American journal of human genetics最新文献

{"title":"Identifying deleterious noncoding variation through gain and loss of CTCF binding activity.","authors":"Colby Tubbs, Mary Lauren Benton, Evonne McArthur, John A Capra, Douglas M Ruderfer","doi":"10.1016/j.ajhg.2025.02.009","DOIUrl":"10.1016/j.ajhg.2025.02.009","url":null,"abstract":"<p><p>CCCTC binding factor (CTCF) regulates gene expression through DNA binding at thousands of genomic loci. Genetic variation in these CTCF binding sites (CBSs) is an important driver of phenotypic variation, yet extracting those that are likely to have functional consequences in whole-genome sequencing remains challenging. To address this, we develop a hypothesis-driven framework to identify and prioritize CBS variants in gnomAD. We synthesize CTCF's binding patterns at 1,063,878 genomic loci across 214 biological contexts into a summary of binding activity. We find that high binding activity significantly correlates with both conserved nucleotides (Pearson R = 0.35, p < 2.2 × 10^-16) and sequences that contain high-quality CTCF binding motifs (Pearson R = 0.63, p = 2.9 × 10^-12). We then use binding activity to evaluate high-confidence allelic binding predictions for 1,253,329 single-nucleotide variations (SNVs) in gnomAD that disrupt a CBS. We find a strong, positive relationship between the mutability-adjusted proportion of singletons (MAPS) metric and the loss of CTCF binding at loci with high in vitro activity (Pearson R = 0.74, p < 2.2 × 10^-16). To contextualize these findings, we apply MAPS to other functional classes of variation and find that a subset of 339,380 loss of CTCF binding variants is observed as infrequently as missense variants are. This work nominates these thousands of rare, noncoding variants that disrupt CTCF binding for further functional studies while providing a blueprint for prioritizing variation in other transcription factor binding sequences.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"892-902"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571875","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":"Data-driven insights to inform splice-altering variant assessment.","authors":"Patricia J Sullivan, Julian M W Quinn, Pamela Ajuyah, Mark Pinese, Ryan L Davis, Mark J Cowley","doi":"10.1016/j.ajhg.2025.02.012","DOIUrl":"10.1016/j.ajhg.2025.02.012","url":null,"abstract":"<p><p>Disease-causing genetic variants often disrupt mRNA splicing, an intricate process that is incompletely understood. Thus, accurate inference of which genetic variants will affect splicing and what their functional consequences will be is challenging, particularly for variants outside of the essential splice sites. Here, we describe a set of data-driven heuristics that inform the interpretation of human splice-altering variants (SAVs) based on the analysis of annotated exons, experimentally validated SAVs, and the currently understood principles of splicing biology. We defined requisite splicing criteria by examining around 202,000 canonical protein-coding exons and 19,000 experimentally validated splicing branchpoints. This analysis defined the sequence, spacing, and motif strength required for splicing, with 95.9% of the exons examined meeting these criteria. By considering over 12,000 experimentally validated variants from the SpliceVarDB, we defined a set of heuristics that inform the evaluation of putative SAVs. To ensure the applicability of each heuristic, only those supported by at least 10 experimentally validated variants were considered. This allowed us to establish a measure of spliceogenicity: the proportion of variants at a location (or motif site) that affected splicing in a given context. This study makes considerable advances toward bridging the gap between computational predictions and the biological process of splicing, offering an evidence-based approach to identifying SAVs and evaluating their impact. Our splicing heuristics enhance the current framework for genetic variant evaluation with a robust, detailed, and comprehensible analysis by adding valuable context over traditional binary prediction tools.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"764-778"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584356","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":"An evolving understanding of multiple causal variants underlying genetic association signals.","authors":"Erping Long, Jacob Williams, Haoyu Zhang, Jiyeon Choi","doi":"10.1016/j.ajhg.2025.01.018","DOIUrl":"10.1016/j.ajhg.2025.01.018","url":null,"abstract":"<p><p>Understanding how genetic variation contributes to phenotypic variation is a fundamental question in genetics. Genome-wide association studies (GWASs) have discovered numerous genetic associations with various human phenotypes, most of which contain co-inherited variants in strong linkage disequilibrium (LD) with indistinguishable statistical