TCOF1 Gene variation in Treacher Collins syndrome and evaluation of speech rehabilitation after bone bridge surgery
-
摘要: 目的 对2例Treacher Collins综合征(Treacher Collins syndrome,TCS)患者的临床表型特点及基因序列进行分析,确定其生物学致病原因,并探讨骨桥植入的听力干预疗效。方法 收集2个家系成员的临床资料,签署知情同意书,抽取先证者及其家系成员的外周血,提取DNA,进行全外显子组测序,并针对变异位点对家系成员进行Sanger测序验证,对患者进行TCOF1基因变异分析,并对家系2先证者在声场下评估并比较裸耳及佩戴骨桥后的听阈及言语识别率。结果 2个家系中先证者均有耳廓畸形、颧骨和下颌骨发育不全、小下颌、眼裂下斜、内侧睫毛发育不全的表现。家系1先证者合并右侧前鼻孔狭窄、牙齿发育不全等特殊表现,均符合TCS的临床诊断。对2个家系进行基因检测,检测出TCOF1基因有2个杂合突变:c.1350_1351dupGG(p.A451Gfs*43)、c.4362_4366del(p.K1457Efs*12),导致氨基酸发生移码突变。家系1先证者父母TCOF1基因Sanger测序验证未检测到突变,先证者1 TCOF1 c.1350_1351dupGG杂合变异此前未见报道。家系2先证者术后单音节言语识别率为76%,听觉行为分级(CAP)为6分,言语可懂度分级(SIR)为4分,行有意义听觉整合量表(MAIS)评估,患者对声音的觉察能力、理解能力及助听装置的使用情况均获得明显改善。行格拉斯格儿童收益量表及生活质量测定量表评估,患儿家长认为患儿在生活自理能力、日常生活学习、社会交际及心理健康方面有显著提高。结论 本研究明确了TCS生物学致病原因,丰富了中国人群TCOF1基因突变谱,骨桥植入可提高TCS患者听力及言语识别率。
-
关键词:
- Treacher Collins综合征 /
- 耳聋 /
- 遗传性 /
- TCOF1基因 /
- 基因突变
Abstract: Objective By analyzing the clinical phenotypic characteristics and gene sequences of two patients with Treacher Collins syndrome(TCS), the biological causes of the disease were determined. Then discuss the therapeutic effect of hearing intervention after bone bridge implantation.Methods All clinical data of the two family members were collected, and the patients signed the informed consent. The peripheral blood of the proband and family members was extracted, DNA was extracted for whole exome sequencing, and Sanger sequencing was performed on the family members for the mutation site. TCOF1 genetic mutations analysis was performed on the paitents. Then, the hearing threshold and speech recognition rate of family 2 proband were evaluated and compared under the sound field between bare ear and wearing bone bridge.Results In the two pedigrees, the probands of both families presented with auricle deformity, zygomatic and mandibular hypoplasia, micrognathia, hypotropia of the eye fissure, and hypoplasia of the medial eyelashes. The proband of Family 1 also presents with specific features including right-sided narrow anterior nasal aperture and dental hypoplasia, which were consistent with the clinical diagnosis of Treacher Collins syndrome. Genetic testing was conducted on both families, and two heterozygous mutations were identified in the TCOF1 gene: c. 1350_1351dupGG(p. A451Gfs*43) and c. 4362_4366del(p. K1457Efs*12), resulting in frameshift mutations in the amino acid sequence. Sanger sequencing validation of the TCOF1 gene in the parents of the proband in Family 1 did not detect any mutations. Proband 1 TCOF1 c. 1350_1351dupGG heterozygous variants have not been reported previously. The postoperative monosyllabic speech recognition rate of family 2 proband was 76%, the Categories of Auditory Performance(CAP) score was 6, and the Speech Intelligibility Rating(SIR) score was 4. Assessment using the Meaningful Auditory Integration Scale(MAIS) showed notable improvement in the patient's auditory perception, comprehension, and usage of hearing aids. Evaluation using the Glasgow Children's Benefit Inventory and quality of life assessment revealed significant improvements in the child's self care abilities, daily living and learning, social interactions, and psychological well being, as perceived by the parents.Conclusion This study has elucidated the biological cause of Treacher Collins syndrome, enriched the spectrum of TCOF1 gene mutations in the Chinese population, and demonstrated that bone bridge implantation can improve the auditory and speech recognition rates in TCS patients.-
