American journal of human genetics最新文献

{"title":"Competition in human genetic technologies: The current US legal landscape","authors":"Abdulai I. Rashid, Nicole A. Rincon, Nathan Rihani, Jennifer K. Wagner","doi":"10.1016/j.ajhg.2025.12.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.012","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"1 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A gene-specific variance-control approach corrects polygenicity-driven inflation observed in transcriptome-wide association studies","authors":"Yanyu Liang, Festus Nyasimi, Hae Kyung Im","doi":"10.1016/j.ajhg.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.014","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"63 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic variants in neuronal adhesion molecule astrotactin 1 gene ASTN1 cause diverse neurodevelopmental disorders.","authors":"Jesse M Levine,Daniel G Calame,Riccardo Sangermano,Haowei Du,Ahmed Saad,Jasmin Lisfeld,Tatjana Bierhals,Jonas Denecke,Eyyup Uctepe,Merve Yoldas Celik,Ahmet Yesilyurt,Hilal Yildiz Er,Elif Yilmaz Gulec,Aziza Mushiba,Naif Almontashiri,Pawel Gawlinski,Wojciech Wiszniewski,Ender Karaca,Lama Alabdi,Davut Pehlivan,Dana Marafi,Maha S Zaki,Fowzan S Alkuraya,Joseph G Gleeson,Shalini N Jhangiani,Richard A Gibbs,Jennifer E Posey,Kinga M Bujakowska,James R Lupski","doi":"10.1016/j.ajhg.2025.12.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.011","url":null,"abstract":"ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2. We expand the clinical phenotypic descriptions of ASTN1-related NDDs, which range from mild to profound developmental delay or intellectual disability and can be associated with autism, attention-deficient hyperactivity disorder (ADHD), and epilepsy. Other recurrent abnormalities include dysmorphic facial features, hypotonia, spasticity, and ataxia. Additionally, we add to the neuroradiographic phenotype of this condition, which can be normal, mildly dysmorphic (a thin corpus callosum and cerebellar dysgenesis), or severely dysmorphic (polymicrogyria and lissencephaly). Remarkably, three genetic models of multilocus pathogenic variation (MPV), including tri-allelic, double heterozygous, and double homozygous due to distributive absence of heterozygosity (AOH), were observed. This ASTN1 allelic series characterizes the consequences of perturbations in radial-glia-guided neuronal migration in humans, the phenotypic spectrum of ASTN1-related NDDs, and the contribution of MPV to the genetic basis of NDDs.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"36 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic regulation of fatty acid content in adipose tissue","authors":"Xinyu Yan, Amy L. Roberts, Julia S. El-Sayed Moustafa, Sergio Villicaña, Maryam Al-Hilal, Max Tomlinson, Cristina Menni, Thomas A.B. Sanders, Maxim B. Freidin, Jordana T. Bell, Kerrin S. Small","doi":"10.1016/j.ajhg.2025.12.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.008","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"46 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies","authors":"Nataliya Di Donato, NMA Consortium, Andrew Thom, Andreas Rump, Johannes N. Greve, Juan Cadiñanos, Salvatore Calabro, Sara Cathey, Brian Chung, Heidi Cope, Maria Costales, Sara Cuvertino, Philine Dinkel, Kalliopi Erripi, Andrew E. Fry, Livia Garavelli, Sabine Hoffjan, Wibke G. Janzarik, Insa Kreimer, Grazia Mancini, Purificacion Marin-Reina, Andrea Meinhardt, Indra Niehaus, Daniela Pilz, Ivana Ricca, Fernando Santos Simarro, Evelin Schrock, Anja Marquardt, Manuel H. Taft, Kamer Tezcan, Sofia Thunström, Judith Verhagen, Alain Verloes, Bernd Wollnik, Peter Krawitz, Tzung-Chien Hsieh, Michael Seifert, Michael Heide, Catherine B. Lawrence, Neil A. Roberts, Dietmar J. Manstein, Adrian S. Woolf, Siddharth Banka","doi":"10.1016/j.ajhg.2025.12.