Base by Base

Peters R et al., The American Journal of Human Genetics - This episode reviews a nationwide survey of 2,509 Australian adults using two discrete choice experiments to quantify public preferences and the monetary value placed on genomic newborn screening (gNBS), and to identify preferred implementation features such as consent model and result delivery. Key terms: genomic newborn screening, discret...

Provided PDF (truncated source text) et al., Cell - This episode reviews a study that examines SLC7A11 (7A11) localization to lysosomes and its impact on lysosomal acidification, cystine/cysteine balance, lysosomal function, and cell viability using genetic and pharmacologic tools and isolated lysosome assays. Key terms: SLC7A11, lysosome, lysosomal pH, cystine, ferroptosis. Study Highlights: The...

Zabad S et al., The American Journal of Human Genetics - This episode covers Zabad et al.'s methods to scale summary-statistics-based polygenic risk score (PRS) inference to millions of variants. The authors introduce compressed LD storage, memory-efficient coordinate-ascent variational algorithms, and multi-level parallelism to cut storage, runtime, and RAM by orders of magnitude while retaining...

Pekar JE et al., Cell - Recombination-aware, whole-genome analyses of sarbecoviruses show that genomic fragments very closely related to SARS-CoV and SARS-CoV-2 circulated in horseshoe bats only years before human emergence. Phylogeography places recent ancestors in western China and northern Laos and indicates movement patterns inconsistent with bat-only dispersal, implicating intermediate hosts...

Palafox MF et al., The American Journal of Human Genetics - This episode explores a multi-omic study showing that mass spectrometry–based chemoproteomic detection of cysteine, lysine, and tyrosine (CpDAAs) highlights protein sites and regions enriched for pathogenic missense variants and variant uncertainty. Key terms: chemoproteomics, missense_variants, CpDAA, fumarate_hydratase, variant_interpre...

Nicastro M et al., The American Journal of Human Genetics - This episode covers Nicastro et al. (2025), who identify bi-allelic POPDC2 variants in four families causing a recessive cardiac syndrome marked by sinus-node dysfunction, atrioventricular conduction defects and, in some cases, hypertrophic cardiomyopathy. The study combines genetic sequencing, structural modeling, electrophysiology, tiss...

This episode summarizes a study that genotyped the CCR5Δ32 deletion in ancient and modern human genomes, compared genotyping methods for low‑coverage ancient DNA, reconstructed CCR5 haplotypes, and modeled the deletion's spatiotemporal frequency and selection history. The work benchmarks HAPI (with informed priors) against GATK and VG, maps haplotype distributions (A,B,C), and infers allele freque...

Ficicioglu C et al., Genetics in Medicine (2025) 27, 101456 - Phase 1/2 COMPOSE trial tested subcutaneous pegtibatinase in 24 participants with classical homocystinuria; treatment was generally well tolerated and produced rapid, dose-dependent reductions in total plasma homocysteine (tHcy). Key terms: classical homocystinuria, pegtibatinase, enzyme replacement therapy, total plasma homocysteine, c...

Kim WJ et al., Cell - This episode examines a study that identifies recurrent neoantigens produced by SRSF2 and ZRSR2 splicing factor mutations in myeloid leukemias, isolates cognate TCRs, and demonstrates antigen-specific TCR-T cell activity in vitro and in vivo. Key terms: neoantigens, SRSF2, ZRSR2, TCR-T therapy, myeloid leukemia. Study Highlights: The authors used large-scale RNA-seq to identi...

Idursulfase Beta — A New Therapeutic Option for MPS II with Strong Clinical Evidence Article title: Efficacy and safety of idursulfase beta in the treatment of mucopolysaccharidosis II: a phase 3, two-part study compared to a historical placebo cohort Journal: Genetics in Medicine DOI: 10.1016/j.gim.2025.101460 Reference: Sohn YB, Yang A, Kim MS, Kim J, Kim JS, Oh Y, Jin DK. Efficacy and safety of...

Walker S et al., Genetics in Medicine - Genome sequencing of 78,195 participants in the 100,000 Genomes Project identified ultra-rare non-canonical FBN1 splice variants enriched among individuals recruited with familial thoracic aortic aneurysm disease (FTAAD). Experimental RNA assays confirmed aberrant splicing for most candidates, including multiple deep intronic pseudoexon events, indicating a...

Nicastro M et al., The American Journal of Human Genetics - Researchers identify bi-allelic POPDC2 variants in multiple families causing sinus-node dysfunction, atrioventricular conduction defects and, in some cases, hypertrophic cardiomyopathy, and investigate structural, electrophysiological and population-level evidence for pathogenicity. Key terms: POPDC2, cardiac conduction, TREK-1, cAMP bind...

Chavez-Yenter D et al., Genetics in Medicine - A cross-sectional SEM study of 503 English-fluent Latino adults applied the Integrated Behavioral Model to identify predictors of intention for carrier screening (CS) and cancer predisposition testing (CPT). Perceived agency emerged as the strongest predictor for both testing types, with family/friend norms supporting CS and attitudes showing negative...

