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首页> 外文期刊>Genetic testing and molecular biomarkers >Exome Sequencing Reveals Novel TTN Variants in Saudi Patients with Congenital Titinopathies
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Exome Sequencing Reveals Novel TTN Variants in Saudi Patients with Congenital Titinopathies

机译：外显子组测序揭示小说TTN变体沙特先天性Titinopathies患者

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Aim: Our goal was to determine the genetic basis of early-onset myopathy in patients from two unrelated families.Materials and Methods: Whole-exome sequencing, autozygosity mapping, and confirmatory targeted Sanger sequencing were performed using genomic DNA extracted from blood samples from three myopathic patients of two unrelated families. Variant filtering and pathogenicity analyses were evaluated according to standard protocols and up-to-date pipelines applied at the King Faisal Specialist Hospital and Research Center.Results: A novel homozygous variant was detected in TTN gene within the first three M-line-encoding exons in a 9-year-old female in the first family who had delayed motor development and proximal weakness. Her 4-year-old affected brother, with the same homozygous variant, could not yet walk without help. This pathogenic nonsense variant is predicted to cause a premature stop during translation. In the second family we identified two novel variants as compound heterozygosites (a deletion and a variant affecting a canonical splice site) in an affected 9-year-old female with weakness that developed at age 3, in the second family. SpliceAI predicted the variants being splice-altering with high probability. These variants were fully segregated in the family. The deletion was found to be on the paternal allele, whereas the splicing variant was on the maternal allele. The patient's echocardiography revealed mitral valve prolapse with mild mitral regurgitation. Muscle histology showed minicores that were also confirmed by electron microscopy.Conclusion: Our study identified novel pathogenic variants in the TTN gene that are likely responsible for the phenotype of early-onset myopathy; hence, expanding genotype-phenotype relationship of titinopathies.
机译：目的:我们的目标是确定的遗传基础早发性肌病的患者从两个家庭无关。Whole-exome测序,autozygosity映射确认目标Sanger测序使用从血液中提取的DNA进行从三种肌病患者的两个样品家庭无关。致病性分析显示进行了评估标准协议和最新的管道在国王费萨尔专家医院应用和研究中心。在第一个TTN基因的变异检测三个M-line-encoding外显子9岁女性在第一家庭推迟电动机发展和近端无力。哥哥的影响,相同的纯合子变体,没有走不帮助。预计导致致病性废话变体在翻译过程中过早停止。第二个家庭我们确定了两个新的变种复合heterozygosites(删除和变异影响规范拼接网站)9岁的女性与软弱的影响开发了3岁,在第二个家庭。SpliceAI预测变量splice-altering有高概率的。在家庭中变异完全隔离。删除被发现父亲的等位基因,而剪接变体孕产妇等位基因。二尖瓣脱垂有轻度二尖瓣返流。这也证实了电子显微镜。TTN致病性变异的基因可能负责的表型早发性肌病;genotype-phenotype titinopathies关系。

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