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.007","url":null,"abstract":"Recent advances in Mendelian genomics reveal the importance of variant-level characterization of allelic disorders. Non-muscle actin isoforms, encoded by the genes <ce:italic>ACTB</ce:italic> and <ce:italic>ACTG1</ce:italic>, are the most abundant intracellular proteins, but historically, they are often regarded as merely being “housekeeping” molecules. Here, we illuminate the extraordinary clinical heterogeneity and complex pathobiology of genetic non-muscle actinopathies. To do this, we combine human genomics studies with molecular biology. Strikingly, variants in <ce:italic>ACTB</ce:italic> and <ce:italic>ACTG1</ce:italic> isoforms generate at least eight distinct clinical disorders. A subset of disease-associated missense variants causes dysregulated actin polymerization-depolymerization and neuronal migration defects. In contrast, nonsense, frameshift, and missense variants enhancing protein degradation cause milder phenotypes or are benign. These results emphasize the essential functional aspects of the non-muscle actin isoforms. Critically, they additionally constitute a template for the personalized genetic variant-level-driven management of the pleiotropic allelic single-gene disorders.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"259 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional analysis of NPR2 variants supports the therapeutic rationale for CNP in short stature.","authors":"Raehoon Jeong,Sergio Covarrubias,Devanshi Shanghavi,Donald Ruhrmund,Karol Estrada,Dejie Zhou,Nofar Marom,Christopher R Bauer,Steven Froelich","doi":"10.1016/j.ajhg.2025.12.006","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.006","url":null,"abstract":"Human height is a complex trait regulated by genetic and environmental factors. Several components of chondrocyte proliferation and differentiation regulatory pathways are implicated in short-stature disorders; one such component is natriuretic peptide receptor 2 (NPR2), the receptor for C-type natriuretic peptide. We developed a high-throughput GFP reporter assay to evaluate the functional impact of NPR2 missense variants on receptor activity, which was utilized alongside a commercially available CatchPoint assay, and previously published data. Measurements from these sources were integrated and annotated, providing an \"activity score\" for each variant, based on reduced or increased receptor activity. Unlike variant effect prediction tools that assign scores from benign to pathogenic, our method enabled us to distinguish loss-of-function and gain-of-function variants, categorizing 245 NPR2 missense variants, including 47 loss-of-function, 34 partial loss-of-function, and 14 gain-of-function variants, across the functional domains of NPR2. Activity scores showed a near-linear association with standing height (Pearson's correlation R2 = 0.438, p = 5.8 × 10-10), with the effects additive and apparent across polygenic backgrounds. Moreover, phenome-wide association analysis demonstrated that NPR2 activity was significantly associated only with height and height-associated traits, suggesting that modulating NPR2 activity may modulate height only. To summarize, the relationship between NPR2 activity and height resembles a dimmer switch, whereby subtle variations in activity cause subtle variations in height. We demonstrate the therapeutic potential of modulating NPR2 activity in short-stature conditions, owing to both its strong association with height and its lack of association with traits unrelated to height.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"10 1","pages":"117-132"},"PeriodicalIF":9.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De novo variants in KDM2A cause a syndromic neurodevelopmental disorder.","authors":"Eric N Anderson, Stephan Drukewitz, Sukhleen Kour, Anuradha V Chimata, Deepa S Rajan, Senta Schönnagel, Karen L Stals, Deirdre Donnelly, Siobhan O'Sullivan, John F Mantovani, Tiong Y Tan, Zornitza Stark, Pia Zacher, Nicolas Chatron, Pauline Monin, Severine Drunat, Yoann Vial, Xenia Latypova, Jonathan Levy, Alain Verloes, Jennefer N Carter, Devon E Bonner, Suma P Shankar, Jonathan A Bernstein, Julie S Cohen, Anne Comi, Deanna Alexis Carere, Lisa M Dyer, Sureni V Mullegama, Pedro A Sanchez-Lara, Katheryn Grand, Hyung-Goo Kim, Afif Ben-Mahmoud, Sidney M Gospe, Rebecca S Belles, Gary Bellus, Klaske D Lichtenbelt, Renske Oegema, Anita Rauch, Ivan Ivanovski, Frederic Tran Mau-Them, Aurore Garde, Rachel Rabin, John Pappas, Annette E Bley, Janna Bredow, Timo Wagner, Eva Decker, Carsten Bergmann, Louis Domenach, Henri Margot, Johannes R Lemke, Rami Abou Jamra, Julia Hentschel, Heather Mefford, Amit Singh, Udai Bhan Pandey, Konrad Platzer","doi":"10.1016/j.ajhg.2025.12.004","DOIUrl":"10.1016/j.ajhg.2025.12.004","url":null,"abstract":"<p><p>Germline