American journal of human genetics最新文献

{"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081223/pdf/","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":"OA","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081239/pdf/","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":"OA","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081226/pdf/","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":"OA","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081231/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2024 Lifetime Achievement Award: Biology unbalanced: Genes, gene dosage, and disease susceptibility.","authors":"James R Lupski","doi":"10.1016/j.ajhg.2025.01.025","DOIUrl":"10.1016/j.ajhg.2025.01.025","url":null,"abstract":"<p><p>This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 3","pages":"467-469"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11993854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584364","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":"Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study.","authors":"Emilio Ugalde-Morales, Rona Wilf, John Pluta, Alexander Ploner, Mengyao Fan, Mohammad Damra, Katja K Aben, Lynn Anson-Cartwright, Chu Chen, Victoria K Cortessis, Siamak Daneshmand, Alberto Ferlin, Marija Gamulin, Jourik A Gietema, Anna Gonzalez-Niera, Tom Grotmol, Robert J Hamilton, Mark Harland, Trine B Haugen, Russ Hauser, Michelle A T Hildebrandt, Robert Karlsson, Lambertus A Kiemeney, Jung Kim, Davor Lessel, Ragnhild A Lothe, Chey Loveday, Stephen J Chanock, Katherine A McGlynn, Coby Meijer, Kevin T Nead, Jeremie Nsengimana, Maja Popovic, Thorunn Rafnar, Lorenzo Richiardi, Maria S Rocca, Stephen M Schwartz, Rolf I Skotheim, Kari Stefansson, Douglas R Stewart, Clare Turnbull, David J Vaughn, Sofia B Winge, Tongzhang Zheng, Alvaro N Monteiro, Kristian Almstrup, Peter A Kanetsky, Katherine L Nathanson, Fredrik Wiklund","doi":"10.1016/j.ajhg.2025.01.022","DOIUrl":"10.1016/j.ajhg.2025.01.022","url":null,"abstract":"<p><p>Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis tested 19,805 gene-disease links, revealing 165 TGCT-associated genes with a false discovery rate of less than 0.01. We prioritized 46 candidate genes by considering GWAS-inflated signals, correlations between neighboring genes, and evidence of colocalization. Among these, 23 genes overlap with 22 GWAS loci, with 7 being associations not previously implicated in TGCT risk. Additionally, 23 genes located within 21 loci are at least 1 Mb away from published GWAS index variants. The 46 prioritized genes display expression levels consistent with expected expression levels in human gonadal cell types and precursor tumor cells and significant enrichment in TGCTs. Additionally, immunohistochemistry revealed protein-level accumulation of two candidate genes, ARID3B and GINM1, in both precursor and tumor cells. These findings enhance our understanding of the genetic predisposition to TGCTs and underscore the importance of further functional investigations into these candidate genes.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"630-643"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497586","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":"Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network.","authors":"Darcy T Ahern, Prakhar Bansal, Isaac V Faustino, Owen M Chambers, Erin C Banda, Heather R Glatt-Deeley, Rachael E Massey, Yuvabharath Kondaveeti, Stefan F Pinter","doi":"10.1016/j.ajhg.2025.01.013","DOIUrl":"10.1016/j.ajhg.2025.01.013","url":null,"abstract":"<p><p>Viable human aneuploidy can be challenging to model in rodents due to syntenic boundaries or primate-specific biology. Human monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which in contrast remain unaffected in X-monosomic mice. To learn how monosomy-X may impact embryonic development, we turned to 45,X and isogenic euploid human induced pluripotent stem cells (hiPSCs) from male and female mosaic donors. Because the neural crest (NC) is hypothesized to give rise to craniofacial and cardiovascular changes in TS, we assessed differential expression of hiPSC-derived anterior NC cells (NCCs). Across three independent isogenic panels, 45,X NCCs show impaired acquisition of PAX7⁺SOX10⁺ markers and disrupted expression of other NCC-specific genes relative to isogenic euploid controls. Additionally, 45,X NCCs increase cholesterol biosynthesis genes while reducing transcripts with 5' terminal oligopyrimidine (TOP) motifs, including those of ribosomal and nuclear-encoded mitochondrial proteins. Such metabolic pathways are also over-represented in weighted co-expression modules that are preserved in monogenic neurocristopathy and reflect 28% of all TS-associated terms of the human phenotype ontology. We demonstrate that 45,X NCCs reduce protein synthesis despite activation of mammalian target of rapamycin (mTOR) but are partially rescued by mild mTOR suppression. Our analysis identifies specific sex-linked genes that are expressed from two copies in euploid males and females alike and qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. This study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as powerful models of early NC development in TS and inform new hypotheses toward its etiology.