Abstract
Background
Limb-girdle muscular dystrophy type 3 (LGMDR3) is an autosomal recessive disorder caused by pathogenic variants in the SGCA gene encoding α-sarcoglycan. While LGMDR3 predominantly presents with progressive proximal muscle weakness, cardiac involvement is less frequent and not well-characterized, occurring in approximately 10% of cases.
Purpose
To present novel findings of genetic mechanism and clinical features of cardiomyopathy and arrhythmic events in carriers of a homozygous synonymous SGCA variant, highlighting distinctions from prior knowledge and emphasizing implications for cardiological practice
Methods
Five consanguineous families with members exhibiting myopathy, cardiomyopathy, and arrhythmic features were identified. Initial exome sequencing was uninformative; however, reanalysis revealed a homozygous synonymous variant in SGCA (NM_000023.4:c.600G>A; p.Val200=). Homozygous variant carriers underwent comprehensive clinical evaluations, including creatine phosphokinase (CPK) levels, electrocardiograms (ECG), 24-hour Holter monitoring, two-dimensional echocardiography, and cardiac magnetic resonance imaging (CMR). RNA studies from one carrier were performed to assess the variant's impact on gene splicing.
Results
A total of 12 homozygous variant carriers (mean age at first presentation: 10.9 ± 7.3 years; 50% female) were studied. All exhibited elevated CPK levels and hepatocellular enzymes. Cardiac evaluations revealed left ventricular systolic dysfunction in 42% (5/12) of subjects, ranging from mild to severe impairment; two had left ventricular dilatation. CMR showed epicardial and mid-myocardial late gadolinium enhancement (LGE) in the lateral and inferior walls in all examined individuals (4/4). Arrhythmic events included sustained ventricular tachycardia or fibrillation in two subjects, non-sustained ventricular tachycardia in another and non-frequent premature ventricular beats in two more. One family member died suddenly at age 18 (no DNA available). Heterozygous carriers showed no clinical signs. RNA analysis demonstrated mis-spliced transcripts due to loss of an exonic splicing enhancer motif in the synonymous variant which resulted in aberrant splicing.
Conclusion
This study expands the phenotypic spectrum of LGMDR3 to include significant cardiomyopathy with arrhythmogenic features. The findings highlight the importance of genetic reanalysis and cautious interpretation of synonymous variants when assessing patients with unexplained cardiomyopathy and arrhythmic events. Integrating clinical expertise with periodic genetic data is important for patient management, risk stratification, and therapeutic decision-making in clinical electrophysiology.
Figure 1.
– Clinical characteristics