significance. The experimental and analytical difficulty in identifying the \"causal variant\" among the co-inherited variants has traditionally led mechanistic studies to focus on relatively simple loci, where a single functional variant is presumed to explain most of the association signal and affect a target gene. The notion that a single causal variant is responsible for an association signal, while other variants in LD are merely correlated, has often been assumed in functional studies. However, emerging evidence powered by high-throughput experimental tools and context-specific functional databases argues that even a single independent signal may involve multiple functional variants in strong LD, each contributing to the observed genetic association. In this perspective, we articulate this evolving understanding of causal variants through examples from both traditional locus-by-locus approaches and more recent high-throughput functional studies. We then discuss the implications and prospects of this notion in understanding the genetic architecture of complex traits and interpreting the variant-level causality in GWAS follow-up studies.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"741-750"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447816","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":"Artificial variables help to avoid over-clustering in single-cell RNA sequencing.","authors":"Alan DenAdel, Michelle L Ramseier, Andrew W Navia, Alex K Shalek, Srivatsan Raghavan, Peter S Winter, Ava P Amini, Lorin Crawford","doi":"10.1016/j.ajhg.2025.02.014","DOIUrl":"10.1016/j.ajhg.2025.02.014","url":null,"abstract":"<p><p>Standard single-cell RNA sequencing (scRNA-seq) pipelines nearly always include unsupervised clustering as a key step in identifying biologically distinct cell types. A follow-up step in these pipelines is to test for differential expression between the identified clusters. When algorithms over-cluster, downstream analyses can produce misleading results. In this work, we present \"recall\" (calibrated clustering with artificial variables), a method for protecting against over-clustering by controlling for the impact of reusing the same data twice when performing differential expression analysis, commonly known as \"double dipping.\" Importantly, our approach can be applied to a wide range of clustering algorithms. Using real and simulated data, we show that recall provides state-of-the-art clustering performance and can rapidly analyze large-scale scRNA-seq studies, even on a personal laptop.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"940-951"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623102","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 MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations.","authors":"Charlotte Guillouet, Valeria Agostini, Geneviève Baujat, Dario Cocciadiferro, Tommaso Pippucci, Marion Lesieur-Sebellin, Mathieu Georget, Ulrich Schatz, Christine Fauth, Raymond J Louie, Curtis Rogers, Jessica M Davis, Vassiliki Konstantopoulou, Johannes A Mayr, Arjan Bouman, Martina Wilke, Grace E VanNoy, Eleina M England, Kristen L Park, Kathleen Brown, Margarita Saenz, Antonio Novelli, Maria Cristina Digilio, Gioia Mastromoro, Mauro Ciro Antonio Rongioletti, Gerardo Piacentini, Rauan Kaiyrzhanov, Sughra Guliyeva, Lala Hasanova, Deborah Shears, Ishita Bhatnagar, Karen Stals, Oliver Klaas, Judit Horvath, Patrice Bouvagnet, P Dane Witmer, Gretchen MacCarrick, Katarina Cisarova, Jean-Marc Good, Svetlana Gorokhova, Odile Boute, Thomas Smol, Ange-Line Bruel, Olivier Patat, Julia R Broadbent, Tiong Y Tan, Natalie B Tan, Stanislas Lyonnet, Tiffany Busa, Claudio Graziano, Jeanne Amiel, Christopher T Gordon","doi":"10.1016/j.ajhg.2025.02.016","DOIUrl":"10.1016/j.ajhg.2025.02.016","url":null,"abstract":"<p><p>The Mediator complex regulates protein-coding gene transcription by coordinating the interaction of upstream enhancers with the basal transcription machinery at the promoter. Pathogenic variants in Mediator subunits typically lead to neurodevelopmental or neurodegenerative disorders with variable clinical presentations, designated as MEDopathies. Here, we report the identification of 25 individuals from 18 families with bi-allelic MED16 variants who have a multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. The 26 variants identified were comprised of eight predicted protein-truncating (three intragenic deletions, two frameshifts, and one nonsense and two essential splice site variants) and 18 missense or in-frame duplication variants affecting conserved residues, without clear correlation between phenotypic severity and variant type combination. Three-dimensional modeling indicated that the missense and duplication variants likely have a destabilizing effect on the structural elements of the protein. Immunofluorescence assays demonstrated protein mislocalization from the nucleus to the cytoplasm for 16 of the 17 variants studied. Homozygous mutant med16 zebrafish presented growth delay and increased mortality compared with wild-type fish, and Med16 knockout mice are preweaning lethal, highlighting the conserved requirement of MED16 for development. Overall, we describe an autosomal recessive MCAs-intellectual disability MEDopathy, emphasizing the importance of Mediator during neurodevelopment and suggesting that some tissues are particularly sensitive to the loss of certain subunits.