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"615-629"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373698","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":"Distinct explanations underlie gene-environment interactions in the UK Biobank.","authors":"Arun Durvasula, Alkes L Price","doi":"10.1016/j.ajhg.2025.01.014","DOIUrl":"10.1016/j.ajhg.2025.01.014","url":null,"abstract":"<p><p>The role of gene-environment (GxE) interaction in disease and complex trait architectures is widely hypothesized but currently unknown. Here, we apply three statistical approaches to quantify and distinguish three different types of GxE interaction for a given trait and environmental (E) variable. First, we detect locus-specific GxE interaction by testing for genetic correlation (r_g) < 1 across E bins. Second, we detect genome-wide effects of the E variable on genetic variance by leveraging polygenic risk scores (PRSs) to test for significant PRSxE in a regression of phenotypes on PRS, E, and PRSxE, together with differences in SNP heritability across E bins. Third, we detect genome-wide proportional amplification of genetic and environmental effects as a function of the E variable by testing for significant PRSxE with no differences in SNP heritability across E bins. We applied our framework to 33 UK Biobank traits (25 quantitative traits and 8 diseases; average n = 325,000) and 10 E variables spanning lifestyle, diet, and other environmental exposures. First, we identified 19 trait-E pairs with r_g significantly <1 (false discovery rate < 5%); 28 trait-E pairs with significant PRSxE and significant SNP heritability differences across E bins; and 15 trait-E pairs with significant PRSxE but no SNP heritability differences across E bins. Across the three scenarios, eight of the trait-E pairs involved disease traits, whose interpretation is complicated by scale effects. Analyses using biological sex as the E variable produced additional significant findings in each of these scenarios. Overall, we infer a significant contribution of GxE and GxSex effects to complex trait variance.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"644-658"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447817","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":"2024 ASHG awards and addresses.","authors":"","doi":"10.1016/j.ajhg.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.01.023","url":null,"abstract":"<p><p>Each year at the annual meeting of The American Society of Human Genetics (ASHG), addresses are given in honor of the Society and several award winners. A summary of each of these is provided below. On the following pages, we have printed the Presidential Address as well as the addresses for the Lifetime Achievement, Scientific Achievement, and Leadership awards. Recordings of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 3","pages":"459-460"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584358","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":"reg-eQTL: Integrating transcription factor effects to unveil regulatory variants.","authors":"Rekha Mudappathi, Tatiana Patton, Hai Chen, Ping Yang, Zhifu Sun, Panwen Wang, Chang-Xin Shi, Junwen Wang, Li Liu","doi":"10.1016/j.ajhg.2025.01.015","DOIUrl":"10.1016/j.ajhg.2025.01.015","url":null,"abstract":"<p><p>Regulatory single-nucleotide variants (rSNVs) in noncoding regions of the genome play a crucial role in gene transcription by altering transcription factor (TF) binding, chromatin states, and other epigenetic modifications. Existing expression quantitative trait locus (eQTL) methods identify genomic loci associated with gene-expression changes, but they often fall short in pinpointing causal variants. We introduce reg-eQTL, a computational method that incorporates TF effects and interactions with genetic variants into eQTL analysis. This approach provides deeper insights into the regulatory mechanisms, bringing us one step closer to identifying potential causal variants by uncovering how TFs interact with SNVs to influence gene expression. This method defines a trio consisting of a genetic variant, a target gene, and a TF and tests its impact on gene transcription. In comprehensive simulations, reg-eQTL shows improved power of detecting rSNVs with low population frequency, weak effects, and synergetic interaction with TF as compared to traditional eQTL methods. Application of reg-eQTL to GTEx data from lung, brain, and whole-blood tissues uncovered regulatory trios that include eQTLs and increased the number of eQTLs shared across tissue types. Regulatory networks constructed on the basis of these trios reveal intricate gene regulation across tissue types.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"659-674"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373705","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}