A Titin Truncating Variant Causing a Dominant Myopathy With Cardiac Involvement in a Large Family: The Exception That Proves the Rule.

IF 3 3区 医学 Q2 CLINICAL NEUROLOGY Neurology-Genetics Pub Date : 2024-08-12 eCollection Date: 2024-10-01 DOI:10.1212/NXG.0000000000200185
Kristl G Claeys, Marco Savarese, Per Harald Jonson, Veerle Goosens, Ana Topf, Anna Vihola, Volker Straub, Bjarne Udd
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Abstract

Background: Titin truncating variants (TTNtvs) have been repeatedly reported as causative of recessive but not dominant skeletal muscle disorders.

Objective: To determine whether a single heterozygous nonsense variant in TTN can be responsible for the observed dominant myopathy in a large family.

Methods: In this case series, all available family members (8 affected and 6 healthy) belonging to a single family showing autosomal dominant inheritance were thoroughly examined clinically and genetically.

Results: All affected family members showed a similar clinical phenotype with a combination of cardiac and skeletal muscle involvement. Muscle imaging data revealed titin-compatible hallmarks. Genetic analysis revealed in all affected patients a nonsense TTN variant c.70051C>T p.(Arg23351*), in exon 327. RNA sequencing confirmed the lack of complete nonsense-mediated decay, and protein studies convincingly revealed expression of a shortened titin fragment of the expected size.

Discussion: We conclude that a single heterozygous nonsense variant in titin occasionally can cause a dominant myopathy as shown in this large family. Therefore, monoallelic titin truncating variants should be considered as possible disease-causing variants in unsolved patients with a dominant myopathy. However, large segregation studies, muscle imaging, and RNA and protein assays are needed to support the clinical and genetic interpretation.

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在一个大家族中,一个 Titin 截短变异体导致了伴有心脏受累的显性肌病:例外证明规则。
背景:Titin截短变体(TTNtvs)被反复报道为隐性骨骼肌疾病的致病因子,但不是显性骨骼肌疾病的致病因子:目的:确定 TTN 中的单杂合子无义变异是否可能是一个大家族中观察到的显性肌病的原因:在本病例系列中,对一个常染色体显性遗传家族的所有成员(8 名患者和 6 名健康患者)进行了全面的临床和遗传学检查:结果:所有受影响的家庭成员都表现出类似的临床表型,心脏和骨骼肌同时受累。肌肉成像数据显示出与钛蛋白兼容的特征。基因分析表明,所有患者的第 327 号外显子均存在无义 TTN 变异 c.70051C>T p.(Arg23351*)。RNA 测序证实了缺乏完全无义介导的衰变,蛋白质研究令人信服地显示了预期大小的缩短的 titin 片段的表达:讨论:我们得出结论,在这个大家庭中,偶尔出现的单杂合无义变异可导致显性肌病。因此,对于尚未确诊的显性肌病患者,应将单等位基因的 titin 截短变异视为可能的致病变异。不过,还需要进行大规模的分离研究、肌肉成像以及 RNA 和蛋白质检测,以支持临床和遗传学解释。
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来源期刊
Neurology-Genetics
Neurology-Genetics Medicine-Neurology (clinical)
CiteScore
6.30
自引率
3.20%
发文量
107
审稿时长
15 weeks
期刊介绍: Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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