Genetics

ClinGen-aligned scoring framework boosts exome detection of pathogenic splicing SNVs

The authors created a scoring system for splicing SNVs that directly operationalizes 2023 ACMG/AMP and ClinGen recommendations. It assigns each coding-region SNV a single priority score from -10 to 14, simplifying pathogenicity assessment. Against HGMD pathogenic splicing variants and gnomAD common variants, performance exceeded SpliceAI alone (AUC 0.991 vs 0.983; P = 2.11 × 10⁻23). In 1,257 exome-negative patients, the framework uncovered pathogenic variants in COL2A1, PDHA1, MECP2, and JAKMIP1 and nominated UBN1 and NFE2L1 as candidates. Clinically, this provides a workflow-ready triage tool to rank splicing SNVs and systematically improve Mendelian diagnostic yield from exome data. 1

Massive multi-ancestry GWAS refines aortic stenosis biology and polygenic risk

A multi-ancestry meta-analysis of 2,853,408 individuals identified 241 autosomal and 3 X-chromosome loci associated with aortic stenosis. Sex- and ancestry-stratified GWAS yielded additional loci, including signals specific to European and African ancestry groups. A valve-based transcriptome-wide association study found 54 genes whose genetically predicted expression alters aortic stenosis risk. The investigators derived a new polygenic risk score, providing a substrate for future risk prediction across ancestries. Silencing CMKLR1 and LTBP4 in human valvular interstitial cells reduced mineralization, nominating PUFA and TGF-β pathways as therapeutic targets. 2

Polygenic background shapes structure, function, and disease risk in HCM and DCM

Among 49,434 Penn Medicine BioBank participants, HCM and DCM polygenic scores independently influenced left ventricular structure and function. Higher HCM polygenic score increased ejection fraction, increased septal thickness, and reduced end-diastolic internal diameter. Higher DCM polygenic score decreased ejection fraction and increased end-diastolic internal diameter, without a clear septal effect. Each 1-SD increment in disease-specific score raised risk for that cardiomyopathy and lowered risk for the opposing phenotype. Monogenic pathogenic variants and polygenic scores had independent effects, and including scores improved disease discrimination beyond rare variants alone. 3