American journal of human genetics最新文献

{"title":"2024 ASHG Lifetime Achievement Award.","authors":"Margaret A Pericak-Vance","doi":"10.1016/j.ajhg.2025.02.002","DOIUrl":"10.1016/j.ajhg.2025.02.002","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":"470-472"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11993870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584360","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":"Genome-wide prediction of dominant and recessive neurodevelopmental disorder-associated genes.","authors":"Ryan S Dhindsa, Blake A Weido, Justin S Dhindsa, Arya J Shetty, Chloe F Sands, Slavé Petrovski, Dimitrios Vitsios, Anthony W Zoghbi","doi":"10.1016/j.ajhg.2025.02.001","DOIUrl":"10.1016/j.ajhg.2025.02.001","url":null,"abstract":"<p><p>Despite great progress, thousands of neurodevelopmental disorder (NDD) risk genes remain to be discovered. We present a computational approach that accelerates NDD risk gene identification using machine learning. First, we demonstrate that models trained solely on single-cell RNA sequencing data can robustly predict genes implicated in autism spectrum disorder (ASD), developmental and epileptic encephalopathy (DEE), and developmental delay (DD). Notably, we find differences in gene expression patterns of genes with monoallelic and bi-allelic inheritance patterns in the developing human cortex. We then integrate expression data with 300 orthogonal features, including intolerance metrics, protein-protein interaction data, and others, in a semi-supervised machine learning framework (mantis-ml) to train inheritance-specific models for these disorders. The models have high predictive power (area under the receiver operator curves [AUCs]: 0.84-0.95), and the top-ranked genes were up to 2-fold (monoallelic models) and 6-fold (bi-allelic models) more enriched for high-confidence NDD risk genes compared to genic intolerance metrics alone. Additionally, genes ranking in the top decile were 45 to 180 times more likely to have literature support than those in the bottom decile. Collectively, this work provides robust NDD risk gene predictions that can complement large-scale gene discovery efforts and underscores the importance of considering inheritance in gene risk prediction.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"693-708"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522309","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":"Experience using conventional compared to ancestry-based population descriptors in clinical genomics laboratories.","authors":"Kathryn E Hatchell, Sarah R Poll, Emily M Russell, Trevor J Williams, Rachel E Ellsworth, Flavia M Facio, Sienna Aguilar, Edward D Esplin, Alice B Popejoy, Robert L Nussbaum, Swaroop Aradhya","doi":"10.1016/j.ajhg.2025.01.008","DOIUrl":"10.1016/j.ajhg.2025.01.008","url":null,"abstract":"<p><p>Various scientific and professional groups, including the American Medical Association (AMA), American Society of Human Genetics (ASHG), American College of Medical Genetics (ACMG), and the National Academies of Sciences, Engineering, and Medicine (NASEM), have appropriately clarified that certain population descriptors, such as race and ethnicity, are social and cultural constructs with no basis in genetics. Nevertheless, these conventional population descriptors are routinely collected during the course of clinical genetic testing and may be used to interpret test results. Experts who have examined the use of population descriptors, both conventional and ancestry based, in human genetics and genomics have offered guidance on using these descriptors in research but not in clinical laboratory settings. This perspective piece is based on a decade of experience in a clinical genomics laboratory and provides insight into the relevance of conventional and ancestry-based population descriptors for clinical genetic testing, reporting, and clinical research on aggregated data. As clinicians, laboratory geneticists, genetic counselors, and researchers, we describe real-world experiences collecting conventional population descriptors in the course of clinical genetic testing and expose challenges in ensuring clarity and consistency in the use of population descriptors. Current practices in clinical genomics laboratories that are influenced by population descriptors are identified and discussed through case examples. In relation to this, we describe specific types of clinical research projects in which population descriptors were used and helped derive useful insights related to practicing and improving genomic medicine.