Genetics

Exome meta-analysis broadens ALS rare-variant architecture and supports oligogenic risk

Exome analysis of 17,919 ALS cases and 200,703 controls identified several new rare-variant risk genes, including replicated association of YKT6. The study provided strong independent validation for ARPP21, DNAJC7, and CFAP410 as ALS risk genes. In ARPP21, a new high-effect variant (p.P747L) and confirmation of p.P563L were linked to aggressive disease course. Rare variants contributed risk in over 20% of ALS cases, supporting a cumulative oligogenic model rather than single-gene causation. 1

Ultra-rare functional variants reveal early-onset breast cancer genes and ancestry-specific effects

EA-Pathways aggregated ultra-rare coding variants weighted by Evolutionary Action to detect functional impact biases without matched controls. In UK Biobank women with breast cancer, variants from eight pathways, including homology-directed repair and TP53, were linked to earlier onset. The early-onset effect replicated in All of Us, with markedly earlier diagnoses across European, admixed American, and African ancestries. Risk alleles showed ancestry-differentiated frequencies, indicating partially ancestry-specific early-onset susceptibility architecture. 2

RNU2-2 snRNA is a major locus for developmental and epileptic encephalopathies

Systematic analysis of 200 snRNA genes in 34,329 individuals with rare disorders identified RNU2-2 variants in 141 affected individuals. Thirty-five individuals carried recurrent dominant pathogenic variants, and 91 individuals from 73 families had biallelic variants. Recessive RNU2-2 neurodevelopmental disorder was at least twice as frequent as the dominant form and often involved a de novo plus inherited allele. Dominant and recessive cases shared overlapping neurodevelopmental and epileptic phenotypes, with blood omics showing subtle, variant-specific splicing and methylation signatures. 3

The 1000 Chinese Pangenome refines East Asian structural and regulatory variation

The 1000 Chinese Pangenome generated 1,116 diploid assemblies, revealing 405.3 Mb of sequence absent from GRCh38 and CHM13. This included 26.2 Mb of functional genic and predicted regulatory sequence and a broad spectrum of small and structural variants. Researchers catalogued 35.4 million small variants, 110,530 structural variants, 485,575 tandem repeats, and 0.86 million nested variants within nonreference sequence. Pan-variant eQTL mapping identified 3,256 eQTLs involving complex variants, enhancing regulatory interpretation beyond SNPs alone. 4