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Abstract：
BACKGROUND: Treacher Collins syndrome (TCS; OMIM 154500) is a craniofacial developmental disorder.
METHODS: To investigate the genetic features of a four-generation Chinese family with TCS, clinical examinations, hearing tests, computed tomography, whole-exome sequencing (WES), Sanger sequencing, reverse transcription (RT)-PCR, and the Minigene assay were performed.
RESULTS: The probands, an 11-year-old male and his cousin exhibited typical clinical manifestations of TCS including conductive hearing loss, downward slanting palpebral fissures, and mandibular hypoplasia. Computed tomography revealed bilateral fusion of the anterior and posterior stapedial crura and malformation of the long crura of the incus. WES of both patients revealed a novel heterozygous intronic variant, i.e., c.4342 + 5_4342 + 8delGTGA (NM_001371623.1) in TCOF1. Minigene expression analysis revealed that the c.4342 + 5_4342 + 8delGTGA variant in TCOF1 caused a partial deletion of exon 24 (c.4115_4342del: p.Gly1373_Arg1448del), which was predicted to yield a truncated protein. The deletion was further confirmed via RT-PCR and sequencing of DNA from proband blood cells. A heterozygous variant in the POLR1C gene (NM_203290; exon6; c.525delG) was found almost co-segregated with the TCOF1 pathogenic variant.
CONCLUSIONS: In conclusion, we identified a heterozygous TCOF1 splicing variant c.4342 + 5_4342 + 8delGTGA (splicing) in a Chinese TSC family with ossicular chain malformations and facial anomalies. Our findings broadened the spectrum of TCS variants and will facilitate diagnostics and prognostic predictions.
METHODS: To investigate the genetic features of a four-generation Chinese family with TCS, clinical examinations, hearing tests, computed tomography, whole-exome sequencing (WES), Sanger sequencing, reverse transcription (RT)-PCR, and the Minigene assay were performed.
RESULTS: The probands, an 11-year-old male and his cousin exhibited typical clinical manifestations of TCS including conductive hearing loss, downward slanting palpebral fissures, and mandibular hypoplasia. Computed tomography revealed bilateral fusion of the anterior and posterior stapedial crura and malformation of the long crura of the incus. WES of both patients revealed a novel heterozygous intronic variant, i.e., c.4342 + 5_4342 + 8delGTGA (NM_001371623.1) in TCOF1. Minigene expression analysis revealed that the c.4342 + 5_4342 + 8delGTGA variant in TCOF1 caused a partial deletion of exon 24 (c.4115_4342del: p.Gly1373_Arg1448del), which was predicted to yield a truncated protein. The deletion was further confirmed via RT-PCR and sequencing of DNA from proband blood cells. A heterozygous variant in the POLR1C gene (NM_203290; exon6; c.525delG) was found almost co-segregated with the TCOF1 pathogenic variant.
CONCLUSIONS: In conclusion, we identified a heterozygous TCOF1 splicing variant c.4342 + 5_4342 + 8delGTGA (splicing) in a Chinese TSC family with ossicular chain malformations and facial anomalies. Our findings broadened the spectrum of TCS variants and will facilitate diagnostics and prognostic predictions.
摘要：
背景：TreacherCollins综合征（TCS;OMIM154500）是一种颅面发育障碍。
方法：为了研究中国四代TCS家族的遗传特征，临床检查,听力测试,计算机断层扫描,全外显子组测序（WES），桑格测序,逆转录（RT）-PCR，并进行了Minigene测定。
结果：先证者，一名11岁男性和他的堂兄表现出典型的TCS临床表现，包括传导性听力损失，向下倾斜的睑裂,下颌骨发育不全.计算机断层扫描显示前和后s骨cr的双侧融合和砧骨长cr的畸形。两名患者的WES揭示了一种新的杂合内含子变体，即，在TCOF1中c.4342+5_4342+8delGTGA(NM_001371623.1)。Minigene表达分析显示，TCOF1中的c.43425_43428delGTGA变体导致外显子24的部分缺失（c.4115_4342del：p.Gly1373_Arg1448del），预测会产生截短的蛋白质。通过RT-PCR和来自先证者血细胞的DNA测序进一步证实缺失。发现POLR1C基因中的杂合变体（NM_203290;exon6;c.525delG）几乎与TCOF1致病性变体共分离。
结论：结论：我们在一个具有听骨链畸形和面部异常的中国TSC家族中鉴定了一个杂合的TCOF1剪接变体c.43425_43428delGTGA（剪接）。我们的发现扩大了TCS变体的范围，并将有助于诊断和预后预测。
方法：为了研究中国四代TCS家族的遗传特征，临床检查,听力测试,计算机断层扫描,全外显子组测序（WES），桑格测序,逆转录（RT）-PCR，并进行了Minigene测定。
结果：先证者，一名11岁男性和他的堂兄表现出典型的TCS临床表现，包括传导性听力损失，向下倾斜的睑裂,下颌骨发育不全.计算机断层扫描显示前和后s骨cr的双侧融合和砧骨长cr的畸形。两名患者的WES揭示了一种新的杂合内含子变体，即，在TCOF1中c.4342+5_4342+8delGTGA(NM_001371623.1)。Minigene表达分析显示，TCOF1中的c.43425_43428delGTGA变体导致外显子24的部分缺失（c.4115_4342del：p.Gly1373_Arg1448del），预测会产生截短的蛋白质。通过RT-PCR和来自先证者血细胞的DNA测序进一步证实缺失。发现POLR1C基因中的杂合变体（NM_203290;exon6;c.525delG）几乎与TCOF1致病性变体共分离。
结论：结论：我们在一个具有听骨链畸形和面部异常的中国TSC家族中鉴定了一个杂合的TCOF1剪接变体c.43425_43428delGTGA（剪接）。我们的发现扩大了TCS变体的范围，并将有助于诊断和预后预测。
