遗传性视神经病变患者临床表型及基因检测多态性分析—单中心队列研究

Clinical phenotypes and polymorphism analysis of hereditary optic neuropathy in Chinese patients:a single-center cohort study

目的分析临床常见遗传性视神经病变(HON)患者基因突变的基因型及临床表现的多样性。方法2013年5月~2021年10月本院神经眼科中心纳入的拟诊遗传性视神经病变患者,经二代基因测序分析与疾病相关的线粒体环状DNA基因突变,并进行多态性分析。结果537例拟诊HON患者,其中遗传性视网膜病变88例(16.4%)、视神经病变449例(83.6%)。完成基因检测者375例,阳性率为66.4%(249/375)。249例基因检测阳性患者中男女比为3.7∶1,以40岁以下的儿童及青少年为主。其中主要致病基因突变为线粒体环基因点突变导致的Leber遗传性视神经病变(LHON)及核基因OPA1突变导致的显性遗传性视神经病变(DOA)。在103例LHON阳性样本中检测出线粒体chrM-11778 G>A突变,占41.4%;其他特殊线粒体点突变有3291、8344、13413等。发现罕见基因突变包括OPA3、WSF1、CISD2、DNM1L、ACO2、AFG3L2、SPG7、NDUFS2、FGFR2、BBS10、TUBA8、NBAS、RAB18等,均与视神经萎缩相关。结论临床拟诊HON及不明原因的视神经萎缩患者中,线粒体相关的遗传性疾病占比高。这类患者通过有针对性的基因检测技术可以最大限度明确潜在的突变位点及多态性,为精准医疗及基因治疗奠定基础。

Objective To evaluate the spectrum of gene mutations and clinical phenotypes in a cohort of hereditary optic neuropathy(HON)patients.Methods A single center cohort study.Patients suspected with hereditary optic neuropathy in Neuro-Ophthalmology division of our hospital between May 2013 and October 2021 were enrolled.Gene mutation screened focus on mtDNA and whole exon genome-wide mutation were tested by next-generation sequencing technique.Meanwhile,the demographic data together with the ophthalmologic examinations were evaluated.Results Among 537 patients with suspected hereditary visual disorders,88 cases(16.4%)were diagnosed with hereditary retinopathy,whereas 449 patients(83.6%)with hereditary optic neuropathy.Gene testing was performed in 375 cases with a positive rate of 66.4%(249/375).Among the 249 cases with positive gene mutation related to optic neuropathy,the ratio of male to female was 3.7:1 and most of them were pediatric and adolescent under 40 years old.Most of the mutations were identified in mitochondrial ring DNA which leaded to Leber hereditary optic neuropathy(LHON)and nuclear mitochondrial gene OPA1 mutations causing dominant optic atrophy(DOA).Among 103 cases of LHON,the percentage of primary chrM-11778 G>A mutation was 41.4%,and other special mitochondrial secondary mutations were 3291,8344,and 13413 etc.Other rare gene mutations were detected,including OPA3,WSF1,CISD2,DNM1L,ACO2,AFG3L2,SPG7,NDUFS2,FGFR2,BBS10,TUBA8,NBAS and RAB18 etc,which were related to optic atrophy.Conclusions Mitochondrial-related genetic diseases accounted for a high proportion of clinically suspected HON patients and unexplained optic nerve atrophy.The targeted and precise gene sequencing can help identifying the diversity of genotype and also provide effective diagnosis and potential gene therapy in the future.