Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower's sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a "template" defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown-models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity.

中文翻译：

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不协调的突变体编号为45的肌球蛋白伴侣B中的双等位基因突变是先天性肌病的原因。

先天性肌病（CM）形成了以围产期肌无力为特征的遗传异质性疾病组。在这里，我们报道了一个来自黎巴嫩的近亲父母的11岁男性后代。他表现出包括高尔氏体征在内的近端肌无力，骨骼肌活检显示其核心样结构的肌病性改变。该索引患者的整个外显子组测序导致发现了一种新的遗传定义的CM亚型，其基于未协调的突变体编号45肌球蛋白伴侣B（UNC45B）NM_173167：c.2261G> A，p。该突变在进化上是保守的，并且在与表型的系谱内共分离，并且位于肌球蛋白结合犰狳重复结构域3（ARM3）中，并且CADD得分为35。在多聚体水平上，UNC45B聚集成一条链，用作一条装配线，并充当“模板”，定义了排列成肌肉粗细丝的肌球蛋白的几何形状，规则性和周期性。我们的发现与秀丽隐杆线虫以及脊椎动物突变体和基因敲除模型中先前描述的肌病理学表型一致。总而言之，我们在此首次报道了具有UNC45B突变的患者，该突变导致了新型的遗传定义的先天性肌病疾病实体。