55例OTOF基因变异相关听力损失患者的基因型与临床表型分析
Analysis of genotype-phenotype correlation in 55 patients with OTOF-related hearing loss
王奕哲;俞莎;张博文;李为韬;韩磊;舒易来
1:上海理工大学健康科学与工程学院
2:复旦大学附属眼耳鼻喉科医院耳鼻喉科
3:上海市罕见病基因编辑与细胞治疗重点实验室
4:国家卫生健康委员会听觉医学重点实验室(复旦大学)
摘要关键词基金项目(Foundation):作者参考文献[1] 白雪晶，冯磊.OTOF基因突变在非综合征性聋中的研究进展[J].中华耳科学杂志，2019,17(6):978-981.
[2] 韩磊，陈黎恒，俞莎，等.OTOF突变相关基因型与听力学表型关系的自然病史[J].临床耳鼻咽喉头颈外科杂志，2025,39(4):379-385.
[3] IWASA Y I,NISHIO S Y,YOSHIMURA H,et al.Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan[J].Human Genetics,2022,141(3):865-875.
[4] 钟佳珂，蒋罗颖，崔冲，等.OTOF基因突变听神经病的基因治疗临床试验与设计[J].听力学及言语疾病杂志，2025,33(1) :1-7.
[5] LV J,WANG H,CHENG X,et al.AAV1-h OTOF gene therapy for autosomal recessive deafness 9:a single-arm trial[J].The Lancet,2024,403(10441) :2317-2325.
[6] WANG H,CHEN Y,LV J,et al.Bilateral gene therapy in children with autosomal recessive deafness 9:single-arm trial results[J].Nature Medicine,2024,30(7):1898-1904.
[7] QI J,ZHANG L,LU L,et al.AAV gene therapy for autosomal recessive deafness 9:a single-arm trial[J].Nature Medicine,2025,31(9):2917-2926.
[8] QI J,TAN F,ZHANG L,et al.AAV-mediated gene therapy restores hearing in patients with DFNB9 deafness[J].Advanced Science,2024,11(11):2306788.
[9] VALAYANNOPOULOS V,BANCE M,CARVALHO D S,et al.DB-OTO gene therapy for inherited deafness [J].The New England Journal of Medicine,2025.DOI:10.1056/NEJMoa2400521.
[10] ZHANG J,GUO Z,PAN C,et al.Preliminary evidence for enhanced auditory cortex activation and mental development after gene therapy in children with autosomal recessive deafness 9[J].Nature Human Behaviour,2025.DOI:10.1038/s41562-025-02184-8.
[11] CHENG X,ZHONG J,ZHANG J,et al.Gene therapy vs cochlear implantation in restoring hearing function and speech perception for individuals with congenital deafness [J].JAMA Neurol,2025,82(9) :941-951.
[12] FAN X,GAO Z,ZHONG J,et al.International expert consensus on gene therapy for hereditary hearing loss:based on clinical trials[J].Med,2025:100886.
[13] ORGANIZATION W H.Highlighting priorities for ear and hearing care-World Report on Hearing[J].Retrieved March,2021,31:242-242A.
[14] VILA P M,LIEU J E C.Asymmetric and unilateral hearing loss in children[J].Cell and Tissue Research,2015,361(1):271-278.
[15] 彭丹丹，张金慧，李晓华，等.多种听力学检测方法在未引出听性脑干反应患儿诊断中的价值[J].听力学及言语疾病杂志，2024,32(3) :245-248.
[16] LI M M,DATTO M,DUNCAVAGE E J,et al.Standards and guidelines for the interpretation and reporting of sequence variants in cancer:a joint consensus recommendation of the Association for Molecular Pathology,American Society of Clinical Oncology,and college of American pathologists[J].The Journal of Molecular Diagnostics,2017,19(1):4-23.
[17] MORALES-ANGULO C,GALLO-TER??N J,GONZ??LEZ-AGUADO R,et al.Hearing loss secondary to variants in the OTOF gene[J].International Journal of Pediatric Otorhinolaryngology,2024,186:112082.
[18] FORD C L,RIGGS W J,QUIGLEY T,et al.The natural history,clinical outcomes,and genotype-phenotype relationship of otoferlin-related hearing loss:a systematic,quantitative literature review[J].Human Genetics,2023,142(10):1429-1449.
[19] BAI X,XU W,ZHU Y,et al.Transcriptomics and phenotypic analysis of OTOF gene knockdown in zebrafish mediated by CRISPR/Cas9[J].Gene Expression Patterns,2025,55:119394.
[20] KITAO K,MUTAI H,NAMBA K,et al.Deterioration in distortion product otoacoustic emissions in auditory neuropathy patients with distinct clinical and genetic backgrounds[J].Ear and Hearing,2019,40(1):184-191.
[21] STALMANN U,FRANKE A J,AL-MOYED H,et al.Otoferlin is required for proper synapse maturation and for maintenance of inner and outer hair cells in mouse models for DFNB9[J].Frontiers in Cellular Neuroscience,2021,15:677543.
[22] MICHALSKI N,GOUTMAN J D,AUCLAIR S M,et al.Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses[J].eLife,2017,6:e31013.
[23] LECL??RE J C,DULON D.Otoferlin as a multirole Ca2+ signaling protein:from inner ear synapses to cancer pathways[J].Frontiers in Cellular Neuroscience,2023,17:1197611.
[24] MATSUNAGA T,MUTAI H,KUNISHIMA S,et al.A prevalent founder mutation and genotype-phenotype correlations of OTOF in Japanese patients with auditory neuropathy[J].Clinical Genetics,2012,82(5):425-432.
[25] LIN P H,TSAI C Y,CHIANG Y T,et al.Unraveling the complex genetic landscape of OTOF-related hearing loss:a deep dive into cryptic variants and haplotype phasing[J].Molecular Medicine,2025,31(1):181.