目的：通过高通量测序分析进行基因诊断，鉴别视网膜病变中的神经纤维瘤病，为其早诊早治提供重要依据。方法：回顾性分析眼遗传病高通量测序数据库中的NF1和NF2基因变异，根据ACMG/AMP指南解析变异致病性；进一步结合患者的临床表型、家族史以及其他检查结果，综合判断明确是否患有神经纤维瘤病，同时进行疾病的进展和随访的研究分析。结果：通过分析不同眼部表型家系的高通量测序结果，共在11例先证者中发现NF1和NF2基因的10个可能致病变异，包括7个NF1变异和3个NF2变异。这11例先证者的初始诊断包括家族性渗出性玻璃体视网膜病变、黄斑/视网膜发育不良、斜视、视网膜色素变性、Coats病和牵牛花综合征等。其中，在1例初诊为家族性渗出性玻璃体视网膜病变的患儿中，检测到3个基因的致病变异，即NF2: c.122G>A/p.(W41*)、RS1: c.520C>T/p.(R174W)和NYX: c.1027C>T/p.(R343C)。随访检查发现，该患儿的复杂眼部表型符合NF2、RS1和NYX致病变异的临床改变，且MRI检查发现双侧前庭神经鞘瘤、脊髓室管膜瘤和多发性神经鞘瘤改变。除该患者外，还有4例患者在随访中发现存在牛奶咖啡斑或雀斑样色素沉着等皮肤改变，1 例合并小脑神经纤维瘤浸润。结论: 高通量测序分析能有效检测出神经纤维瘤病相关基因的变异，有助于筛选非典型表现的神经纤维瘤病，为疾病的早期诊断，尤其是对严重中枢神经系统病变的早期筛查和及时干预，提供了重要依据。

Objective: To identify neurofibromatosis in retinopathy through high-throughput sequencing analysis and provide important indicators for early diagnosis and treatment. Methods: Variants in NF1 and NF2 were selected from in-house high-throughput sequencing, including targeted exome sequencing, exome sequencing and whole genome sequencing, of individuals with different eye conditions. Pathogenic or likely pathogenic variants were assessed according to ACMG/AMP criteria. All the available clinical data, including clinical manifestation, family history and other examination results, were summarized and further analyzed to determine whether neurofibromatosis. Results: Based on the results of in-house high-throughput sequencing, a total of ten pathogenic or likely pathogenic variants in NF1 and NF2 were identified in 11 unrelated cases with various eye conditions, including three NF2 variants in four cases and seven NF1 variants in seven cases. The unrelated cases with NF1 and NF2 variants had initial clinical manifestation similar to familial exudative vitreoretinopathy (FEVR), macular or retinal dystrophy, strabismus, retinitis pigmentosa, Coats disease, or morning glory syndrome. In one of these cases, who was diagnosed as FEVR at the initial visit, three pathogenic variants of three different genes were identified, namely NF2: c.122G>A/p.(W41*), RS1: c.520C>T/p.(R174W) and NYX: c.1027C>T/p.(R343C). Follow-up examination on this case revealed a complex retinopathy, which were consistent with clinical presentations due to pathogenic variants in NF2, RS1, and NYX, as well as bilateral vestibular schwannomas, spinal ependymoma and multiple schwannomas by MRI. In addition to this patient, a follow-up examination on four of the seven cases present Café-au-lait macules or freckling, which could be easily neglected if neurofibromatosis is not realized on the initial visit, while one had neurofibromatosis in cerebellum. Conclusions: Complex retinopathy may present as the initial sign of neurofibromatosis, and high-throughput sequencing analysis for neurofibromatosis related genes contribute to early diagnosis of neurofibromatosis and facilitating early identification of vital systemic complication.

