Folkhälsan Research Center, Medicum, University of Helsinki, Helsinki, Finland.
Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania "Luigi Vanvitelli," Napoli, Italy.
JAMA Neurol. 2018 May 1;75(5):557-565. doi: 10.1001/jamaneurol.2017.4899.
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.
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.
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.
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.
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.
肌联蛋白（TTN）基因突变可引起广泛的遗传性疾病。由于 TTN 基因庞大，其大小给众多鉴定出来的罕见变异的解释带来了困难。
鉴定一组肌肉疾病患者中的肌联蛋白基因突变。
设计、地点和参与者：在本病例系列研究中，鉴定出 9 例肌联蛋白病患者和 4 例可能因 TTN 基因突变引起的疾病的患者。通过对 504 例患有肌肉营养不良症、先天性肌病或其他骨骼肌疾病的患者的 DNA 进行靶向重测序，发现肌联蛋白突变。这些患者于 2012 年 4 月至 2013 年 12 月在 10 个临床中心招募。所有患者在经过广泛的调查后，包括候选基因的 Sanger 测序，仍未得到诊断。数据分析于 2013 年 9 月至 2017 年 1 月进行。使用内部定制的生物信息学管道分析测序数据。
在 TTN 基因中发现新的突变和新的肌联蛋白病患者。我们结合遗传、临床和影像学数据以及信使 RNA 和/或蛋白研究，对 TTN 基因中的假定致病变异进行了评估。
9 例新的肌联蛋白病患者中，5 例（55.5%）为男性，发病年龄的平均值（标准差）为 25（15.8）岁（范围，0-46 岁）。4 例其他（3 例男性和 1 例女性）可能因 TTN 变异引起的疾病的患者中，2 例（50%）患有先天性肌病，2 例（50%）患有发病于 20 岁出头的慢性进展性远端肌病。大多数鉴定出来的突变以前都没有报道过。然而，所有的变异，即使是已描述的突变，都需要对先证者和亲属进行仔细的临床和分子评估。杂合截断变异或独特的错义变化不足以诊断肌联蛋白病。
TTN 变异的解释通常需要进一步分析，包括对临床表型（深度表型）以及信使 RNA 和蛋白研究的全面评估。我们提出了一种用于肌联蛋白基因检测结果临床解释的特定工作流程。