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"829-845"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623103","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 three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy.","authors":"Karolina Kaminska, Francesca Cancellieri, Mathieu Quinodoz, Abigail R Moye, Miriam Bauwens, Siying Lin, Lucas Janeschitz-Kriegl, Tamar Hayman, Pilar Barberán-Martínez, Regina Schlaeger, Filip Van den Broeck, Almudena Ávila Fernández, Lidia Fernández-Caballero, Irene Perea-Romero, Gema García-García, David Salom, Pascale Mazzola, Theresia Zuleger, Karin Poths, Tobias B Haack, Julie Jacob, Sascha Vermeer, Frédérique Terbeek, Nicolas Feltgen, Alexandre P Moulin, Louisa Koutroumanou, George Papadakis, Andrew C Browning, Savita Madhusudhan, Lotta Gränse, Eyal Banin, Ana Berta Sousa, Luisa Coutinho Santos, Laura Kuehlewein, Pietro De Angeli, Bart P Leroy, Omar A Mahroo, Fay Sedgwick, James Eden, Maximilian Pfau, Sten Andréasson, Hendrik P N Scholl, Carmen Ayuso, José M Millán, Dror Sharon, Miltiadis K Tsilimbaris, Veronika Vaclavik, Hoai V Tran, Tamar Ben-Yosef, Elfride De Baere, Andrew R Webster, Gavin Arno, Panagiotis I Sergouniotis, Susanne Kohl, Cristina Santos, Carlo Rivolta","doi":"10.1016/j.ajhg.2025.02.015","DOIUrl":"10.1016/j.ajhg.2025.02.015","url":null,"abstract":"<p><p>Inherited retinal diseases (IRDs) are a genetically heterogeneous group of Mendelian disorders that often lead to progressive vision loss and involve approximately 300 distinct genes. Although variants in these loci account for the majority of molecular diagnoses, other genes associated with IRD await molecular identification. In this study, we uncover bi-allelic assortments of 23 different (22 loss-of-function) variants in AP5Z1, AP5M1, and AP5B1 as independent causes of recessive IRD in members of 19 families from nine countries. Affected individuals, regardless of their genotypes, exhibit a specific form of macular degeneration, sometimes presenting in association with extraocular features. All three genes encode different subunits of the vesicular fifth adaptor protein (AP-5) complex, a component of the intracellular trafficking system involved in maintaining cellular homeostasis and ensuring the proper functioning of lysosomal pathways. The retinal pigment epithelium (RPE), a cellular monolayer located posteriorly to the neural retina, is characterized by intense lysosomal and phagocytic activity. Immunostaining of RPE cells revealed a punctate pattern of AP5Z1, AP5M1, and AP5B1 staining and co-localization with markers of late endosomes and the Golgi, suggesting a role of AP-5 in the normal physiology of this tissue. Overall, the identification of independently acting variants in three distinct proteins within the same macromolecular complex reveals AP-5 as having an important function in the preservation and maintenance of normal macular functions.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"808-828"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623104","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":"Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.","authors":"Evon DeBose-Scarlett, Andrew K Ressler, Carol J Gallione, Gonzalo Sapisochin Cantis, Cassi Friday, Shantel Weinsheimer, Katharina Schimmel, Edda Spiekerkoetter, Helen Kim, James R Gossage, Marie E Faughnan, Douglas A Marchuk","doi":"10.1016/j.ajhg.2025.03.007","DOIUrl":"10.1016/j.ajhg.2025.03.007","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"963"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639367","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 CDKL1 and CDKL2 are associated with neurodevelopmental symptoms.","authors":"Ali H Bereshneh, Jonathan C Andrews, Daniel F Eberl, Guney Bademci, Nicholas A Borja, Stephanie Bivona, Wendy K Chung, Shinya Yamamoto, Michael F Wangler, Shane McKee, Mustafa Tekin, Hugo J Bellen, Oguz Kanca","doi":"10.1016/j.ajhg.2025.02.019","DOIUrl":"10.1016/j.ajhg.2025.02.019","url":null,"abstract":"<p><p>The CDKL (cyclin-dependent kinase-like) family consists of five members in humans, CDKL1-5, that encode serine-threonine kinases. The only member that has been associated with a Mendelian disorder is CDKL5, and variants in CDKL5 cause developmental and epileptic encephalopathy type 2 (DEE2). Here, we study four de novo variants in CDKL2 identified in five individuals, including three unrelated