Key words:
- treacher collins syndrome /
- deafness /
- hereditary /
- TCOF1 genes /
- genetic mutations
-
表 1 已报道的中国人群TCS突变情况
参考文献 cDNA 氨基酸 参考文献 cDNA 氨基酸 Pan等(2021)[18] 1766delC p.L589Pfs*7 Fan等(2019)[22] 3047-2A>G - Pan等(2018)[19] 3496delG p.A1166Pfs*7 He等(2017)[21] 3438T>G p.Ser1146Arg Wang等(2021)[20] 314_315delTA p.L105Rfs*68 Pan等(2018)[19] 430dupA p.T144Nfs*31 He等(2017)[21] 326A>G p.Asn109Ser Pan等(2018)[19] 451delC p.L151Ffs*68 He等(2017)[21] 1535T>C p.Met512Thr He等(2017)[21] 1961C>T p.Ala654Val He等(2017)[21] 810dupA p.Ser922Leu Zhang等(2021)[23] 1719delG p.N574Tfs*22 Pan等(2018)[19] 1307_1344del38 p.V436Efs*9 Yan等(2018)[25] 165-1G>A - Fan等(2019)[22] 489delC p.S164Qfs*55 He等(2017)[21] 1130C>T p.Pro377Leu He等(2017)[21] 503C>T p.Thr168Met Zhang等(2013)[26] 4420C>T p.Gln1474Term Pan等(2018)[19] 136C>G p.Leu46Val Wang等(2021)[20] 4342+2_4342+3delTG - Zhang等(2021)[23] 4342+5G>C - Pan等(2018)[19] 3386delA p.K1129Sfs*45 Wang等(2021)[20] 320delC p.S107Lfs*15 Wang等(2014)[27] 1303dupC p.Q435Pfs*23 Pan等(2021)[18] 939dupA p.G314Rfs*35 Su等(2007)[28] 1315G>A p.Ala439Thr Zhang等(2021)[23] 1146delC p.R383Gfs*110 Fan等(2019)[22] 2478+5G>A - He等(2017)[21] 2777C>G p.Ala926Gly Wang等(2014)[27] 1658C>G p.Ser553Term Pan等(2018)[19] 1719dupG p.N574Efs*29 Su等(2006)[29] 3703_3707delACTCT p.T1235Gfs*6 He等(2017)[21] 2762C>T p.Pro921Leu Fan等(2019)[22] 648delC p.S217Pfs*3 Zhang等(2021)[23] 384_385delGA p.E128Dfs*46 Zhang等(2021)[23] 1393C>T p.Gln465Term Xiong等(2015)[24] 2452C>T p.Gln818Term He等(2017)[21] 1783G>A p.Val595Ile He等(2017)[21] 2672G>A p.Gly891Glu He等(2017)[21] 2245C>T p.Pro749Ser Xiong等(2015)[24] 1229C>T p.Ser410 LeuHe等(2017)[21] 4004A>G p.Lys1335Arg -
[1] Chang CC, Steinbacher DM. Treacher collins syndrome[J]. Semin Plast Surg, 2012, 26(2): 83-90. doi: 10.1055/s-0032-1320066
[2] Peck CJ, Lopez J, Smetona JT, et al. Treacher Collins Mandibular Distraction[J]. Clin Plast Surg, 2021, 48(3): 431-444. doi: 10.1016/j.cps.2021.02.005
[3] Sakai D, Trainor PA. Treacher Collins syndrome: unmasking the role of Tcof1/treacle[J]. Int J Biochem Cell Biol, 2009, 41(6): 1229-1232. doi: 10.1016/j.biocel.2008.10.026
[4] Sanchez E, Laplace-Builhe B, Mau-Them FT, et al. POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4[J]. Genet Med, 2020, 22(3): 547-556. doi: 10.1038/s41436-019-0669-9
[5] Ma J, Ma X, Lin K, et al. Genetic screening of a Chinese cohort of children with hearing loss using a next-generation sequencing panel[J]. Hum Genomics, 2023, 17(1): 1. doi: 10.1186/s40246-022-00449-1
[6] Archbold S, Lutman ME, Marshall DH. Categories of Auditory Performance[J]. Ann Otol Rhinol Laryngol Suppl, 1995, 166(null): 312-314.
