Department of Otolaryngology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Allwegene Technology Inc, Tianjin, China.
Orphanet J Rare Dis. 2019 Jul 15;14(1):178. doi: 10.1186/s13023-019-1136-z.
Treacher Collins syndrome (TCS, OMIM 154500) is an autosomal disorder of craniofacial development with an incidence rate of 1/50,000 live births. Although TCOF1, POLR1D, and POLR1C, have been identified as the pathogenic genes for about 90% TCS patients, the pathogenic variants of about 8-11% cases remain unknown. The object of this study is to describe the molecular basis of 14 clinically diagnosed TCS patients from four families using Whole-exome sequencing (WES) followed by Sanger sequencing confirmation, and to analyze the effect of bone conduction hearing rehabilitation in TCS patients with bilateral conductive hearing loss.
Four previously unreported heterozygous pathogenic variants (c.3047-2A > G, c.2478 + 5G > A, c.489delC, c.648delC) were identified in the TCOF1 gene, one in each of the four families. Sanger sequencing in family members confirmed co-segregation of the identified TCOF1 variants with the phenotype. The mean pure-tone threshold improvements measured 3 months after hearing intervention were 28.8 dB for soft-band BAHA, 36.6 ± 2.0 dB for Ponto implantation, and 27.5 dB SPL for Bonebridge implantation. The mean speech discrimination improvements measured 3 months after hearing intervention in a sound field with a presentation level of 65 dB SPL were 44%, 51.25 ± 5.06, and 58%, respectively. All six patients undergoing hearing rehabilitation in this study got a satisfied hearing improvement.
WES combined with Sanger sequencing enables the molecular diagnosis of TCS and may detect other unknown causative genes. Bone conduction hearing rehabilitation may be an optimal option for TCS patients with bilateral conductive hearing loss.
特雷彻·柯林斯综合征（TCS，OMIM 154500）是一种常染色体颅面发育障碍，发病率为每 50,000 例活产儿中有 1 例。尽管已经确定 TCOF1、POLR1D 和 POLR1C 是大约 90% TCS 患者的致病基因，但仍有约 8-11%的病例的致病变体未知。本研究的目的是使用全外显子组测序（WES）对来自四个家庭的 14 例临床诊断的 TCS 患者进行分子基础描述，然后进行 Sanger 测序确认，并分析骨导听力康复对双侧传导性听力损失 TCS 患者的影响。
在 TCOF1 基因中发现了四个先前未报道的杂合致病性变异（c.3047-2A>G、c.2478+5G>A、c.489delC、c.648delC），分别来自四个家庭。对家庭成员的 Sanger 测序证实了所鉴定的 TCOF1 变异与表型的共分离。听力干预 3 个月后，软带 BAHA 的平均纯音阈值改善为 28.8dB，Ponto 植入的平均纯音阈值改善为 36.6±2.0dB，Bonebridge 植入的平均纯音阈值改善为 27.5dB SPL。听力干预 3 个月后，在 65dB SPL 的呈现水平下声场中的平均言语辨别率改善分别为 44%、51.25±5.06%和 58%。本研究中接受听力康复的所有 6 例患者均获得了满意的听力改善。
WES 结合 Sanger 测序可实现 TCS 的分子诊断，并且可能检测到其他未知的致病基因。骨导听力康复可能是双侧传导性听力损失 TCS 患者的最佳选择。
