[TCOF1 Gene variation in Treacher Collins syndrome and evaluation of speech rehabilitation after bone bridge surgery].

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.TCOF1genetic 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.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1TCOF1c.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。.