variants that disrupt components of the epigenetic machinery cause syndromic neurodevelopmental disorders. Using exome and genome sequencing, we identified de novo variants in KDM2A, a lysine demethylase crucial for embryonic development, in 18 individuals with developmental delays and/or intellectual disabilities. The severity ranged from learning disabilities to severe intellectual disability. Other core symptoms included feeding difficulties; growth issues, such as intrauterine growth restriction, short stature, and microcephaly; and recurrent facial features, such as epicanthic folds, upslanted palpebral fissures, thin vermillion of the lips, and low-set ears. Expression of human disease-causing KDM2A variants in a Drosophila melanogaster model led to neural degeneration, motor defects, and reduced lifespan. Interestingly, pathogenic variants in KDM2A affected physiological attributes, including subcellular distribution, expression, and stability in human cells. Genetic epistasis experiments indicated that KDM2A variants act via a dual mechanism-loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes. Data from enzymatic-methylation sequencing support the suggested gene-disease association by showing aberrant methylome profiles in affected individuals' peripheral blood. Combining our genetic, phenotypic, and functional findings, we establish de novo variants in KDM2A as causative for a syndromic neurodevelopmental disorder.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"100-116"},"PeriodicalIF":8.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12824617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LiMA: Robust inference of molecular mediation from summary statistics.","authors":"Kaido Lepik,Chiara Auwerx,Marie C Sadler,Adriaan van der Graaf,Sven Erik Ojavee,Zoltán Kutalik","doi":"10.1016/j.ajhg.2025.12.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.005","url":null,"abstract":"Understanding the molecular mechanisms mediating the causal effects of epidemiological risk factors on complex traits can advance targeted disease interventions. Statistical mediation analysis facilitates this by disentangling direct and indirect causal effects. Current approaches to causal mediation leverage Mendelian randomization, using summary statistics from the exposure, mediator, and outcome studies that estimate the genetic effects of instruments. However, differences in study sample sizes (measurement errors) lead to substantial biases and poorly controlled type I error rates for these methods, which become especially pronounced when simultaneously estimating the mediation proportion of numerous mediators. To address these limitations, we introduce Likelihood-based Mediation Analysis (LiMA), which estimates molecular mediation more accurately and robustly by jointly modeling the variability in all estimates involved. Through extensive simulation studies and benchmarking, we demonstrate that our approach achieves several-fold lower bias and improved control for type I error than state-of-the-art methods. Applying our method to real data highlighted several plausible metabolites-such as glutamate and carnitine-as well as proteins mediating the causal effects of obesity-related risk factors on cardiometabolic outcomes. These findings underscore the potential of our framework to reveal promising molecular pathways underlying complex diseases. By accommodating the variability inherent to summary statistics of varying precision, LiMA enables robust mediation analyses across large sets of mediators.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"244 1","pages":"202-220"},"PeriodicalIF":9.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"This month in The Journal","authors":"Paul W. Hook, Alyson B. Barnes","doi":"10.1016/j.ajhg.2025.12.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.009","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"187 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dawn of interventional genetics.","authors":"Kiran Musunuru","doi":"10.1016/j.ajhg.2025.12.010","DOIUrl":"10.1016/j.ajhg.2025.12.010","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"113 1","pages":"1-2"},"PeriodicalIF":8.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12824614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}