[7] Robbins AM, Renshaw JJ, Berry SW. Evaluating meaningful auditory integration in profoundly hearing-impaired children[J]. Am j otol, 1991, 12 Suppl: 144-150.
[8] Nikolopoulos TP, Archbold SM, Gregory S. Young deaf children with hearing aids or cochlear implants: early assessment package for monitoring progress[J]. Int j pediatr otorhi, 2005, 69(2): 175-186. doi: 10.1016/j.ijporl.2004.08.016
[9] 李果, 刘莉, 杨婷, 等. Waardenburg综合征患儿人工耳蜗植入术后听觉与言语康复效果评价[J]. 临床耳鼻咽喉头颈外科杂志, 2022, 36(5): 347-352. doi: 10.13201/j.issn.2096-7993.2022.05.005 https://lceh.whuhzzs.com/article/doi/10.13201/j.issn.2096-7993.2022.05.005
[10] 郗昕, 陈艾婷, 李佳楠, 等. 嘈杂语噪声下普通话儿童语句测听表的标准化[J]. 听力学及言语疾病杂志, 2009, 17(4): 318-322. https://www.cnki.com.cn/Article/CJFDTOTAL-TLXJ200904004.htm
[11] Saadeh P, Reavey PL, Siebert JW. A soft-tissue approach to midfacial hypoplasia associated with Treacher Collins syndrome[J]. Ann Plast Surg, 2006, 56(5): 522-525. doi: 10.1097/01.sap.0000214939.21590.76
[12] Tse WK. Treacher Collins syndrome: New insights from animal models[J]. Int J Biochem Cell Biol, 2016, 81(Pt A): 44-47.
[13] Beaumont CA, Dunaway DJ, Padwa BL, et al. Extracraniofacial anomalies in Treacher Collins syndrome: A multicentre study of 248 patients[J]. Int J Oral Maxillofac Surg, 2021, 50(11): 1471-1476. doi: 10.1016/j.ijom.2021.03.001
[14] Franceschetti A, Klein D. The mandibulofacial dysostosis; a new hereditary syndrome[J]. Acta Ophthalmol(Copenh), 1949, 27(2): 143-224.
[15] Marszalek-Kruk BA, Wojcicki P, Dowgierd K, et al. Treacher Collins Syndrome: Genetics, Clinical Features and Management[J]. Genes(Basel), 2021, 12(9): 1392.
[16] Guo P, Pan B, Jiang H, et al. Prevention methods for Treacher Collins syndrome: A systematic review[J]. Int J Pediatr Otorhinolaryngol, 2020, 134: 110062. doi: 10.1016/j.ijporl.2020.110062
[17] Li X, Su Y, Huang S, et al. Genotype-phenotype variability in Chinese cases of Treacher Collins syndrome[J]. Acta Otolaryngol, 2019, 139(7): 567-575. doi: 10.1080/00016489.2019.1612530
[18] Pan Z, Xu H, Chen B, et al. Treacher Collins syndrome: Clinical report and retrospective analysis of Chinese patients[J]. Mol Genet Genomic Med, 2021, 9(2): e1573.
[19] Pan Y, Guo L, Li CL, et al. Mutation screening of Chinese Treacher Collins syndrome patients identified novel TCOF1 mutations[J]. Mol Genet Genomics, 2018, 293(2): 569-577. doi: 10.1007/s00438-017-1384-3
[20] Wang H, Xiao F, Dong X, et al. Diagnostic and clinical utility of next-generation sequencing in children born with multiple congenital anomalies in the China neonatal genomes project[J]. Hum Mutat, 2021, 42(4): 434-444. doi: 10.1002/humu.24170
[21] He Z, Zhang D, Renton AE, et al. The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data[J]. Am J Hum Genet, 2017, 100(2): 193-204. doi: 10.1016/j.ajhg.2016.12.001
[22] Fan X, Wang Y, Fan Y, et al. TCOF1 pathogenic variants identified by Whole-exome sequencing in Chinese Treacher Collins syndrome families and hearing rehabilitation effect[J]. Orphanet J Rare Dis, 2019, 14(1): 178. doi: 10.1186/s13023-019-1136-z
[23] Zhang C, An L, Xue H, et al. Mutation analysis of TCOF1 gene in Chinese Treacher Collins syndrome patients[J]. J Clin Lab Anal, 2021, 35(1): e23567.
