根据不同外显子的使用情况推断滴虫病的病程。

IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY
Maria Francesca Di Feo, Ali Oghabian, Ella Nippala, Mathias Gautel, Heinz Jungbluth, Francesca Forzano, Edoardo Malfatti, Claudia Castiglioni, Ilona Krey, David Gomez Andres, Angela F. Brady, Maria Iascone, Anna Cereda, Lidia Pezzani, Daniel Natera De Benito, Andres Nascimiento Osorio, Berta Estévez Arias, Sergei A. Kurbatov, Tania Attie-Bitach, Sheela Nampoothiri, Erin Ryan, Michelle Morrow, Svetlana Gorokhova, Brigitte Chabrol, Juha Sinisalo, Heli Tolppanen, Johanna Tolva, Francina Munell, Jessica Camacho Soriano, Maria Angeles Sanchez Duran, Mridul Johari, Homa Tajsharghi, Peter Hackman, Bjarne Udd, Marco Savarese
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引用次数: 0

摘要

目的:双叶titin截短变体(TTNtv)与广泛的表型谱相关,从具有畸形特征的复杂产前肌肉疾病到成人发病的肢腰肌营养不良症,伴有或不伴有心脏受累。鉴于 TTN 的规模和复杂性,做出明确的分子诊断和精确的疾病预后仍具有挑战性:在本病例系列中,我们在 2022 年 11 月至 2023 年 9 月期间从多个国际医疗中心收集了 12 例未发表的病例和 1 例已发表的病例,这些病例均为双性 TTNtv。通过外显子组或基因组测序检测了TTN突变。有关家族史和个人临床史的信息以标准化表格的形式收集。对内部样本队列(包括出生后骨骼肌、胎儿骨骼肌、出生后心肌和胎儿心肌)进行了RNA测序和TTN外显子使用分析。此外,我们还从ENCODE.Results中检索了公开的RNA测序数据:我们生成了关于TTN外显子的新RNA-seq数据,并利用所涉及外显子的剪接百分比(PSI)数据,确定了对每位滴虫病患者具有预后意义的基因型-表型相关性(在产前和产后是否恶化或改善)。有趣的是,由于外显子的使用,我们还能排除一个产前病例的滴虫病诊断:这项研究表明,外显子的使用为更详尽地临床解读 TTNtv 提供了宝贵的见解;此外,由于大多数基因都会发生替代剪接,它还可作为在许多其他遗传疾病中实施个性化医疗的模型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Inferring disease course from differential exon usage in the wide titinopathy spectrum

Inferring disease course from differential exon usage in the wide titinopathy spectrum

Objective

Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult-onset limb-girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging.

Methods

In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA-sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA-sequencing data was retrieved from ENCODE.

Results

We generated new RNA-seq data on TTN exons and identified genotype–phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case.

Interpretation

This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing.

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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
期刊介绍: Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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