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Recessive myotonia congenita caused by a homozygous splice site variant in CLCN1 gene: a case report
BMC Medical Genetics ( IF 2.023 ) Pub Date : 2020-10-22 , DOI: 10.1186/s12881-020-01128-5
Peter Sparber , Margarita Sharova , Alexandra Filatova , Olga Shchagina , Evgeniya Ivanova , Elena Dadali , Mikhail Skoblov

Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can be inherited in a dominant (Thomsen disease) and recessive form (Becker disease) and both are caused by pathogenic variants in the CLCN1 gene. Noncanonical splice site variants are often classified as variants of uncertain significance, due to insufficient accuracy of splice-predicting tools. Functional analysis using minigene plasmids is widely used in such cases. Moreover, functional analysis is very useful in investigation of the disease pathogenesis, which is necessary for development of future therapeutic approaches. To our knowledge only one noncanonical splice site variant in the CLCN1 gene was functionally characterized to date. We further contribute to this field by evaluation the molecular mechanism of splicing alteration caused by the c.1582 + 5G > A in a homozygous state. We report a clinical case of an affected 6-y.o boy with athletic appearance due to muscle hypertrophy, calf muscle stiffness, cramping and various myotonic signs in a consanguineous family with no history of neuromuscular disorders. The neurological examination showed percussion-activated myotonia in the hands and legs. Plasma creatine kinase enzyme and transaminases levels were normal. Electromyography at the time of examination shows myotonic runs in the upper and lower extremities. Functional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic.

中文翻译:

CLCN1基因纯合剪接位点变异引起的隐性先天性肌强直:一例报告

先天性肌强直是一种罕见的神经肌肉疾病,其特征是诱发或自发性收缩后肌肉松弛延迟。先天性肌强直可以以显性遗传(汤姆森病)和隐性遗传(贝克尔病)遗传,两者均由CLCN1基因的致病变异引起。由于剪接预测工具的准确性不足,通常将非规范的剪接位点变异归为不确定意义的变异。在这种情况下,使用小基因质粒的功能分析被广泛使用。此外,功能分析在疾病发病机理的研究中非常有用,这对于开发未来的治疗方法必不可少。据我们所知,迄今为止,仅在功能上表征了CLCN1基因中的一种非规范剪接位点变体。我们通过评估由纯合子态的c.1582 + 5G> A引起的剪接改变的分子机制,进一步为这一领域做出了贡献。我们报告了在没有神经肌肉疾病史的近亲家庭中,由于肌肉肥大,小腿肌肉僵硬,痉挛和各种强直性体征而受到运动影响的6岁男孩的临床病例。神经系统检查显示手和腿有敲击激活的肌强直。血浆肌酸激酶和转氨酶水平正常。检查时的肌电图显示在上肢和下肢的肌强直运动。在小基因系统中对该变体进行功能分析表明,剪接发生改变,导致功能丧失,从而证实该变体具有致病性。
更新日期:2020-10-26
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