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波兰肌原纤维肌病患者的致病突变及可能影响表型的变异

Pathogenic Mutations and Putative Phenotype-Affecting Variants in Polish Myofibrillar Myopathy Patients.

作者信息

Potulska-Chromik Anna, Jędrzejowska Maria, Gos Monika, Rosiak Edyta, Kierdaszuk Biruta, Maruszak Aleksandra, Opuchlik Andrzej, Zekanowski Cezary, Fichna Jakub P

机构信息

Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097 Warsaw, Poland.

Neuromuscular Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland.

出版信息

J Clin Med. 2021 Feb 26;10(5):914. doi: 10.3390/jcm10050914.

Abstract

Myofibrillar myopathies (MFM) are heterogeneous hereditary muscle diseases with characteristic myopathological features of Z-disk dissolution and aggregates of its degradation products. The onset and progression of the disease are variable, with an elusive genetic background, and around half of the cases lacking molecular diagnosis. Here, we attempted to establish possible genetic foundations of MFM by performing whole exome sequencing (WES) in eleven unrelated families of 13 patients clinically diagnosed as MFM spectrum. A filtering strategy aimed at identification of variants related to the disease was used and included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of muscle-expressed genes, and analysis of the disease-associated interactome. Genetic diagnosis was possible in eight out of eleven cases. Putative causative mutations were found in the (two cases), , , and (four cases) genes, the latter typically presenting with a rigid spine syndrome. Moreover, a variety of additional, possibly phenotype-affecting variants were found. These findings indicate a markedly heterogeneous genetic background of MFM and show the usefulness of next generation sequencing in the identification of disease-associated mutations. Finally, we discuss the emerging concept of variant load as the basis of phenotypic heterogeneity.

摘要

肌原纤维肌病(MFM)是一类具有异质性的遗传性肌肉疾病,具有特征性的肌病理表现,即Z盘溶解及其降解产物的聚集。该病的起病和进展各不相同,遗传背景不明,约半数病例缺乏分子诊断。在此,我们对13例临床诊断为MFM谱系的患者的11个无关家庭进行全外显子组测序(WES),试图确定MFM可能的遗传基础。我们采用了一种旨在识别与疾病相关变异的筛选策略,包括对WES数据和人类表型本体(HPO)术语进行综合分析、对肌肉表达基因进行分析以及对疾病相关相互作用组进行分析。11例中有8例可进行基因诊断。在 (2例)、 、 以及 (4例)基因中发现了可能的致病突变,后者通常表现为僵人综合征。此外,还发现了多种可能影响表型的其他变异。这些发现表明MFM具有明显异质性的遗传背景,并显示了新一代测序在识别疾病相关突变方面的有用性。最后,我们讨论了作为表型异质性基础的变异负荷这一新兴概念。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15df/7956316/e01c01f27a15/jcm-10-00914-g001.jpg

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