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"481-491"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063249","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 presidential address: Incomplete penetrance and variable expressivity: Old concepts, new urgency.","authors":"Bruce D Gelb","doi":"10.1016/j.ajhg.2025.01.010","DOIUrl":"10.1016/j.ajhg.2025.01.010","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":"461-466"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11993877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584362","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":"SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns.","authors":"Tara L Wenger, Abbey Scott, Lukas Kruidenier, Megan Sikes, Alexandra Keefe, Kati J Buckingham, Colby T Marvin, Kathryn M Shively, Tamara Bacus, Olivia M Sommerland, Kailyn Anderson, Heidi Gildersleeve, Chayna J Davis, Jamie Love-Nichols, Katherine E MacDuffie, Danny E Miller, Joon-Ho Yu, Amy Snook, Britt Johnson, David L Veenstra, Julia Parish-Morris, Kirsty McWalter, Kyle Retterer, Deborah Copenheaver, Bethany Friedman, Jane Juusola, Erin Ryan, Renee Varga, Daniel A Doherty, Katrina Dipple, Jessica X Chong, Paul Kruszka, Michael J Bamshad","doi":"10.1016/j.ajhg.2025.02.003","DOIUrl":"10.1016/j.ajhg.2025.02.003","url":null,"abstract":"<p><p>Access to a precise genetic diagnosis (PrGD) in critically ill newborns is limited and inequitable because the complex inclusion criteria used to prioritize testing eligibility omit many patients at high risk for a genetic condition. SeqFirst-neo is a program to test whether a genotype-driven workflow using simple, broad exclusion criteria to assess eligibility for rapid genome sequencing (rGS) increases access to a PrGD in critically ill newborns. All 408 newborns admitted to a neonatal intensive care unit between January 2021 and February 2022 were assessed, and of 240 eligible infants, 126 were offered rGS (i.e., intervention group [IG]) and compared to 114 infants who received conventional care in parallel (i.e., conventional care group [CCG]). A PrGD was made in 62/126 (49.2%) IG neonates compared to 11/114 (9.7%) CCG infants. The odds of receiving a PrGD were ∼9 times greater in the IG vs. the CCG, and this difference was maintained at 12 months follow-up. Access to a PrGD in the IG vs. CCG differed significantly between infants identified as non-White (34/74, 45.9% vs. 6/29, 20.7%; p = 0.024) and Black (8/10, 80.0% vs. 0/4; p = 0.015). Neonatologists were significantly less successful at predicting a PrGD in non-White than non-Hispanic White infants. The use of a standard workflow in the IG with a PrGD revealed that a PrGD would have been missed in 26/62 (42%) infants. The use of simple, broad exclusion criteria that increase access to genetic testing significantly increases access to a PrGD, improves access equity, and results in fewer missed diagnoses.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"508-522"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497663","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":"Contribution of autosomal rare and de novo variants to sex differences in autism.","authors":"Mahmoud Koko, F Kyle Satterstrom, Varun Warrier, Hilary Martin","doi":"10.1016/j.ajhg.2025.01.016","DOIUrl":"10.1016/j.ajhg.2025.01.016","url":null,"abstract":"<p><p>Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of rare variants between individuals with and without cognitive impairment or motor delay. Although these variants mediated different likelihoods of autism with versus without cognitive or motor difficulties, their effect sizes on the liability scale did not differ significantly by sex exome wide or in genes sex-differentially expressed in the cortex. De novo mutations were enriched in genes with male-biased expression in the adult cortex, but these genes did not show a significant sex difference on the liability scale, nor did the liability conferred by these genes differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. Exome-wide female bias in de novo protein-truncating mutation rates on the observed scale was driven by high-confidence and syndromic autism-predisposition genes. In summary, autosomal rare and damaging coding variants confer similar liability for autism in females and males.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"599-614"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424813","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 Leadership Award.","authors":"Cynthia C Morton","doi":"10.1016/j.ajhg.2025.01.009","DOIUrl":"10.1016/j.ajhg.2025.01.009","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":"478-480"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11993890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584359","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":"Misattributed paternity discovery: A critique of medical organizations' recommendations.","authors":"Richard Wenzel, Gina Daniel, Jodi Girard, Lily Wood, Eve Sturges","doi":"10.1016/j.ajhg.2025.01.006","DOIUrl":"10.1016/j.ajhg.2025.01.006","url":null,"abstract":"<p><p>The five authors recently discovered their misattributed paternity (MP), two ascertaining that, decades ago, their pediatricians abetted the paternity deception. From their unique perspective, the authors critique medical organizations' current MP discovery guidance, identifying shortcomings, contradictions, and clinical and legal hazards. They also discuss opportunities to improve MP discovery management.