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Orphanet Journal of Rare Diseases

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Open Access 01-12-2019 | Research

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

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

Published in: Orphanet Journal of Rare Diseases | Issue 1/2019

Abstract

Background

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.

Results

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.

Conclusions

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.

Trainor PA, Andrews BT. Facial dysostoses: etiology, pathogenesis and management. Am J Med Genet C Semin Med Genet. 2013;163c(4):283–94.PubMedCrossRef

Zhang X, Fan Y, Zhang Y, Xue H, Chen X. A novel mutation in the TCOF1 gene found in two Chinese cases of Treacher Collins syndrome. Int J Pediatr Otorhinolaryngol. 2013;77(9):1410–5.PubMedCrossRef

Vincent M, Genevieve D. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet Med. 2016;18(1):49–56.

Teber OA, Gillessen-Kaesbach G, Fischer S, Bohringer S, Albrecht B, Albert A, Arslan-Kirchner M, Haan E, Hagedorn-Greiwe M, Hammans C, et al. Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. Eur J Hum Genet. 2004;12(11):879–90.PubMedCrossRef

Splendore A, Silva EO, Alonso LG, Richieri-Costa A, Alonso N, Rosa A, Carakushanky G, Cavalcanti DP, Brunoni D, Passos-Bueno MR. High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes. Hum Mutat. 2000;16(4):315–22.PubMedCrossRef

Dauwerse JG, Dixon J, Seland S, Ruivenkamp CA, van Haeringen A, Hoefsloot LH, Peters DJ, Boers AC, Daumer-Haas C, Maiwald R, et al. Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nat Genet. 2011;43(1):20–2.PubMedCrossRef

Bowman M, Oldridge M, Archer C, O'Rourke A, McParland J, Brekelmans R, Seller A, Lester T. Gross deletions in TCOF1 are a cause of Treacher-Collins-Franceschetti syndrome. Eur J Hum Genet. 2012;20(7):769–77.PubMedPubMedCentralCrossRef

Chen Y, Guo L, Li CL, Shan J, Xu HS, Li JY, Sun S, Hao SJ, Jin L, Chai G, et al. Mutation screening of Chinese Treacher Collins syndrome patients identified novel TCOF1 mutations. Mol Genet Genomics. 2018;293(2):569–77.PubMedCrossRef

Dixon MJ, Marres HA, Edwards SJ, Dixon J, Cremers CW. Treacher Collins syndrome: correlation between clinical and genetic linkage studies. Clin Dysmorphol. 1994;3(2):96–103.PubMedCrossRef

10.

Li H, Zhang X, Li Z, Chen J, Lu Y, Jia J, Yuan H, Han D. Clinical and genetic analysis of a patient with Treacher Collins syndrome in TCOF1 gene. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2012;26(10):459–62.PubMed

11.

Wang Y, Yin XJ, Han T, Peng W, Wu HL, Liu X, Feng ZC. A novel silent deletion, an insertion mutation and a nonsense mutation in the TCOF1 gene found in two Chinese cases of Treacher Collins syndrome. Mol Gen Genomics. 2014;289(6):1237–40.CrossRef

12.

Cobb AR, Green B, Gill D, Ayliffe P, Lloyd TW, Bulstrode N, Dunaway DJ. The surgical management of Treacher Collins syndrome. Br J Oral Maxillofac Surg. 2014;52(7):581–9.PubMedCrossRef

13.

Posnick JC, Tiwana PS, Costello BJ. Treacher Collins syndrome: comprehensive evaluation and treatment. Oral Maxillofac Surg Clin North Am. 2004;16(4):503–23.PubMedCrossRef

14.

Plomp RG, van Lieshout MJ, Joosten KF, Wolvius EB, van der Schroeff MP, Versnel SL, Poublon RM, Mathijssen IM. Treacher Collins syndrome: a systematic review of evidence-based treatment and recommendations. Plast Reconstr Surg. 2016;137(1):191–204.PubMedCrossRef

15.

Yan Z, Lu Y, Wang Y, Zhang X, Duan H, Cheng J, Yuan H, Han D. Identification of a novel TCOF1 mutation in a Chinese family with Treacher Collins syndrome. Exp Ther Med. 2018;16(3):2645–50.PubMedPubMedCentral

16.

