Genetics

HaploNIPD delivers near-universal NIPD for monogenic disorders plus aneuploidy/MMS

HaploNIPD uses a 120,000–SNP capture panel on maternal cfDNA and family gDNA to derive genome-wide fetal haplotypes and copy number. In 70 families with monogenic disorders, fetal haplotypes were correctly determined in 69, perfectly matching invasive prenatal results. Plasma-derived haplotypes showed approximately 99–100% accuracy for paternal and about 98% for maternal inheritance compared with chorionic villus or amniotic DNA. The same assay accurately detected common autosomal and sex-chromosome aneuploidies and microdeletion/microduplication syndromes. One recombination-related no-call highlights a residual need for invasive backup when noninvasive results are indeterminate. 1

Long-read plus RNA-seq solves all previously undiagnosed dystrophinopathy cases

In 50 biopsy-confirmed dystrophinopathy patients previously negative by MLPA and exome sequencing, targeted long-read sequencing plus muscle RNA-seq achieved a molecular diagnosis in every proband. Sixty percent harbored intronic single-nucleotide variants causing pseudoexon inclusion or exon skipping, and 40% carried complex structural variants. Structural variants included inversions, translocations, and indels, with nearly half of all identified variants being novel to disease databases. RNA-seq confirmed aberrant splicing, including a 1.9 kb intronic inversion that activated antisense cryptic splice sites as a new pathogenic mechanism. Cascade testing identified numerous familial carriers with high maternal carrier rates, directly informing counseling and therapy eligibility assessment. 2

Classic CFTR risk variants are strongly protective against inflammatory bowel disease

Exome data from 38,558 IBD cases and 66,945 controls showed CFTR deltaF508 significantly associated with reduced IBD risk. This protective association replicated in a multi-ancestry dataset totaling 42,475 cases and 192,050 controls. Gene-based burden tests of CF-risk variants also supported a protective effect on IBD susceptibility. The study evaluated variant-prioritization tools, including AlphaMissense, against clinically annotated CF-risk variants and highlighted limitations in current methods. These findings indicate that CFTR loss-of-function alleles can decrease IBD risk, complicating risk interpretation for heterozygous carriers. 3

Whole-genome sequencing of 1,364 breast cancers links genomic patterns to outcomes

Whole-genome sequencing of 1,364 clinically annotated breast cancers expanded the catalog of driver genes, recurrent gene fusions, structural variants, and copy-number changes. Copy-number timing analyses suggested genomic instability and key alterations can arise decades before breast cancer diagnosis. Mutational signatures, homologous recombination deficiency, tumor mutational burden, and heterogeneity scores were associated with clinical outcomes. These pattern-based genomic features showed potential as predictive biomarkers for CDK4/6 inhibitors, HER2-directed therapies, and perioperative chemotherapy. The dataset provides a resource for integrating tumor genomic architecture into prognostication and treatment selection. 4