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"492-507"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188198","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":"Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.","authors":"Iris Verbinnen, Sofia Douzgou Houge, Tzung-Chien Hsieh, Hellen Lesmann, Aron Kirchhoff, David Geneviève, Elise Brimble, Lisa Lenaerts, Dorien Haesen, Rebecca J Levy, Julien Thevenon, Laurence Faivre, Elysa Marco, Jessica X Chong, Mike Bamshad, Karynne Patterson, Ghayda M Mirzaa, Kimberly Foss, William Dobyns, Susan M White, Lynn Pais, Emily O'Heir, Raphaela Itzikowitz, Kirsten A Donald, Celia Van der Merwe, Alessandro Mussa, Raffaela Cervini, Elisa Giorgio, Tony Roscioli, Kerith-Rae Dias, Carey-Anne Evans, Natasha J Brown, Anna Ruiz, Juan Pablo Trujillo Quintero, Rachel Rabin, John Pappas, Hai Yuan, Katherine Lachlan, Simon Thomas, Anita Devlin, Michael Wright, Richard Martin, Joanna Karwowska, Renata Posmyk, Nicolas Chatron, Zornitza Stark, Oliver Heath, Martin Delatycki, Rebecca Buchert, Georg-Christoph Korenke, Keri Ramsey, Vinodh Narayanan, Dorothy K Grange, Judith L Weisenberg, Tobias B Haack, Stephanie Karch, Patricia Kipkemoi, Moses Mangi, Karen G C B Bindels de Heus, Marie-Claire Y de Wit, Tahsin Stefan Barakat, Derek Lim, Géraldine Van Winckel, Rebecca C Spillmann, Vandana Shashi, Maureen Jacob, Antonia M Stehr, Peter Krawitz, Gunnar Douzgos Houge, Veerle Janssens","doi":"10.1016/j.ajhg.2025.01.021","DOIUrl":"10.1016/j.ajhg.2025.01.021","url":null,"abstract":"<p><p>Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively. Here, we describe an additional condition in the HJS spectrum in 26 individuals with variants in PPP2R5C, encoding the regulatory B56γ subunit. Most changes were de novo and of the missense type. The clinical features were well within the HJS spectrum with strongest resemblance to HJS type 1, caused by B56δ variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. Head circumferences were above average or macrocephalic. The degree of intellectual disability was, on average, milder than in other HJS types. All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19). Five variants were recurrent. Catalytic activity of the phosphatase was variably affected by the variants. Of note, PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"554-571"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466733","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":"Single-cell transcriptomics reveals inter-ethnic variation in immune response to Falciparum malaria.","authors":"Tala Shahin, Jakub Jurkovic, Mame Massar Dieng, Vinu Manikandan, Wael Abdrabou, Bana Alamad, Odmaa Bayaraa, Aïssatou Diawara, Samuel Sindié Sermé, Noëlie Béré Henry, Salif Sombie, Dareen Almojil, Marc Arnoux, Nizar Drou, Issiaka Soulama, Youssef Idaghdour","doi":"10.1016/j.ajhg.2025.01.020","DOIUrl":"10.1016/j.ajhg.2025.01.020","url":null,"abstract":"<p><p>Africa's environmental, cultural, and genetic diversity can profoundly shape population responses to infectious diseases, including malaria caused by Plasmodium falciparum. Differences in malaria susceptibility among populations are documented, but the underlying mechanisms remain poorly understood. Notably, the Fulani ethnic group in Africa is less susceptible to malaria compared to other sympatric groups, such as the Mossi. They exhibit lower disease rates and parasite load as well as enhanced serological protection. However, elucidating the molecular and cellular basis of this protection has been challenging in part due to limited immunological characterization at the cellular level. To address this question, we performed single-cell transcriptomic profiling of peripheral blood mononuclear cells from 126 infected and non-infected Fulani and Mossi children in rural Burkina Faso. This analysis generated over 70,000 single-cell transcriptomes and identified 30 distinct cell subtypes. We report a profound effect of ethnicity on the transcriptional landscape, particularly within monocyte populations. Differential expression analysis across cell subtypes revealed ethnic-specific immune signatures under both infected and non-infected states. Specifically, monocytes and T cell subtypes of the Fulani exhibited reduced pro-inflammatory responses, while their B cell subtypes displayed stronger activation and inflammatory profiles. Furthermore, single-cell expression quantitative trait locus (eQTL) analysis in monocytes of infected children revealed several significant regulatory variants with ethnicity-specific effects on immune-related genes, including CD36 and MT2A. Overall, we identify ethnic, cell-type-specific, and genetic regulatory effects on host immune responses to malaria and provide valuable single-cell eQTL and transcriptomic datasets from under-represented populations.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"709-723"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456884","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}