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Identification of a novel gross deletion of TCOF1 in a Chinese prenatal case with Treacher Collins syndrome.

ABSTRACT: BACKGROUND:Treacher Collins syndrome (TCS) is the most common mandibulofacial dysostosis with an autosomal dominant or rarely recessive manner of inheritance. It is still challenging to make a definite diagnosis for affected fetuses with TCS only depending on the ultrasound screening. Genetic tests can contribute to the accurate diagnosis for those prenatal cases. METHODS:Targeted exome sequencing was performed in a fetus of a Chinese family, who presenting an abnormal facial appearance by prenatal 2D and 3D ultrasound screening, including micrognathia, nasal bridge pit, and abnormal auricle. The result was validated with multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (qPCR). RESULTS:A novel 2-6 exons deletion of TCOF1 gene was identified and confirmed by the MLPA and qPCR in the fetus, which was inherited from the affected father with similar facial anomalies. CONCLUSION:The heterozygous deletion of 2-6 exons in TCOF1 results in the TCS of this Chinese family. Our findings not only enlarge the spectrum of mutations in TCOF1 gene, but also highlight the values of combination of ultrasound and genetics tests in diagnosis of craniofacial malformation-related diseases during perinatal period.

SUBMITTER: Liu J

PROVIDER: S-EPMC7434750 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Identification of a novel gross deletion of TCOF1 in a Chinese prenatal case with Treacher Collins syndrome.

Liu Jing J Lin Pengsiyuan P Pang Jialun J Jia Zhengjun Z Peng Ying Y Xi Hui H Wu Lingqian L Li Zhuo Z Wang Hua H

Molecular genetics & genomic medicine 20200615 8

<h4>Background</h4>Treacher Collins syndrome (TCS) is the most common mandibulofacial dysostosis with an autosomal dominant or rarely recessive manner of inheritance. It is still challenging to make a definite diagnosis for affected fetuses with TCS only depending on the ultrasound screening. Genetic tests can contribute to the accurate diagnosis for those prenatal cases.<h4>Methods</h4>Targeted exome sequencing was performed in a fetus of a Chinese family, who presenting an abnormal facial appe ...[more]

PMID: 32543076

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Project description:BACKGROUND: Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial disorder caused by frameshift deletions or duplications in the TCOF1 gene. These mutations cause premature termination codons, which are predicted to lead to mRNA degradation by nonsense mediated mRNA decay (NMD). Haploinsufficiency of the gene product (treacle) during embryonic development is the proposed molecular mechanism underlying TCS. However, it is still unknown if TCOF1 expression levels are decreased in post-embryonic human cells. METHODS: We have estimated TCOF1 transcript levels through real time PCR in mRNA obtained from leucocytes and mesenchymal cells of TCS patients (n = 23) and controls (n = 18). Mutational screening and analysis of NMD were performed by direct sequencing of gDNA and cDNA, respectively. RESULTS: All the 23 patients had typical clinical features of the syndrome and pathogenic mutations were detected in 19 of them. We demonstrated that the expression level of TCOF1 is 18-31% lower in patients than in controls (p < 0.05), even if we exclude the patients in whom we did not detect the pathogenic mutation. We also observed that the mutant allele is usually less abundant than the wild type one in mesenchymal cells. CONCLUSIONS: This is the first study to report decreased expression levels of TCOF1 in TCS adult human cells, but it is still unknown if this finding is associated to any phenotype in adulthood. In addition, as we demonstrated that alleles harboring the pathogenic mutations have lower expression, we herein corroborate the current hypothesis of NMD of the mutant transcript as the explanation for diminished levels of TCOF1 expression. Further, considering that TCOF1 deficiency in adult cells could be associated to pathologic clinical findings, it will be important to verify if TCS patients have an impairment in adult stem cell properties, as this can reduce the efficiency of plastic surgery results during rehabilitation of these patients.

Dataset Information

Identification of a novel gross deletion of TCOF1 in a Chinese prenatal case with Treacher Collins syndrome.

Publications

Identification of a novel gross deletion of TCOF1 in a Chinese prenatal case with Treacher Collins syndrome.

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