Reconsidering Silent Variant Unveils SGCA's Role in Atypical Cardiomyopathy

Abstract

We investigated an atypical form of limb-girdle muscular dystrophy type R3 (LGMDR3) associated with a homozygous synonymous variant in SGCA that significantly expands the recognized clinical phenotype to include prominent cardiac involvement. While LGMDR3, caused by pathogenic variants in SGCA, typically presents as progressive muscle weakness with relatively limited cardiac manifestations, the individuals in our study developed substantial left ventricular dysfunction, arrhythmias, and even life-threatening ventricular tachyarrhythmias. Five consanguineous families, initially evaluated through exome sequencing, showed no conclusive results until a focused genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant. Despite its location distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and, presumably, a nonfunctional or structurally altered -sarcoglycan protein. 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 arrhythmias requiring implantable cardioverter-defibrillators. This case broadens current understanding of LGMDR3 and its molecular underpinnings, ultimately guiding more personalized management strategies for affected individuals. It illustrates that thorough and ongoing variant interpretation is crucial, particularly in consanguineous populations where seemingly benign alterations may confer significant phenotypic consequences. By integrating carefully curated genomic data with clinical insights, clinicians can better identify patients at risk, tailor surveillance protocols, and implement timely interventions. In doing so, this discovery not only refines our appreciation of the intricate interplay between genetic variants and their phenotypic manifestations, but also underscores the importance of precision medicine approaches in the evolving landscape of inherited cardiomyopathies.