Pub Date : 2026-01-08Epub Date: 2025-12-29DOI: 10.1016/j.ajhg.2025.12.004
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
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.
{"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}
Pub Date : 2026-01-08DOI: 10.1016/j.ajhg.2025.12.005
Kaido Lepik,Chiara Auwerx,Marie C Sadler,Adriaan van der Graaf,Sven Erik Ojavee,Zoltán Kutalik
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.
{"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}
Pub Date : 2026-01-08DOI: 10.1016/j.ajhg.2025.12.009
Paul W. Hook, Alyson B. Barnes
{"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}
Pub Date : 2026-01-08DOI: 10.1016/j.ajhg.2025.12.010
Kiran Musunuru
{"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}
Pub Date : 2025-12-23DOI: 10.1016/j.ajhg.2025.12.001
Lauren Rekerle, Daniel Danis, Filip Rehburg, Adam S.L. Graefe, Viktor Bily, Andrés Caballero-Oteyza, Pilar Cacheiro, Leonardo Chimirri, Jessica X. Chong, Evan Connelly, Bert B.A. de Vries, Alexander J.M. Dingemans, Michael H. Duyzend, Tomas Freiberger, Petra Gehle, Tudor Groza, Peter Hansen, Julius O.B. Jacobsen, Adam Klocperk, Markus S. Ladewig, Michael I. Love, Allison J. Marcello, Alexander Mordhorst, Monica C. Munoz-Torres, Justin Reese, Catharina Schuetz, Damian Smedley, Timmy Strauss, Ondrej Vladyka, David Zocche, Sylvia Thun, Christopher J. Mungall, Melissa A. Haendel, Peter N. Robinson
{"title":"GA4GH phenopacket-driven characterization of genotype-phenotype correlations in Mendelian disorders","authors":"Lauren Rekerle, Daniel Danis, Filip Rehburg, Adam S.L. Graefe, Viktor Bily, Andrés Caballero-Oteyza, Pilar Cacheiro, Leonardo Chimirri, Jessica X. Chong, Evan Connelly, Bert B.A. de Vries, Alexander J.M. Dingemans, Michael H. Duyzend, Tomas Freiberger, Petra Gehle, Tudor Groza, Peter Hansen, Julius O.B. Jacobsen, Adam Klocperk, Markus S. Ladewig, Michael I. Love, Allison J. Marcello, Alexander Mordhorst, Monica C. Munoz-Torres, Justin Reese, Catharina Schuetz, Damian Smedley, Timmy Strauss, Ondrej Vladyka, David Zocche, Sylvia Thun, Christopher J. Mungall, Melissa A. Haendel, Peter N. Robinson","doi":"10.1016/j.ajhg.2025.12.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.001","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"14 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822761","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}
Pub Date : 2025-12-23DOI: 10.1016/j.ajhg.2025.12.002
Alan Mejia Maza, Madison Hincher, Kevin Correia, Tammy Gillis, Ayumi Nishiyama, Ellen B. Penney, Aloysius Domingo, Rachita Yadav, Micaela G. Murcar, Patrick D. Villafria Mercado, Justin S. Han, Ean P. Norenberg, Cara Fernandez-Cerado, G. Paul Legarda, Michelle Sy, Edwin L. Muñoz, Mark C. Ang, Cid Czarina E. Diesta, Criscely Go, Nutan Sharma, D. Cristopher Bragg, Michael E. Talkowski, Marcy E. MacDonald, Jong-Min Lee, Laurie J. Ozelius, Vanessa Chantal Wheeler
{"title":"MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism","authors":"Alan Mejia Maza, Madison Hincher, Kevin Correia, Tammy Gillis, Ayumi Nishiyama, Ellen B. Penney, Aloysius Domingo, Rachita Yadav, Micaela G. Murcar, Patrick D. Villafria Mercado, Justin S. Han, Ean P. Norenberg, Cara Fernandez-Cerado, G. Paul Legarda, Michelle Sy, Edwin L. Muñoz, Mark C. Ang, Cid Czarina E. Diesta, Criscely Go, Nutan Sharma, D. Cristopher Bragg, Michael E. Talkowski, Marcy E. MacDonald, Jong-Min Lee, Laurie J. Ozelius, Vanessa Chantal Wheeler","doi":"10.1016/j.ajhg.2025.12.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.002","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"22 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822762","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}
Pub Date : 2025-12-22DOI: 10.1016/j.ajhg.2025.11.016
M. Dybdahl Krebs, Vivek Appadurai, Kajsa-Lotta Georgii Hellberg, Henrik Ohlsson, Jette Steinbach, Emil Pedersen, iPSYCH Study Consortium, Thomas Werge, Jan Sundquist, Kristina Sundquist, Richard Border, Na Cai, Noah Zaitlen, Andy Dahl, Bjarni Vilhjalmsson, Jonathan Flint, Silviu-Alin Bacanu, Kenneth S. Kendler, Andrew J. Schork
