Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing.
Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing.
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DOI：
10.1136/jclinpath-2017-204978
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发表时间：
2018-08
影响因子：
3.4
通讯作者：
Hajek R
中科院分区：
文献类型：
--
作者：
Chyra Kufova Z;Sevcikova T;Januska J;Vojta P;Boday A;Vanickova P;Filipova J;Growkova K;Jelinek T;Hajduch M;Hajek R
淀粉样变性是由异常蛋白原纤维沉积引起的，导致器官功能损害。遗传性淀粉样变性是由11个淀粉样前体蛋白基因的种系突变引起的单基因疾病。肥厚型心肌病是淀粉样变性的一个重要但非特异性的症状。遗传性淀粉样变性的诊断是复杂的，真实的原因可能仍然被忽视。我们的目的是设计遗传性淀粉样变性基因组，并引入新的下一代测序（NGS）方法来研究一组意义不明的肥厚型心肌病患者的遗传性淀粉样变性。使用含有11个淀粉样蛋白生成基因的Haloplex定制试剂盒设计靶富集DNA文库制备，然后在40名患者的队列中使用工具VarScan进行MiSeq Illumina测序和种系变体的生物信息学鉴定。我们设计了与各种淀粉样变性相关的11个基因（TTR、FGA、APOA 1、APOA 2、LYZ、GSN、CST 3、PRNP、APP、B2 M、ITM 2B）的NGS面板。我们检测到一个突变，这是负责遗传性淀粉样变性。其他一些单核苷酸变异是迄今为止未描述的或罕见的变异，或代表欧洲人群中常见的多态性。我们报告了一个意义不明的肥厚型心肌病患者队列中遗传性淀粉样变性的阳性病例，并建立了遗传性淀粉样变性的第一组NGS。这项工作可能有助于其他研究人员或临床医生成功实施NGS方法，并可能在验证后改善诊断过程。
Amyloidosis is caused by deposition of abnormal protein fibrils, leading to damage of organ function. Hereditary amyloidosis represents a monogenic disease caused by germline mutations in 11 amyloidogenic precursor protein genes. One of the important but non-specific symptoms of amyloidosis is hypertrophic cardiomyopathy. Diagnostics of hereditary amyloidosis is complicated and the real cause can remain overlooked. We aimed to design hereditary amyloidosis gene panel and to introduce new next-generation sequencing (NGS) approach to investigate hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance. Design of target enrichment DNA library preparation using Haloplex Custom Kit containing 11 amyloidogenic genes was followed by MiSeq Illumina sequencing and bioinformatics identification of germline variants using tool VarScan in a cohort of 40 patients. We present design of NGS panel for 11 genes (TTR, FGA, APOA1, APOA2, LYZ, GSN, CST3, PRNP, APP, B2M, ITM2B) connected to various forms of amyloidosis. We detected one mutation, which is responsible for hereditary amyloidosis. Some other single nucleotide variants are so far undescribed or rare variants or represent common polymorphisms in European population. We report one positive case of hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance and set up first panel for NGS in hereditary amyloidosis. This work may facilitate successful implementation of the NGS method by other researchers or clinicians and may improve the diagnostic process after validation.
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