一个遗传性听神经病伴视神经萎缩家系研究

A Pedigree Study of Hereditary Auditory Neuropathy with Optic Atrophy

董佩;索利敏;张磊;何敏;贾薇;李通;范林静;李青峰;杨洁;靳玲;李丹;薛金梅;赵长青;张亚茜;段建雄

1:山西医科大学第二医院耳鼻咽喉头颈外科

2:山西省气道炎性疾病神经免疫研究省级重点培育实验室

3:山西医科大学第二医院眼科

4:山西医科大学基础医学院生物化学与分子生物学教研室

摘要
目的 研究探讨一个听神经病伴视神经萎缩家系遗传性致病原因。方法 详细询问先证者病史及家族史、进行临床相关检查确诊听神经病伴视神经萎缩,绘制该家系遗传系谱。抽取先证者(Ⅲ-7)外周血行全外显子组测序,对检出的突变进行致病性判读,对先证者妻子(Ⅲ-8)、大女儿(Ⅳ-7)、二女儿(Ⅳ-9)和儿子(Ⅳ-10)进行Sanger测序验证突变位点,并结合临床表现和检查结果进行研究。结果 该家系遗传方式为常染色体显性遗传,先证者(Ⅲ-7)19岁时出现视力下降,30岁时出现双侧感音神经性聋,言语识别率下降,其所在5代20人大家系中10人(2人已故)有类似听力及视力下降症状。先证者(Ⅲ-7)、大女儿(Ⅳ-7)和儿子(Ⅳ-10)听力学检查:纯音测听示双侧感音神经性聋,ABR双耳未引出,40 Hz相关电位(AERP)双耳均未引出,OAE部分或全部频率可引出,镫骨肌声反射阈值未引出;Ⅲ-7、Ⅳ-10眼底检查有不同程度视乳头萎缩,OCT示双眼视盘神经纤维层厚度变薄、视觉诱发电位示P100波峰时延长,确诊为遗传性听神经病伴视神经萎缩。Ⅲ-7行全外显子检测发现3号染色体有一个致病位点OPA1基因c.1334G>A(p.Arg445His, NM_015560.2)突变,一代测序结果示Ⅳ-7和Ⅳ-10也有该突变,Ⅲ-8和Ⅳ-9该位点的基因型是野生纯合型,即未发生突变。结论 OPA1基因c.1334G>A(p.Arg445His, NM_015560.2)突变位点为该家系致病突变。
关键词
听神经病;遗传性视神经萎缩;OPA1基因
基金项目(Foundation):
山西省重点研发计划项目(201803D31122);; 山西省留学人员科技活动择优资助项目(2019-39)
作者
董佩;索利敏;张磊;何敏;贾薇;李通;范林静;李青峰;杨洁;靳玲;李丹;薛金梅;赵长青;张亚茜;段建雄
参考文献

1 王秋菊,Tobias Moser.听神经病及亚型听突触病:声音编码与突触研究进展[J].中华耳科学杂志,2019,17(1):1-8.

2 中国听神经病临床诊断与干预多中心研究协作组,中华耳鼻咽喉头颈外科杂志编辑委员会,中华医学会耳鼻咽喉头颈外科学分会,等.中国听神经病临床实践指南(2022版)[J].中华耳鼻咽喉头颈外科杂志,2022,57(3):241-262.

3 Hansen AW,Murugan M,Li H,et al.A genocentric approach to discovery of mendelian disorders[J].Am J Hum Genet,2019,105(5):974-986.

4 Arruti N,Rodríguez-Solana P,Nieves-Moreno M,et al.OPA1 dominant optic atrophy:diagnostic approach in the pediatric population[J].Current Issues in Molecular Biology,2023,45(1):465-478.

5 Cartes-Saavedra B,Macuada J,Lagos D,et al.OPA1 modulates mitochondrial Ca2+ uptake through ER-mitochondria coupling[J].Front Cell Dev Biol,2021,9:774108.

6 睢瑞芳.正确解读遗传性视神经病变基因检测结果[J].中华眼科杂志,2021,57(5):326-330.

7 Cascavilla ML,Parisi V,Triolo G,et al.Retinal dysfunction characterizes subtypes of dominant optic atrophy[J].Acta Ophthalmologica,2018,96(2):e156-e163.

8 Jurkute N,Majander A,Bowman R,et al.Clinical utility gene card for:inherited optic neuropathies including next-generation sequencing-based approaches[J].Eur J Hum Genet,2019,27(3):494-502.

9 谢玥,陈洁琼,许可,等.中国人可疑遗传性视神经萎缩患者OPA1基因突变分析及临床特征[J].眼科,2015,24(2):79-84.

10 Othman BA,Ong JE,Dumitrescu AV.OPA1 biallelic optic atrophy 1 related disorder-case report and literature review[J].Genes,2022,13(6).DOI:10.3390/genes13061005.

11 Mizutari K,Matsunaga T,Inoue Y,et al.Vestibular dysfunction in a Japanese patient with a mutation in the gene OPA1[J].J Neurol Sci,2010,293(1-2):23-28.

12 柯铁,聂尚武,杨琴波,等.OPA1基因G401D突变导致常染色体视神经萎缩和听力受损(英文)[J].中华医学遗传学杂志,2006(5):481-485.

13 Li H,Jones EM,Li H,et al.Clinical and genetic features of eight Chinese autosomal-dominant optic atrophy pedigrees with six novel OPA1 pathogenic variants[J].Ophthalmic Genet,2018,39(5):569-576.

14 Napolitano F,Terracciano C,Bruno G,et al.Intrafamilial “DOA-plus” phenotype variability related to different OMI/HTRA2 expression[J].Am J Med Genet A,2020,182(1):176-182.

15 Maeda-Katahira A,Nakamura N,Hayashi T,et al.Autosomal dominant optic atrophy with OPA1 gene mutations accompanied by auditory neuropathy and other systemic complications in a Japanese cohort[J].Mol Vis,2019,25:559-573.

16 Lin PH,Wu HP,Wu CM,et al.Cochlear implantation outcomes in patients with auditory neuropathy spectrum disorder of genetic and non-genetic etiologies:a multicenter study[J].Biomedicines,2022,10(7):1-13.

17 Santarelli R,Rossi R,Scimemi P,et al.OPA1-related auditory neuropathy:site of lesion and outcome of cochlear implantation[J].Brain,2015,138(Pt 3):563-576.

18 田国红.遗传性视神经病变概述[J].中国眼耳鼻喉科杂志,2022,22(6):559-564.

19 Ferro Desideri L,Traverso CE,Iester M.OPA1 current treatment options for treating -mutant dominant optic atrophy[J].Drugs Today (Barc),2022,58(11):547-552.