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Argilli E et al., The American Journal of Human Genetics - This research letter describes nine unrelated individuals with rare heterozygous missense variants in ABI2, a gene for a cytoskeletal adaptor protein that works in Rac-WAVE signaling and actin remodeling. Seven of them carry the same de novo change, p.Tyr491Cys, in the SH3 domain, and their brain MRIs show a consistent pattern led by a thin corpus callosum, the bundle of fibers that links the two brain hemispheres. Key terms: ABI2, corpus callosum hypoplasia, de novo variant, neurodevelopmental disorder, Rac-WAVE signaling. Study Highlights:Individuals were found through exome or genome sequencing and international data sharing via GeneMatcher, with clinical data from medical records and clinician questionnaires and centrally reviewed brain MRIs. Seven individuals carried the recurrent p.Tyr491Cys variant and two carried distinct de novo variants, p.Val204Met and p.Val463Ala; all variants were absent from gnomAD v4.1. All nine had moderate-to-severe developmental delay and/or intellectual disability, epilepsy occurred in six, and macrocephaly ranging from +2.5 to +4.2 SD was seen in seven of eight individuals. Every individual with p.Tyr491Cys showed marked corpus callosum hypoplasia and periventricular T2-FLAIR hyperintensities, while the two individuals with nonrecurrent variants lacked corpus callosum abnormalities. Conclusion:The authors establish ABI2 as a neurodevelopmental disorder-associated gene and identify the recurrent p.Tyr491Cys variant as defining a distinctive syndrome with corpus callosum hypoplasia and white matter abnormalities, consistent with other Rac-WAVE pathway disorders and with Abi2-deficient mice. The cohort is small, nine individuals, and the mechanism is inferred from structural modeling and prediction tools; the authors state that future functional studies will be needed to explain how the variants cause disease. Article title:Recurrent de novo ABI2 p.Tyr491Cys variants define a neurodevelopmental syndrome with corpus callosum hypoplasia and white matter abnormalities First author:Argilli E Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.10.003 Reference:Argilli E., Yang C., Le C., Retallack H., Elashoff A.M., Parks K., et al. Recurrent de novo ABI2 p.Tyr491Cys variants define a neurodevelopmental syndrome with corpus callosum hypoplasia and white matter abnormalities. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.10.003 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/abi2-tyr491cys-corpus-callosum-neurodevelopmental-syndrome QC:This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded. QC Summary:- sentences checked: 81- supported by the article: 80- flagged and reviewed by a human: 1- metadata checks passed: 4 of 4 QC result: Pass. Chapters (00:00:03) - A consistent mark on the brain(00:01:08) - Intro and fact-check note(00:01:29) - Study background and ABI2's biology(00:03:22) - Building the cohort(00:04:35) - Locating the recurrent variant(00:05:13) - Clinical features of affected individuals(00:05:49) - Brain MRI findings and the contrast cases(00:07:41) - What it all means and pathway links(00:08:25) - Limitations of the study(00:09:01) - Conclusions and outro

Penkert J et al., The American Journal of Human Genetics - Carriers of disease-causing TP53 variants range from mild to severe cancer phenotypes. Using relative fitness scores from a deep CRISPR mutagenesis screen of 9,225 TP53 mutations, this registry study of 437 individuals from 168 families shows that variants scoring 0.673 or higher go with earlier cancer and with full Li-Fraumeni syndrome. Key terms: Li-Fraumeni syndrome, TP53, deep CRISPR mutagenesis, relative fitness score, cancer surveillance. Study Highlights:A previous screen introduced 9,225 TP53 mutations into a colorectal cancer cell line and scored how well each mutant survived TP53 activators, giving a relative fitness score (RFS). The authors linked these scores to 437 individuals from 168 families in the German Cancer Predisposition Syndrome Registry. Carriers of variants with an RFS of 0.673 or higher developed cancer earlier; an RFS below 0.673 had a hazard ratio of 0.41 (95% CI 0.25 to 0.66, p 0.0002) for cancer. The association held among the 407 individuals whose variant is predicted to produce an altered protein, excluding NULL variants (hazard