[24] Xiong HY, Alipanahi B, Lee LJ, et al. RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease[J]. Science, 2015, 347(6218): 1254806. doi: 10.1126/science.1254806
[25] Yan Z, Lu Y, Wang Y, et al. Identification of a novel TCOF1 mutation in a Chinese family with Treacher Collins syndrome[J]. Exp Ther Med, 2018, 16(3): 2645-2650.
[26] Zhang X, Fan Y, Zhang Y, et al. A novel mutation in the TCOF1 gene found in two Chinese cases of Treacher Collins syndrome[J]. Int J Pediatr Otorhinolaryngol, 2013, 77(9): 1410-1415. doi: 10.1016/j.ijporl.2013.05.013
[27] Wang Y, Yin XJ, Han T, et al. A novel silent deletion, an insertion mutation and a nonsense mutation in the TCOF1 gene found in two Chinese cases of Treacher Collins syndrome[J]. Mol Genet Genomics, 2014, 289(6): 1237-1240. doi: 10.1007/s00438-014-0883-8
[28] Su PH, Yu JS, Chen JY, et al. Mutations and new polymorphic changes in the TCOF1 gene of patients with oculo-auriculo-vertebral spectrum and Treacher-Collins syndrome[J]. Clin dysmorphol, 2007, 16(4): 261-267. doi: 10.1097/MCD.0b013e3281c108d2
[29] Su PH, Chen JY, Chen SJ, et al. Treacher Collins syndrome with a de Novo 5-bp deletion in the TCOF1 gene[J]. J formos med assoc, 2006, 105(6): 518-521. doi: 10.1016/S0929-6646(09)60194-7
[30] Dixon J, Trainor P, Dixon MJ. Treacher Collins syndrome[J]. Orthod Craniofac Res, 2007, 10(2): 88-95. doi: 10.1111/j.1601-6343.2007.00388.x
[31] So RB, Gonzales B, Henning D, et al. Another face of the Treacher Collins syndrome(TCOF1) gene: identification of additional exons[J]. Gene, 2004, 328: 49-57. doi: 10.1016/j.gene.2003.11.027
[32] Bowman M, Oldridge M, Archer C, et al. Gross deletions in TCOF1 are a cause of Treacher-Collins-Franceschetti syndrome[J]. Eur J Hum Genet, 2012, 20(7): 769-777. doi: 10.1038/ejhg.2012.2
[33] Splendore A, Silva EO, Alonso LG, et al. High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes[J]. Hum Mutat, 2000, 16(4): 315-322. doi: 10.1002/1098-1004(200010)16:4<315::AID-HUMU4>3.0.CO;2-H
[34] 潘博, 蒋海越, 庄洪兴, 等. 综合征性小耳畸形的基因学研究[J]. 中华整形外科杂志, 2005, 21(2): 146-148. https://www.cnki.com.cn/Article/CJFDTOTAL-ZHZX200502021.htm
[35] Ratuszniak A, Skarzynski PH, Gos E, et al. The Bonebridge implant in older children and adolescents with mixed or conductive hearing loss: Audiological outcomes[J]. Int j pediatr otorhi, 2019, 118: 97-102. doi: 10.1016/j.ijporl.2018.12.026
[36] 赵守琴, 任冉, 韩德民, 等. 骨桥在双侧先天性外中耳畸形中应用的初步研究[J]. 中华耳鼻咽喉头颈外科杂志, 2017, 52(7): 512-516.
[37] Sprinzl GM, Wolf-Magele A. The Bonebridge Bone Conduction Hearing Implant: indication criteria, surgery and a systematic review of the literature[J]. Clin otolaryngol all, 2016, 41(2): 131-43. doi: 10.1111/coa.12484