MYH8</i>致病变异引起的7型远端关节挛缩症的临床和遗传特征基因

I. V. Sharkova, S. S. Nikitin, T. V. Markova, A. E. Voskanyan, E. A. Melnik, O. A. Shchagina, E. L. Dadali
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引用次数: 0

摘要

远端关节挛缩是一组遗传异质性的先天性疾病,其特征为非进行性挛缩,主要是上肢和下肢远端关节。11个基因已被确定为致病变异导致常染色体显性和常染色体隐性类型的远端关节挛缩的发生。几乎所有这些基因的产物都在神经肌肉系统的结构中表达,这使得将远端关节挛缩归类为神经肌肉疾病成为可能。7型远端关节挛缩症是一种罕见的常染色体显性遗传病,其特征有两个主要症状:下颌紧张症和假性掌指畸形,这是指间关节在手部背屈时活动受限的特殊症状,在掌屈时不受限制。在文献中描述的所有来自不同人群的7型远端关节挛缩症患者中,在MYH8基因中发现了相同的致病变异c.2021G>A(p.a g674gln),其蛋白产物是肌球蛋白在胚胎期起作用并提供肌纤维结构形成的亚型之一。该工作的目的是描述的临床和遗传特征的第一个家庭病例的7型远端关节挛缩在俄罗斯患者。患者行临床检查和肌电图检查。先证者血液中按照标准方法分离DNA后,在NextSeq 500平台(Illumina, USA)上采用对端读取法(2 × 75 bp)进行外显子组测序。使用自动Sanger测序对鉴定的变异的致病性进行确认。通过对具有7型远端关节挛缩症临床表现的父子进行分子遗传学分析,发现MYH8基因18外显子的c.2021G> a杂合变异,导致蛋白分子中的p.a g674gln (NM_002472.2)被替换,该变异先前在文献中发表的所有患者中都有描述。检查的患者未发现局灶性神经系统症状,以及轻微的发育异常、内脏器官病理、尺侧偏差、马蹄足畸形、距骨垂直定向、髋关节挛缩,这些在先前描述的MYH8基因变异患者中发现的频率不同。7型远端关节挛缩的特定临床体征,结合主要核苷酸变异的存在,使得优化这类遗传性关节挛缩的分子遗传学诊断过程成为可能。
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Clinical and genetic characteristics of type 7 distal arthrogryposis caused by a pathogenic variant in the <i>MYH8</i> gene
Distal arthrogryposis is a group of genetically heterogeneous congenital diseases characterized by non-progressive contractures predominantly distal joints of the upper and lower extremities. 11 genes have been identified as pathogenic variants causing the occurrence of autosomal dominant and autosomal recessive types of distal arthrogryposis. Almost all products of these genes are expressed in the structures of the neuromuscular system, which makes it possible to classify distal arthrogryposis as a neuromuscular disease. Type 7 distal arthrogryposis is a rare autosomal dominant disease characterized by two main symptoms: mandibular trismus and pseudocamptodactyly, a specific symptom of limited mobility of the interphalangeal joints during hand dorsiflexion with no restriction during palmar flexion. In all patients described in the literature from different populations with type 7 distal arthrogryposis, the same pathogenic variant c.2021G>A(p.Arg674Gln) was found in the MYH8 gene, the protein product of which is one of the myosin isoforms functioning in the embryonic period and providing the formation of muscle fiber structures. The aim of the work is to describe the clinical and genetic characteristics of the first family case of type 7 distal arthrogryposis in Russian patients. The patients underwent clinical examination and electromyography. Exome sequencing after DNA isolation from the proband’s blood according to the standard method was carried out on the NextSeq 500 platform (Illumina, USA) using the pairedend reading method (2 × 75 bp). Confirmation of the pathogenicity of the identified variants was carried out using automatic Sanger sequencing. As a result of molecular genetic analysis in a father and son with clinical manifestations of type 7 distal arthrogryposis, a heterozygous c.2021G>A variant in exon 18 of the MYH8 gene, which was previously described in all patients published in the literature, was detected, leading to the replacement of p.Arg674Gln(NM_002472.2) in a protein molecule. The examined patients did not reveal focal neurological symptoms, as well as minor developmental abnomalities, pathology of internal organs, ulnar deviations, equinovarus feet deformities, vertical orientation of the talus, contractures of the hip joints, which were found with varying frequency in previously described patients with variants in the MYH8 gene. Specific clinical signs of type 7 distal arthrogryposis, combined with the presence of a major nucleotide variant, make it possible to optimize the process of molecular genetic diagnosis of this type of hereditary arthrogryposis.
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来源期刊
Nervno-Myshechnye Bolezni
Nervno-Myshechnye Bolezni Medicine-Neurology (clinical)
CiteScore
0.50
自引率
0.00%
发文量
20
审稿时长
8 weeks
期刊介绍: The principal objective of the "Neuromuscular Diseases" journal is publication of state-of-art information about scientific clinical studies, diagnostics, and treatment of neurological diseases. "Neuromuscular Diseases" is a peer-reviewed journal, and members of its editorial board are major professionals in Russia and the CIS countries that have deserved authority not only in our country but abroad as well. Besides, leading scientists of Europe and the USA regularly cooperate with the journal. The journal regularly publishes reviews of modern literature references, proprietary clinical observations, lectures, original articles, results of research protocols in various areas of neuromuscular pathology - clinical presentation, diagnostics, medication, surgical and non-drug therapies, modern trends in drug rehabilitation, and recent drug developments. Due to international cooperation, the journal contains the newest therapeutic and diagnostic approaches to monitoring of patients with neuromuscular pathology.
期刊最新文献
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