ratio 0.43). Families with a high score met the definition of Li-Fraumeni syndrome in 110 of 148 cases (74.3%), against 3 of 20 (15%) with a low score. Conclusion:Relative fitness scores from deep CRISPR mutagenesis separated TP53 variant carriers with earlier cancer and more severe Li-Fraumeni spectrum phenotypes, which suggests they could feed future variant classification and tailored surveillance. The finding was not validated in an independent cohort, the scores come from a single colorectal cell line, and they exist only for variants in the DNA binding domain. Article title:Deep CRISPR mutagenesis predicts cancer risk in Li-Fraumeni syndrome First author:Penkert J Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.09.016 Reference:Penkert J., Großhennig A., Dutzmann C.M., Ewert A., Zimmer R., Schoene-Bake J., et al. Deep CRISPR mutagenesis predicts cancer risk in Li-Fraumeni syndrome. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.09.016 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/crispr-fitness-score-cancer-risk-li-fraumeni QC:This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded. QC Summary:- sentences checked: 88- supported by the article: 87- flagged and reviewed by a human: 1- metadata checks passed: 4 of 4 QC result: Pass. Chapters (00:00:03) - Introduction: TP53 Variants and Li Fraumeni Syndrome(00:01:09) - About This Podcast(00:01:31) - Study Background and Authors(00:02:00) - TP53 Gene Function and Disease Spectrum(00:02:34) - Classifying Full vs Attenuated Li Fraumeni Syndrome(00:03:09) - Measuring Variant Disruption via Deep CRISPR Mutagenesis(00:04:49) - Patient Cohort and Fitness Score Analysis(00:05:30) - Survival Differences by Score Cutoff(00:06:28) - Testing Robustness: Excluding Null Variants(00:07:03) - Family-Level Severity Predictions(00:08:15) - Study Limitations(00:08:47) - Conclusions and Future Implications(00:09:24) - Closing and Credits

Tzoumkas K et al., The American Journal of Human Genetics - COL4A3 and COL4A4 are paralogous genes that build the same collagen IV network in the kidney filter, and variant guidelines have generally treated them as interchangeable. This episode follows a population-scale study in the UK Biobank, replicated in All of Us, showing that truncating and NC1 domain missense variants carry much stronger associations with hematuria and proteinuria in COL4A4 than in COL4A3, while glycine substitutions behave alike in both genes. Key terms: COL4A3, COL4A4, Alport syndrome, hematuria, UK Biobank. Study Highlights:Using whole-genome sequencing from the UK Biobank (n ≈ 500,000) with replication in All of Us (n ≈ 414,000), the authors ran per-variant association tests, gene-based collapsing analyses and phenome-wide association studies across hematuria, proteinuria and chronic kidney disease. They identified 64 COL4A3 and 92 COL4A4 rare variants significantly associated with hematuria or proteinuria. Glycine substitutions in the collagenous domain conferred similar risks in both genes, but truncating and NC1 missense variants were strongly associated with disease only in COL4A4, with proteinuria case rates of 52.7% and 37.2% in COL4A4 compared with 17.1% and 12.1% in COL4A3. The difference persisted after excluding the British founder variant p.Ser969Ter and was independently replicated in All of Us. A genome-wide analysis found the COL4A3 and COL4A4 locus to be the dominant genetic signal for hematuria, accounted for by rare coding variants, with no evidence of independent trans-acting modifiers. Conclusion:The authors conclude that gene identity, not variant class alone, should inform risk stratification, variant interpretation and genetic counseling in collagen IV heterozygotes. The analyses were restricted to individuals of European ancestry, phenotypes came from ICD-10 codes and laboratory data that likely underestimate prevalence, the difference was not extended to severe CKD, and the mechanism behind the gene-specific effect remains speculative. Article title:Population-scale genomics reveals divergent pathogenicity of variant classes across paralogous collagen IV genes First author:Tzoumkas K Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.10.002 Reference:Tzoumkas K., Doctor G.T., Sadeghi-Alavijeh O., Gale D.P. Population-scale genomics reveals divergent pathogenicity of variant classes across paralogous collagen IV genes. The American Journal of