Genotype-phenotype variability in Chinese cases of Treacher Collins syndrome

Abstract

Background: Treacher Collins syndrome (TCS) is a clinically and genetically heterogeneous disorder of craniofacial development mainly caused by variants in TCOF1, POLR1D, and POLR1C.

Objectives: This study examined the causative genes of five TCS cases.

Materials and Methods: In this study, two familial cases and three sporadic cases clinically diagonsed with TCS are described. Mutational analysis in probands was performed by targeted next-generation sequencing (NGS). Mutations identified by NGS were further confirmed by Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA).

Results: A novel gross deletion (exons 9–13), a novel small deletion (c.381_382delAG), and two known deletions (c.4131_4135delAAAAG and c.2394_2395delAG) within TCOF1 as well as a known mutation (c.91C > T) in POLR1D were identified. These five cases exhibited high inter- and intra-familial phenotypic heterogeneity.

Conclusion: This is the first report of Chinese TCS cases caused by a gross deletion within TCOF1 and mutations in POLR1D. In addition to expanding the spectrum of TCS-associated mutation in the Chinese population, our findings present the diversity of its clinical presentation. It is recommended that analyses such as NGS or MLPA capable of detecting large deletions be undertaken as a part of TCS molecular diagnosis.

Chinese abstract

背景：Treacher-Collins综合征（TCS）是一种临床和遗传异质性颅面发育障碍, 主要由TCOF1、POLR1D, and POLR1C 的变异引起。

目的：研究5例TCS患者的致病基因。

材料与方法：本文描述了2例家族性和3例散发性TCS临床诊断病例。先证者的突变分析通过定向下一代测序（NGS）进行。通过Sanger测序或多重连接依赖性探针扩增（MLPA）进一步证实了由NGS鉴定的突变。

结果：在TCOF1中发现了一个新的总缺失（外显子9-13）、一个新的小缺失（c.381_382delAG）、两个已知的缺失（c.4131_4135 delAAAAG和c.2394_2395 delAG）以及一个已知的POLR1D突变（c.91C > T）。这五种病例表现出较高的家族内和家族间表型异质性。

结论：这是中国首次报道由TCF1内的总缺失和POLR1D突变引起的TCS病例, 除了扩展了中国人群中TCS相关突变谱外, 我们的研究结果还呈现出其临床表现的多样性。建议将能够检测大缺失的分析, 如NGS或MLPA, 作为TCS分子诊断的一部分。

Keywords:

• Treacher Collins syndrome
• POLR1D
• TCOF1

Acknowledgments

We sincerely thank all the family members for their participation and cooperation in this study.

Disclosure statement

The authors have no financial interests in companies or other entities, and the funders of all grants supporting this article played no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist.

Additional information

Funding

This study was supported by grants from National Key Research and Development Project (2016YFC1000700, 2016YFC1000704) and National Natural Science Foundation of China (81730029) to Pu Dai, National Key Research and Development Project of China (2016YFC1000706) and National Natural Science Foundation of China (81873704), and Fostering Funds of Chinese PLA General Hospital for National Distinguished Young Scholar Science Fund (2017-JQPY-001) to Yongyi Yuan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.