鞘瘤，双侧海绵窦脑膜瘤，pop神经源性肿瘤，和患者的多个皮下结节。DNA测序显示他有一个NF2基因的从头无意义变体,即c.757A>T，其已经用终止密码子(TAG)替换了253位编码赖氨酸(K)的密码子(AAG)。这导致由NF2基因编码的Merlin蛋白从位置253开始被去除。在公共数据库中找不到该变体。生物信息学分析表明，相应的氨基酸是高度保守的。根据美国医学遗传学和基因组学学院（ACMG）的指南，该变体被评为致病性(PVS1+PS2+PM2_支持+PP3+PP4)。
结论：杂合无义变体c.757A>T（p。NF2基因的K253*）可能是该早发性患者的疾病基础，非典型但严重的表型。
