Genetics

First-tier genome sequencing in Korean rare disease families delivers 46% diagnostic yield

Genome sequencing of 3,317 individuals from 1,452 Korean families with suspected rare disorders achieved a molecular diagnosis in 46.2% of families. Clinical management changed in 18.5% of diagnosed cases, demonstrating tangible utility beyond variant discovery. Family-based genome sequencing outperformed singleton testing (48.5% vs 41.5%), supporting trio or multiplex designs when feasible. GS-specific deep intronic, noncoding, complex structural variants and tandem repeat expansions accounted for 14.6% of diagnoses, inaccessible to standard exomes. 1

Disease-context pQTL mapping nominates causal proteins and improves risk prediction

A large genome–proteome-wide study profiled 2,901 plasma proteins in 7,626 healthy individuals and 28,064 patients across 42 disease states. Investigators identified 25,987 independent pQTLs across 2,224 regions and showed disease-specific pQTLs were more likely to be disease risk variants. Mendelian randomisation implicated 110 high-confidence causal proteins for 21 diseases, including Apolipoprotein(a) in cardiovascular disease and ACE in type 2 diabetes. Risk models combining pQTL-based polygenic scores and protein risk scores discriminated individuals at high risk for 21 disease types. 2

GCOD detects oligogenic gene combinations contributing to congenital heart defects

GCOD is a simulation-based framework that tests oligogenic gene sets by comparing co-occurring damaging variants in probands versus parental genotypes. Applied to 3,377 congenital heart defect trios, GCOD identified 160 gene pairs over-transmitted to probands but rarely co-occurring in unaffected parents. Stratified and higher-order analyses yielded an additional 6,026 gene sets enriched for heart development pathways and relevant cardiac cell-type markers. Mouse experiments showed Gata6–Por compound heterozygosity increased CHD incidence compared with single hemizygotes, validating predicted interactions. 3