目的：总结MAB21L2基因的变异和临床特点，并与高度同源的MAB21L1基因进行比较。 方法：对中山眼科中心临床基因数据库中MAB21L2基因变异患者进行基因型和表型分析，回顾性分析既往文献报道的MAB21L2基因和高度同源基因MAB21L1变异的表型-基因型的关系。结果：在2个小眼畸形家系中发现2个MAB21L2基因杂合变异：先证者1携带已知变异c.151C>G/p.(Arg51Gly)，患者双眼小眼畸形伴虹膜脉络膜缺损，伴骨关节屈曲。母亲携带相同杂合变异但表型正常；先证者2携带未报道的变异c.1042G>T/p.(Glu348*)，左眼小眼畸形，右眼正常且无全身异常。结合文献回顾发现，在显性遗传模式下，80%的MAB21L2杂合致病变异(20/25)和100%的MAB21L1杂合致病变异(25/25)发生在氨基酸49-52 区域，导致小眼无眼或眼缺损异常(microphthalmia, anophthalmia or coloboma,MAC)；携带该区域MAB21L2基因杂合突变的患者除MAC外，部分还伴骨骼关节发育异常(12/24，50%)；杂合截短变异发生在MAB21L2基因可导致MAC(5/5，100%)，而发生在MAB21L1则不致病。 结论：在2个小眼畸形家系中发现了MAB21L2基因1个新致病变异和1个已知热点致病变异，通过文献综述比较和总结了MAB21L1和MAB21L2基因的突变频谱以及基因型-表型相互关系，为此类基因缺陷导致遗传病的诊断和鉴别诊断提供依据。

Objective: To summarize the genetic variations and clinical features of the MAB21L2 and compare them with the highly homologous MAB21L1 gene. Methods: A genotype -genotype analysis was performed on the patients with MAB21L2 gene variants in the clinical genetic database of Zhongshan Ophthalmic Center, Sun Yat-sen University. A retrospective review was undertaken to analyze the phenotype-genotype correlations of MAB21L2 gene variants and the highly homologous MAB21L1 gene variants reported in the previous literature. Results: Two heterozygous MAB21L2 gene variants were identified in two families with microphthalmia: Proband 1 carried the known variant c.151C>G/p.(Arg51Gly), presenting with bilateral microphthalmia with iris-choroidal coloboma and flexion of joints. The mother carried the same heterozygous variant but had a normal phenotype. Proband 2 carried the unreported variant c.1042G>T/p.(Glu348*), manifesting as left-sided microphthalmia with a normal right eye and no other systemic abnormalities. Through literature review, we found that under a dominant inheritance pattern, 80% of heterozygous pathogenic MAB21L2 variants (20/25) and 100% of heterozygous pathogenic MAB21L1 variants (25/25) occurred in the amino acid region 49-52, resulting in microphthalmia, anophthalmia, and coloboma (MAC). Some patients with heterozygous MAB21L2 variants in this region exhibited additional skeletal and joint dysplasia (12/24, 50%). Heterozygous truncating variants in MAB21L2 led to MAC (5/5, 100%), while those in MAB21L1 were non-pathogenic. Conclusions: This study identified a novel pathogenic variant and a known hotspot pathogenic variant of MAB21L2 in two families with microphthalmia. Through a comprehensive literature review, we compared and summarized the mutation spectrums and genotype-phenotype correlations of MAB21L1 and MAB21L2 genes, providing valuable insights for the diagnosis and differential diagnosis of genetic diseases caused by these gene defects.

先天性小眼畸形是一种罕见的先天性眼球发育异常，表现为眼球体积缩小和结构紊乱，常伴有眼组织缺损，严重影响患者的视觉功能。该病可单独发生，仅影响眼部，也可作为全身综合征的表现之一，同时伴有全身多器官或系统的异常。目前已发现82个先天性小眼畸形致病基因，能解释近2/3患者的发病原因。MAB21L1和MAB21L2是高度同源的两个基因，两者的致病变异均可导致小眼畸形，但又各自存在独特的表型特征。本期封面文章报道了MAB21L2基因变异导致小眼畸形2例，并通过回顾文献绘制变异频谱，从变异热点、变异类型、表型特征和基因型-表型相互关系等方面，对MAB21L1和MAB21L2进行比较，为两者缺陷所致眼遗传病的鉴别和诊断提供依据。

先天性小眼畸形是一种罕见的先天性眼球发育异常，表现为眼球体积缩小和结构紊乱，常伴有眼组织缺损，严重影响患者的视觉功能。该病可单独发生，仅影响眼部，也可作为全身综合征的表现之一，同时伴有全身多器官或系统的异常。目前已发现82个先天性小眼畸形致病基因，能解释近2/3患者的发病原因。MAB21L1和MAB21L2是高度同源的两个基因，两者的致病变异均可导致小眼畸形，但又各自存在独特的表型特征。本期封面文章报道了MAB21L2基因变异导致小眼畸形2例，并通过回顾文献绘制变异频谱，从变异热点、变异类型、表型特征和基因型-表型相互关系等方面，对MAB21L1和MAB21L2进行比较，为两者缺陷所致眼遗传病的鉴别和诊断提供依据。