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<p>Congenital myasthenic syndromes (CMS) are genetically heterogeneous disorders in which precise molecular diagnosis is essential for management. Pathogenic variants in <i>PLEC</i> are a rare cause of autosomal recessive CMS and are frequently associated with epidermolysis bullosa simplex (EBS). We report an adult-onset case with EBS from birth, upper limb–predominant weakness, combined myopathic and myasthenic features, and subtle cardiomyopathy. Initial CMS gene panel testing identified a heterozygous canonical splice-site variant in <i>PLEC</i>. Subsequent trio exome sequencing revealed a second heterozygous intronic variant in trans, and RNA analysis demonstrated intron retention resulting in a frameshift, enabling variant reclassification and definitive diagnosis. This case expands the phenotypic spectrum of <i>PLEC</i>-related disease and highlights the value of transcript-level analysis in resolving cryptic Mendelian disorders.</p>

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Adult-onset PLEC-related congenital myasthenic syndrome-myopathy overlap with upper limb predominant weakness

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • Angel Jose,
  • Aina Jasrul Azily,
  • Katie Doyle,
  • Karen Stals,
  • Hayley Lees,
  • Caoimhe McKenna,
  • Amy Jayne McKnight,
  • John McConville,
  • Grace McMacken

摘要

Congenital myasthenic syndromes (CMS) are genetically heterogeneous disorders in which precise molecular diagnosis is essential for management. Pathogenic variants in PLEC are a rare cause of autosomal recessive CMS and are frequently associated with epidermolysis bullosa simplex (EBS). We report an adult-onset case with EBS from birth, upper limb–predominant weakness, combined myopathic and myasthenic features, and subtle cardiomyopathy. Initial CMS gene panel testing identified a heterozygous canonical splice-site variant in PLEC. Subsequent trio exome sequencing revealed a second heterozygous intronic variant in trans, and RNA analysis demonstrated intron retention resulting in a frameshift, enabling variant reclassification and definitive diagnosis. This case expands the phenotypic spectrum of PLEC-related disease and highlights the value of transcript-level analysis in resolving cryptic Mendelian disorders.