Human Genetics. (2026). https://doi.org/10.1016/j.ajhg.2026.10.002 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/col4a3-col4a4-divergent-pathogenicity QC:This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded. QC Summary:- sentences checked: 175- supported by the article: 174- flagged and reviewed by a human: 1- metadata checks passed: 4 of 4 QC result: Pass. Chapters (00:00:03) - Introduction: Two Collagen Genes, One Question(00:00:39) - About Base by Base(00:01:00) - Type 4 Collagen Genes and Alport Syndrome(00:02:50) - Forms of Alport Syndrome and Heterozygote Risk(00:04:07) - Protein Structure and Variant Classes(00:05:03) - Testing the Paralogue Assumption at Population Scale(00:06:02) - Study Data: UK Biobank and Phenotype Definitions(00:07:16) - Three Levels of Analysis Design(00:09:05) - Single Variant Results for Hematuria and Proteinuria(00:10:29) - Gene Divergence Emerges: Truncating Variants(00:11:37) - Testing the Founder Variant's Influence(00:12:20) - NC1 Missense Variants Confirm the Pattern(00:13:03) - Formal Comparison of Effect Sizes(00:13:47) - Replication in All of Us Cohort(00:14:31) - Genome-Wide Scan Findings(00:15:17) - Interpreting the Genome-Wide Signal(00:15:53) - Clinical Implications for Genetic Counseling(00:16:34) - Why Might the Chains Differ?(00:17:14) - Study Limitations(00:17:54) - Summary and Closing Thoughts(00:19:06) - Credits and Sign-off

Klaver M et al., The EMBO Journal - In 1961, Hayflick and Moorhead showed that normal human fibroblasts divide only a finite number of times. This episode follows a review of the six decades since, as senescence moved from a cell-culture limit to a tumor-suppressive stress response, a tissue-remodeling program, a contributor to aging and disease, and a target for therapy. Key terms: cellular senescence, SASP, senolytics, senomorphics, aging. Study Highlights:This review traces cellular senescence from the Hayflick limit of 1961 through telomere shortening, biomarkers and oncogene-induced senescence. The senescence-associated secretory phenotype revealed that senescent cells actively communicate with their tissues, and later work showed there is no single universal SASP. Genetic ablation in mice showed that senescent cells can contribute causally to age-related decline, while other studies showed roles in wound healing, development and tissue repair, and one p16-lineage study reported detrimental effects on the liver. Senolytics such as dasatinib plus quercetin and senomorphics followed, but UBX0101 failed to show significant benefit in Phase 2 and UBX1325 missed its Phase 2b primary endpoint. The authors identify the lack of validated biomarkers of target engagement as the major bottleneck in clinical senotherapy. Conclusion:The authors conclude that senescence is neither inherently beneficial nor inherently detrimental, and that its consequences depend on context, which senescent cells are involved, and how long they persist. This is a narrative review, not a new experiment, and much of the causal evidence comes from mouse models, with human trials so far early, limited by size or design, or unsuccessful. Article title:Cellular senescence: six decades of discovery and reinvention First author:Klaver M Journal:The EMBO Journal DOI:10.1038/s44318-026-00922-w Reference:Klaver M., Steeneken L.S., Veeningen N., Altulea A., Demaria M. Cellular senescence: six decades of discovery and reinvention. The EMBO Journal, 45, 7307-7325. (2026). https://doi.org/10.1038/s44318-026-00922-w License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/cellular-senescence-six-decades-review QC:This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded. QC Summary:- sentences checked: 183- supported by the article: 182- flagged and reviewed by a human: 1- metadata checks passed: 4 of 4 QC result: Pass. Chapters (00:00:03) - Introduction: The Hayflick Discovery(00:00:44) - About This Episode and Paper(00:02:30) - Telomere Shortening as a Mechanism(00:03:11) - Finding Markers for Senescence in Tissue(00:03:58) - Oncogene-Induced Senescence and Tumor Suppression(00:04:41) - Multiplying Triggers of Senescence(00:05:29) - Discovery of the SASP Secretory Phenotype(00:06:18) - Complexity and Diversity of SASP Programs(00:07:08) - Testing Causality: Senescent Cell Clearance Models(00:08:25) - Beneficial Roles in Healing and Repair(00:09:00) - Developmental Senescence Discovery(00:10:12) - Senescence and the Aging Hallmarks Framework(00:10:51) - The Persistence Paradox and Disease Links(00:11:37) - Immune Clearance of Senescent Cells(00:12:37) - Immune Evasion and Immunosenescence(00:13:08) - Senolytics: Targeting Senescent Cells(00:13:59) - Senomorphics: Suppressing the SASP(00:14:47) - Early Human Clinical Trials(00:15:32) - Clinical Setbacks and Failures(00:16:16) - The Biomarker Bottleneck(00:17:04) - Toward Precision Senescence Targeting(00:17:51) - Conclusion: Context-Dependent Senescence(00:18:28) - Future Directions and Closing Thoughts

