TCOF1 pathogenic variants identified by Whole-exome sequencing in Chinese Treacher Collins syndrome families and hearing rehabilitation effect

Xinmiao Fan,Shuyang Zhang,Huiqian Du,Nana Luo,Yue Fan,Xiaowei Chen,Yibei Wang

doi:10.1186/s13023-019-1136-z

Abstract

BackgroundTreacher 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.ResultsFour 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.ConclusionsWES 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.

Highlights

Treacher Collins syndrome (TCS, OMIM 154500) is an autosomal disorder of craniofacial development with an incidence rate of 1/50,000 live births
More than 200 distinct mutations have been reported in TCOF1, accounting for about 70–93% of TCS individuals, which are inherited via an autosomal dominant pattern, while POLR1D and POLR1C mutations have been found in about 11–23% of the remaining patients, which are inherited via autosomal dominant and autosomal recessive patterns, respectively [3, 5,6,7]
Downward slanting palpebral fissures and mandibular hypoplasia were observed in all patients

Summary

Introduction

Treacher Collins syndrome (TCS, OMIM 154500) is an autosomal disorder of craniofacial development with an incidence rate of 1/50,000 live births. 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. TCS is characterized by typical bilateral craniofacial malformations, such as hypoplasia of the mandible and zygomatic complex, downward-slanting palpebral fissures, coloboma. A diagnosis of TCS has been based on the clinical identification of a minimal clinical phenotype: downward slanting palpebral fissures and hypoplasia of. Fan et al Orphanet Journal of Rare Diseases (2019) 14:178 the zygomatic arch This can overlook some mildly affected patients. More than 200 distinct mutations have been reported in TCOF1, accounting for about 70–93% of TCS individuals, which are inherited via an autosomal dominant pattern, while POLR1D and POLR1C mutations have been found in about 11–23% of the remaining patients, which are inherited via autosomal dominant and autosomal recessive patterns, respectively [3, 5,6,7]

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