Interpreting Genetic Variants in Titin in Patients With Muscle Disorders
Interpreting Genetic Variants in Titin in Patients With Muscle Disorders
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DOI：
10.1001/jamaneurol.2017.4899
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发表时间：
2018-05-01
期刊：
影响因子：
29
通讯作者：
Nigro, Vincenzo
中科院分区：
文献类型：
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作者：
Savarese, Marco;Maggi, Lorenzo;Nigro, Vincenzo
肌联蛋白基因（TTN）突变可导致多种遗传性疾病。在TTN中确定的许多罕见的变异的解释是一个困难的挑战，因为它的大size.Objective确定肌联蛋白的遗传变异在一个队列的患者肌肉disorders.DESIGN，设置，和PARTICIPANTS在这种情况下，9例肌联蛋白病和其他4例患者可能致病的TTN变异被确定。通过对504例肌营养不良、先天性肌病或其他骨骼肌疾病患者的DNA进行靶向重测序，检测肌联蛋白突变。患者于2012年4月至2013年12月从10家临床中心入组。所有这些人在接受了广泛的调查后都没有得到诊断，包括候选基因的桑格测序。数据分析在2013年9月至2017年1月期间进行。使用内部定制的生物信息学pipeline.Main结果和措施的分析测序数据的新的TTN基因突变和新的肌钙蛋白病患者的鉴定。我们进行了一项评估TTN基因的假定致病变异，结合基因，临床和成像数据与信使RNA和/或蛋白质study.Results的9个新的Titinopathy患者，5（55.5%）是男性和发病时的平均（SD）年龄为25（15.8）岁（范围，0-46岁）。在其他4名可能致病TTN变异的患者（3名男性和1名女性）中，2名（50%）患有先天性肌病，2名（50%）患有在第二个十年内发作的缓慢进行性远端肌病。大多数已鉴定的突变以前未报告。然而，所有的变异，即使是已经描述的突变，需要仔细的临床和分子评估的先证者和亲属。杂合截断变体或独特的错义变化是不足以作出诊断titinopathy.CONCLUSIONS和相关性TTN变体的解释往往需要进一步的分析，包括临床表型（深表型）以及信使RNA和蛋白质的研究的综合评价。我们提出了一个具体的工作流程，在肌联蛋白的遗传结果的临床解释。
IMPORTANCE Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size.OBJECTIVE To identify genetic variants in titin in a cohort of patients with muscle disorders.DESIGN, SETTING, AND PARTICIPANTS In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline.MAIN OUTCOMES AND MEASURES The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies.RESULTS Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy.CONCLUSIONS AND RELEVANCE The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.