Wienbrandt L et al., Nature Genetics - Most genetic studies read only a fraction of the genome and infer the rest from a reference panel. This episode covers a new panel built from whole-genome sequencing of 490,319 UK Biobank participants, benchmarked against the TOPMed r3 panel across 35 datasets and used to reanalyze COVID-19 association studies from four European countries. Key terms: genotype imputation, haplotype reference panel, UK Biobank, EagleImp, COVID-19 GWAS. Study Highlights:Researchers phased whole-genome data from 490,319 UK Biobank participants into reference panels of more than 361 million variants and extended EagleImp to run on a standalone server and inside the UK Biobank Research Analysis Platform. Compared with the TOPMed r3 panel of 133,597 individuals, the UK Biobank panel achieved lower phasing switch error rates for all superpopulations except AMR and for 25 of 26 1000 Genomes subpopulations. Mean absolute error improved for 4 of 5 superpopulations and 12 subpopulations, while TOPMed performed better across all frequency categories in AFR. Estimated R2 improved across all 5 superpopulations and 22 subpopulations for variants down to 0.01% frequency, with the largest gain, +24.39%, in East Asian samples. Reimputing an Italian severe COVID-19 study of 835 cases and 1,255 controls yielded a genome-wide significant association at 3p21.31 and a new lead SNP, rs73064425, that matched three independent studies. Conclusion:The authors conclude that the UK Biobank panel is the most suitable panel for imputing worldwide populations when no population-specific panel is available, and that common-variant imputation is not yet saturated in the European populations tested. The benchmark has limits: estimated imputation R2 stays low for most subpopulations below 0.01% frequency, truth-based measures may be inaccurate at low frequencies, and TOPMed r3 still performed better in AFR on mean absolute error and holds more panel-specific variants. Article title:A haplotype reference panel constructed from 490,319 UK Biobank genomes improves genotype imputation for global populations First author:Wienbrandt L Journal:Nature Genetics DOI:10.1038/s41588-026-02819-0 Reference:Wienbrandt L., Prieß C., Schmöhl M., Neff V., Gretsova M., Torres G., et al. A haplotype reference panel constructed from 490,319 UK Biobank genomes improves genotype imputation for global populations. Nature Genetics. (2026). https://doi.org/10.1038/s41588-026-02819-0 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/uk-biobank-haplotype-reference-panel-imputation QC:This episode's script was checked sentence by sentence against the full text of the original article, by an automated process with human review, before it was recorded. QC Summary:- sentences checked: 176- supported by the article: 143- flagged and reviewed by a human: 33- metadata checks passed: 4 of 4 QC result: Warn. Chapters (00:00:03) - The Restorer Analogy: Imputation Explained(00:01:03) - Genotyping Chips and the Need for Imputation(00:02:16) - Introducing the Study and Its Authors(00:02:55) - What Haplotypes Are and How Imputation Works(00:03:44) - Limits of Existing Panels: Access and Scale(00:04:37) - Is Imputation Already Saturated?(00:05:20) - Building the UK Biobank Panel(00:06:38) - Creating the Lighter Panel and Software Tools(00:07:11) - Designing the Benchmark(00:08:39) - Phasing Results: UK Biobank vs TopMed(00:09:49) - Checking Against Known Truth: Mixed Results(00:10:38) - Testing on Real GWAS Datasets(00:11:14) - Speed and Efficiency Gains(00:11:52) - The Italian COVID-19 Case Study(00:13:12) - Fine-Mapping the Causal Variant(00:13:53) - Revisiting the Saturation Question(00:14:58) - Limitations of the Study(00:15:35) - Remaining Gaps and Future Directions(00:16:12) - Conclusion: What the Bigger Archive Reveals