From gene to heart: the impact of a novel SGCD variant in familial dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, often resulting in reduced ejection fraction and progressive cardiac dysfunction. Although up to half of idiopathic DCM can be linked to genetic variants, many familial cases still lack a definitive molecular diagnosis. Sarcoglycan delta (SGCD) encodes a crucial component of the dystrophin-glycoprotein complex, and variants in this gene have been implicated in both muscular dystrophies and cardiomyopathies. We evaluated a three-year-old girl presenting with a confirmed diagnosis of DCM. Clinical assessments included echocardiography and cardiac magnetic resonance imaging (CMR), revealing moderate-to-severe systolic and diastolic dysfunction. Whole exome sequencing (WES) was performed to investigate potential causative variants. In silico analysis and Sanger sequencing were used to confirm and characterize any identified alteration in the proband and her parents. WES identified a novel heterozygous SGCD variant, NM_000337.6(SGCD): c.647 A > T, p.(Asn216Ile), located in exon 8. Sanger sequencing confirmed this variant’s presence in the proband and her father, suggesting a familial inheritance pattern. In silico predictive tools supported a likely deleterious effect of the variant,, with functional analysis indicating possible disruption of δ-Sarcoglycan’s structure. This variant was absent in public variant databases, underscoring its rarity. Comparative evaluation of known SGCD variants further highlighted exon 8 as a possible mutational hotspot in DCM. These findings expand the variant spectrum of SGCD and reinforce its role in familial DCM. Genetic screening for SGCD variants in individuals with idiopathic or familial cardiomyopathy can improve early diagnosis, guide targeted interventions, and inform genetic counseling. Our results underscore the clinical importance of integrating molecular diagnostics to enhance personalized management of DCM.