Tackling non-canonical splicing in arrhythmogenic cardiomyopathy to reduce the uncertain significance variants burden

Integrated approach to non-canonical splicing (SpliceAI prediction + minigene validation + segregation + ACMG/ClinGen criteria) to reduce the VUS burden in arrhythmogenic cardiomyopathy

In a cohort of 200 arrhythmogenic cardiomyopathy (ACM) probands, a systematic approach to non-canonical splicing combines bioinformatics prediction (SpliceAI, R²=0.86) with experimental validation (minigene), family segregation, and ACMG/ClinGen criteria. This integrated approach enables reclassification of 80% of initially VUS splicing variants. Results reduce the clinically difficult VUS burden in this hereditary cardiomyopathy with sudden death risk.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An 80% VUS splicing reclassification rate in ACM through this integrated approach is remarkable. This workflow — SpliceAI → minigene → segregation → ACMG — is transposable to other hereditary cardiomyopathies (HCM, DCM) and illustrates how splicing bioinformatics transforms clinical diagnosis.