Genetics

Survey: functional assay use is inconsistent in hearing and vision genetics

Experts (n=82) report frequent VUS in hearing and ocular genetics and inconsistent availability of functional data. Confidence is highest for transcript assays, patient-derived cell models, and computational predictors. Familiarity and trust are lower for non-mammalian models and high-throughput MAVEs. Respondents call for improved data accessibility, standardized evaluation guidelines, and training to integrate functional evidence clinically. 1

Pathogenic-variant testing reclassifies breast screening risk beyond clinical and polygenic models

Among 712 women with pathogenic variants aged 40–74, most would not have been assigned high-risk screening by clinical risk or clinical plus polygenic risk alone. High-penetrance PV carriers (n=232) almost never (2 of 232) received the same high-risk assignment from clinical plus polygenic risk. Many younger carriers (63.8% of ages 40–49) would have been deferred until age 50 by clinical-plus-PRS algorithms. Population-based PV testing therefore identifies high-risk women missed by standard clinical or PRS-informed models. 2

Harmonized DSM phenotyping yields replicable common-variant signal in MDD

A GWAS mega-analysis of 64,941 Dutch participants (25.7% cases) found SNP-based liability heritability around 12% by LDSC. Genetic correlation with the PGC major depression GWAS was high (rG = 0.89), and polygenic scores transferred between cohorts. A single genome-wide significant locus near PALMD was identified but lacks independent replication. Within-family analyses suggest limited confounding of polygenic prediction in this harmonized sample. 3