Homozygous SGCB splice-site variant causes isolated dilated cardiomyopathy through sarcoglycan complex destabilization in East Asians.

Summary

An integrative cardiac tissue genomics approach identified a homozygous SGCB splice-site variant (c.243+6T>A) causing exon 2 skipping and isolated DCM via loss of β-sarcoglycan and sarcoglycan complex destabilization. Despite SGCB’s known role in muscular dystrophy, affected individuals lacked myopathy and had higher risk of early adverse cardiac events.

Key Findings

• Homozygous SGCB c.243+6T>A splice-site variant leads to exon 2 skipping and is significantly enriched among DCM patients.
• Protein analyses show loss of β-sarcoglycan and destabilization of the sarcoglycan complex in cardiac tissue from homozygous individuals.
• Affected individuals exhibit isolated cardiomyopathy without skeletal muscle involvement and face higher risk of early adverse cardiac events than variant-negative DCM patients.

Clinical Implications

Incorporate SGCB (c.243+6T>A) into DCM gene panels and consider sarcoglycan complex assessment in biopsy when available; anticipate higher early adverse event risk and tailor surveillance and management.

Limitations

• Sample size and effect estimates are not detailed in the abstract; the exact prevalence and penetrance remain to be quantified
• Observational design limits causal inference regarding clinical outcomes and therapy response

Future Directions

Broader multi-ethnic validation of SGCB variant burden in DCM, longitudinal natural history studies to refine penetrance and risk, and evaluation of targeted counseling and surveillance strategies.