Zhou Y et al., Cell Genomics - This paper introduces scPrediXcan, which combines a deep-learning model (ctPred) built on Enformer-derived features with single-cell RNA-seq to perform cell-type-specific TWAS via a linearized SNP predictor (ℓ-ctPred), improving gene discovery for T2D and SLE. Key terms: cell-type-specific expression, deep learning, TWAS, single-cell RNA-seq, GWAS. Study Highlights:...

Geilenkeuser J et al., Cell - A Cell paper describing ENVLPE/ENVLPE+, virus-like particles engineered with nucleocytosolic-shuttling Gag-PCP to recruit aptamer-tagged (pe)gRNAs and preferentially package fully assembled CRISPR RNPs. Csy4-mediated 3' protection of pegRNAs and modular minimal budding modules boost prime and base editing in cells and restore gene function in retinal mouse models. Key...

Pepe D et al., The American Journal of Human Genetics (112:1–21, June 5, 2025) - Pepe et al. show that annotating cancer mutations to the transcripts actually expressed in tumors uncovers previously overlooked non-coding promoter mutations in melanoma. Using TCGA mutation calls, RNA-seq, and an automated Salmon+VEP pipeline, they reclassify multiple hotspots and validate functional effects for IRF...

Ratnaike et al et al., The American Journal of Human Genetics - A semi-automated mtDNA reanalysis pipeline using MToolBox and MitoPhen HPO-based phenotype similarity was applied to the Solve-RD cohort, identifying previously undiagnosed mtDNA variants and adding a 0.4% diagnostic uplift. Key terms: mitochondrial DNA, heteroplasmy, MitoPhen, Solve-RD, phenotype similarity. Study Highlights: The aut...

Fu Y et al., The American Journal of Human Genetics - Fu et al. (2025) analyze large biobank datasets to quantify how the X chromosome contributes to complex trait heritability and how dosage-compensation biology shapes those effects. Key terms: X chromosome, dosage compensation, X chromosome inactivation, complex trait heritability, sex differences. Study Highlights: The study analyzed 48 quantit...

Stafford-Smith B et al., Genetics in Medicine - Mixed-methods evaluation of how 100,000 Genomes Project participants experienced receiving positive additional findings (PAFs) for cancer or familial hypercholesterolaemia and no additional findings (NAFs), with implications for clinical return pathways and patient support. Key terms: genome sequencing, additional findings, secondary findings, partic...

Castellano M et al., Cell Genomics - This study shows that extracellular ribonucleases mask the bioactivity of naked extracellular RNA (exRNA). When RNases are inhibited or absent, naked exRNA is internalized, triggers endosomal and cytosolic RNA sensors, and can enable translation of delivered mRNAs. Key terms: extracellular RNA, ribonuclease, TLR13, gymnosis, mRNA translation. Study Highlights:...

Herger M et al., Cell Genomics - Herger et al. present a pooled prime editing platform in haploid human cells that installs and assays thousands of short variants in their endogenous context. Using surrogate targets, co-selection and stringent pegRNA filtering, negative and positive selection screens identify loss-of-function variants in SMARCB1 and MLH1, including non-coding ClinVar variants that...

Mousa A et al., Nature Communications - Pooled analysis of seven therapeutic efficacy trials (1639 participants, 12 African sites) quantifies how dhps resistance genotypes shorten the duration of protection from sulfadoxine-pyrimethamine (SP) and maps predicted chemoprevention impact across Africa. Key terms: sulfadoxine-pyrimethamine, dhps mutations, chemoprevention, malaria, genomic surveillance...

Martin‑Geary AC et al et al., Genome Medicine - A systematic framework to prioritise promoter and UTR variants in 8040 undiagnosed trios from the Genomics England 100,000 Genomes Project, yielding ten likely diagnoses and a validated annotation pipeline for clinical use. Key terms: promoters, untranslated regions, de novo variants, rare disease, Genomics England. Study Highlights: The authors appl...

Dardas Z et al., The American Journal of Human Genetics - This episode reviews Dardas et al. (2025), which identifies bi-allelic UGGT1 variants in 15 affected individuals as the cause of a distinct congenital disorder of glycosylation (UGGT1-CDG), describes the clinical spectrum, and dissects diverse molecular mechanisms that impair UGGT1 function. Key terms: UGGT1, congenital disorder of glycosyl...

Juen Z et al., Cell - This episode examines a cryo-EM study that resolves the human sweet taste receptor (TAS1R2+TAS1R3) bound to two artificial sweeteners, revealing how a single receptor recognizes diverse sweet compounds and couples to G proteins. Key terms: sweet taste receptor, TAS1R2, TAS1R3, cryo-EM, sucralose. Study Highlights: Single-particle cryo-EM determined the structure of the human...