Lim EC, Brett M, Lai AH, Lee SP, Tan ES, Jamuar SS, Ng IS, Tan EC. Next-generation sequencing using a pre-designed gene panel for the molecular diagnosis of congenital disorders in pediatric patients. Hum Genomics. 2015;9:33.PubMedPubMedCentralCrossRef

17.

Marszalek B, Wojcicki P, Kobus K, Trzeciak WH. Clinical features, treatment and genetic background of Treacher Collins syndrome. J Appl Genet. 2002;43(2):223–33.PubMed

18.

Gladwin AJ, Dixon J, Loftus SK, Edwards S, Wasmuth JJ, Hennekam RC, Dixon MJ. Treacher Collins syndrome may result from insertions, deletions or splicing mutations, which introduce a termination codon into the gene. Hum Mol Genet. 1996;5(10):1533–8.PubMedCrossRef

19.

So RB, Gonzales B, Henning D, Dixon J, Dixon MJ, Valdez BC. Another face of the Treacher Collins syndrome (TCOF1) gene: identification of additional exons. Gene. 2004;328:49–57.PubMedCrossRef

20.

Edwards SJ, Gladwin AJ, Dixon MJ. The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon. Am J Hum Genet. 1997;60(3):515–24.PubMedPubMedCentral

21.

Wise CA, Chiang LC, Paznekas WA, Sharma M, Musy MM, Ashley JA, Lovett M, Jabs EW. TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins syndrome throughout its coding region. Proc Natl Acad Sci U S A. 1997;94(7):3110–5.PubMedPubMedCentralCrossRef

22.

Marsh KL, Dixon J, Dixon MJ. Mutations in the Treacher Collins syndrome gene lead to mislocalization of the nucleolar protein treacle. Hum Mol Genet. 1998;7(11):1795–800.PubMedCrossRef

23.

Isaac C, Marsh KL, Paznekas WA, Dixon J, Dixon MJ, Jabs EW, Meier UT. Characterization of the nucleolar gene product, treacle, in Treacher Collins syndrome. Mol Biol Cell. 2000;11(9):3061–71.PubMedPubMedCentralCrossRef

24.

Splendore A, Fanganiello RD, Masotti C, Morganti LS, Passos-Bueno MR. TCOF1 mutation database: novel mutation in the alternatively spliced exon 6A and update in mutation nomenclature. Hum Mutat. 2005;25(5):429–34.PubMedCrossRef

25.

Conte C, D'Apice MR, Rinaldi F, Gambardella S, Sangiuolo F, Novelli G. Novel mutations of TCOF1 gene in European patients with Treacher Collins syndrome. BMC Med Genet. 2011;12:125.PubMedPubMedCentralCrossRef

26.

Robbins J, Dilworth SM, Laskey RA, Dingwall C. Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequence. Cell. 1991;64(3):615–23.PubMedCrossRef

27.

Woodgett JR, Gould KL, Hunter T. Substrate specificity of protein kinase C. use of synthetic peptides corresponding to physiological sites as probes for substrate recognition requirements. Eur J Biochem. 1986;161(1):177–84.PubMedCrossRef

28.

Aljerian A, Gilardino MS. Treacher Collins syndrome. Clin Plast Surg. 2019;46(2):197–205.PubMedCrossRef

29.

Jones NC, Lynn ML, Gaudenz K, Sakai D, Aoto K, Rey JP, Glynn EF, Ellington L, Du C, Dixon J, et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat Med. 2008;14(2):125–33.PubMedPubMedCentralCrossRef

30.

Badran K, Bunstone D, Arya AK, Suryanarayanan R, Mackinnon N. Patient satisfaction with the bone-anchored hearing aid: a 14-year experience. Otol Neurotol. 2006;27(5):659–66.PubMedCrossRef

Title: TCOF1 pathogenic variants identified by Whole-exome sequencing in Chinese Treacher Collins syndrome families and hearing rehabilitation effect
Authors: Xinmiao Fan
Yibei Wang
Yue Fan
Huiqian Du
Nana Luo
Shuyang Zhang
Xiaowei Chen
Publication date: 01-12-2019
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2019
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-019-1136-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Results

Conclusions

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