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<p>Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic <i>SGCA</i> variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous families with substantial left ventricular dysfunction, arrhythmias, and life-threatening ventricular tachyarrhythmias. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmia requiring implantable cardioverter-defibrillators. Initial evaluation with exome sequencing showed no conclusive results until a genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous <i>SGCA</i> variant shared by all affected individuals. Despite being distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and a presumably nonfunctional or structurally altered α-sarcoglycan protein. This study broadens the recognized clinical spectrum of LGMDR3 by revealing significant cardiac involvement and exemplifies how a splice-disrupting synonymous variant, initially classified as likely benign, can underlie a severe cardiac phenotype and merit reclassification. Our findings highlight the importance of integrating genotype-phenotype correlation with functional studies to improve diagnostic accuracy, particularly in underrepresented populations.</p>

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Reconsidering a silent variant: SGCA’s role in atypical cardiomyopathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月4日

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  • Smadar Horowitz-Cederboim,
  • Ronit Hoffman-Lipschuetz,
  • Ronen Durst,
  • Shoshi Shpitzen,
  • Ayelet Shauer,
  • Donna R. Zwas,
  • Chaggai Rosenbluh,
  • Israel Antman,
  • Avital Eilat,
  • Tamar Harel,
  • Orr Tomer,
  • Vardiella Meiner

摘要

Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic SGCA variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous families with substantial left ventricular dysfunction, arrhythmias, and life-threatening ventricular tachyarrhythmias. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmia requiring implantable cardioverter-defibrillators. Initial evaluation with exome sequencing showed no conclusive results until a genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant shared by all affected individuals. Despite being distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and a presumably nonfunctional or structurally altered α-sarcoglycan protein. This study broadens the recognized clinical spectrum of LGMDR3 by revealing significant cardiac involvement and exemplifies how a splice-disrupting synonymous variant, initially classified as likely benign, can underlie a severe cardiac phenotype and merit reclassification. Our findings highlight the importance of integrating genotype-phenotype correlation with functional studies to improve diagnostic accuracy, particularly in underrepresented populations.