probands and monozygotic twins. These individuals present with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, and speech deficits. We also identified two individuals with de novo missense variants in CDKL1 in the published Deciphering Developmental Disorders (DDD) and GeneDx cohorts with developmental disorders. Drosophila has a single ortholog of CDKL1-5, CG7236 (Cdkl). Cdkl is expressed in sensory neurons that project to specific regions of the brain that control sensory inputs. Cdkl loss causes semi-lethality, climbing defects, heat-induced seizures, hearing loss, and reduced lifespan. These phenotypes can be rescued by expression of the human reference CDKL1, CDKL2, or CDKL5, showing that the functions of these genes are conserved. In contrast, the CDKL1 and CDKL2 variants do not fully rescue the observed phenotypes, and overexpression of the variant proteins leads to phenotypes that are similar to Cdkl loss. Co-expression of CDKL1 or CDKL2 variants with CDKL1, CDKL2, or CDKL5 references in the mutant background suppresses the rescue ability of the reference genes. Our results suggest that the variants act as dominant negative alleles and are causative of neurological symptoms in these individuals.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"846-862"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633353","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 expanding global genomics landscape: Converging priorities from national genomics programs.","authors":"Caitlin Howley, Matilda A Haas, Wadha A Al Muftah, Robert B Annan, Eric D Green, Bettina Lundgren, Richard H Scott, Zornitza Stark, Patrick Tan, Kathryn N North, Tiffany Boughtwood","doi":"10.1016/j.ajhg.2025.02.008","DOIUrl":"10.1016/j.ajhg.2025.02.008","url":null,"abstract":"<p><p>The global landscape of health genomics is expanding rapidly, with an increasing number of national and international initiatives, many of which are targeted toward accelerating the clinical implementation of genomic technologies and services in the context of local health systems. This includes a range of entities with different levels of maturity, funding sources, and strategies that focus on research and clinical priorities to varying degrees. While there is no \"one-size-fits-all\" approach, analysis of national genomics programs helps to identify common priority areas, barriers, and enablers. Here, we synthesize the converging priorities of several national genomics programs to highlight the importance of progressing genomics research and clinical implementation on a national scale.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"751-763"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603540","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":"Bayesian causal graphical model for joint Mendelian randomization analysis of multiple exposures and outcomes.","authors":"Verena Zuber, Toinét Cronjé, Na Cai, Dipender Gill, Leonardo Bottolo","doi":"10.1016/j.ajhg.2025.03.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.005","url":null,"abstract":"<p><p>Current Mendelian randomization (MR) methods do not reflect complex relationships among multiple exposures and outcomes as is typical for real-life applications. We introduce MrDAG, a Bayesian causal graphical model for summary-level MR analysis to detect dependency relations within the exposures, the outcomes, and between them to improve causal effects estimation. MrDAG combines three causal inference strategies. It uses genetic variation as instrumental variables to account for unobserved confounders. It performs structure learning to detect and orientate the direction of the dependencies within the exposures and the outcomes. Finally, interventional calculus is employed to derive principled causal effect estimates. In MrDAG the directionality of the causal effects between the exposures and the outcomes is assumed known, i.e., the exposures can only be potential causes of the outcomes, and no reverse causation is allowed. In the simulation study, MrDAG outperforms recently proposed one-outcome-at-a-time and multi-response multi-variable Bayesian MR methods as well as causal graphical models under the constraint on edges' orientation from the exposures to the outcomes. MrDAG was motivated to unravel how lifestyle and behavioral exposures impact mental health. It highlights first, education and second, smoking as effective points of intervention given their important downstream effects on mental health. It also enables the identification of a novel path between smoking and the genetic liability to schizophrenia and cognition, demonstrating the complex pathways toward mental health. These insights would have been impossible to delineate without modeling the paths between multiple exposures and outcomes at once.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778738","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}