Hereditary cardiomyopathies exhibit diverse genetic patterns, with autosomal dominant transmission being the most frequent, though recessive, mitochondrial, and X-linked inheritances are also recognized. Limb-girdle muscular dystrophy type R3 (LGMDR3), caused by SGCA mutations, primarily affects proximal musculature, with cardiac involvement being rare (~10% of cases). This study examines five consanguineous families where affected cases have undergone exome sequencing (ES) for various symptoms, along with cardiac and muscle involvement. Early analyses were inconclusive.

Genomic DNA was sequenced using Illumina platforms, with variant calling and annotation performed on the Geneyx Analysis platform.  Segregation analysis confirmed inheritance patterns via Sanger sequencing.

The study clinically described three male patients 20-30 years of age, presented with diverse cardiac symptoms, including non-ischemic dilated cardiomyopathy, ventricular arrhythmias, and myocarditis-like episodes. The ES, initially yielded inconclusive results. However, reanalysis leveraging Geneyx Analysis platform identified a homozygous synonymous SGCA variant (c.600G>A, p.Val200=) shared among affected individuals. This variant, missed due to its synonymous effect, was predicted to disrupt splicing, leading to aberrant transcripts. Functional validation via RT-PCR and Sanger sequencing confirmed impaired splicing.

In summary, this study identifies a homozygous synonymous SGCA variant (c.600G>A, p.Val200=) associated with an extended LGMDR3 phenotype, notably featuring significant cardiac involvement. While SGCA variants are traditionally linked to proximal muscle weakness, this cohort exhibited a high incidence of left ventricular dysfunction (50%) and life-threatening arrhythmias. These findings challenge current classifications of synonymous variants as benign and highlight the need for continuous variant reevaluation, particularly in consanguineous populations. The study underscores the importance of integrating advanced bioinformatics, phenotype-genotype correlations, and functional assays to improve genetic diagnostics and risk stratification, ultimately advocating for population screening and further research into therapeutic interventions.

Abbreviations:

LGMDR3 – Limb-Girdle Muscular Dystrophy type R3

SGCA – Sarcoglycan Alpha

ES – Exome Sequencing

RT-PCR – Reverse Transcription Polymerase Chain Reaction

Recommended article by Eli Sward, PhD (Geneyx FAS):

Empowering Families through Carrier Screening: A Guide to Genetic Testing for Inherited Diseases