Genetics as a science has roots in studying phenotypes of relatives, but molecular approaches facilitate direct measurements of genomic variation between individuals. Agricultural and human biomedical research are both emphasizing genotype-based instruments, such as polygenic scores, but unlike in agriculture, there is an emerging consensus that family variables act nearly independently of genotypes in models of human disease. However, there is insufficient theoretical treatment of these scores, especially guiding our understanding of how and why scores derived from different sources of data may combine. To advance our understanding of this phenomenon, we use 2,066,057 family records of 99,645 genotyped probands from the Integrative Psychiatric Research (iPSYCH)2015 case-cohort study to show that state-of-the-field genotype- and phenotype-based genetic instruments explain largely independent components of liability to psychiatric disorders. We support these empirical results with theoretical analysis and simulations to describe, in a human biomedical context, parameters affecting current and future performance of the two approaches, their expected interrelationships, and consistency of observed results with expectations under simple additive, polygenic liability models of disease. We conclude, at least for psychiatric disorders, that the low correlation between current phenotype- and genotype-based genetic instruments is caused by both being noisy measures of additive genetic liability. We expect they should remain complementary over the near future and therefore expect approaches integrating both sources of information to achieve more power for genetic inference.
{"title":"The relationship between genotype- and phenotype-based estimates of genetic liability to psychiatric disorders, in practice and in theory","authors":"M. Dybdahl Krebs, Vivek Appadurai, Kajsa-Lotta Georgii Hellberg, Henrik Ohlsson, Jette Steinbach, Emil Pedersen, iPSYCH Study Consortium, Thomas Werge, Jan Sundquist, Kristina Sundquist, Richard Border, Na Cai, Noah Zaitlen, Andy Dahl, Bjarni Vilhjalmsson, Jonathan Flint, Silviu-Alin Bacanu, Kenneth S. Kendler, Andrew J. Schork","doi":"10.1016/j.ajhg.2025.11.016","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.016","url":null,"abstract":"Genetics as a science has roots in studying phenotypes of relatives, but molecular approaches facilitate direct measurements of genomic variation between individuals. Agricultural and human biomedical research are both emphasizing genotype-based instruments, such as polygenic scores, but unlike in agriculture, there is an emerging consensus that family variables act nearly independently of genotypes in models of human disease. However, there is insufficient theoretical treatment of these scores, especially guiding our understanding of how and why scores derived from different sources of data may combine. To advance our understanding of this phenomenon, we use 2,066,057 family records of 99,645 genotyped probands from the Integrative Psychiatric Research (iPSYCH)2015 case-cohort study to show that state-of-the-field genotype- and phenotype-based genetic instruments explain largely independent components of liability to psychiatric disorders. We support these empirical results with theoretical analysis and simulations to describe, in a human biomedical context, parameters affecting current and future performance of the two approaches, their expected interrelationships, and consistency of observed results with expectations under simple additive, polygenic liability models of disease. We conclude, at least for psychiatric disorders, that the low correlation between current phenotype- and genotype-based genetic instruments is caused by both being noisy measures of additive genetic liability. We expect they should remain complementary over the near future and therefore expect approaches integrating both sources of information to achieve more power for genetic inference.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"2 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813928","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}
Pub Date : 2025-12-22DOI: 10.1016/j.ajhg.2025.11.014
Gabriela M Ramírez Renta,India D Little,Laura M Koehly,Anna J Hilliard,Kaylee L Foor,Jessica Butts,Jordan Lundeen,Chris Gunter
Genetic literacy goes beyond knowledge of genetic terms, as it requires sufficient skills and understanding to effectively facilitate health-related decision-making and participation in social discussions about genetic issues. Personal identity and beliefs have been shown to affect how individuals interact with new information, but rarely in the context of genetic literacy. In 2021, we created and disseminated a survey to two separate samples: 2,050 members of the US general public and 2,023 participants in a large genetic research study. We assessed genetic literacy through three components: subjective knowledge (Familiarity), objective knowledge (Knowledge), and knowledge comprehension (Skills), making this one of the only large-scale surveys to assess comprehension as a part of genetic literacy. We hypothesized that additional measures of identity and belief factors would enable a better understanding of how individuals process and retain genetic information. We found that confidence in one's genetic knowledge was the strongest predictor of positive scores in all three components, controlling nearly 25% of the variance in scores, while perceived importance of genetic information had a positive but weaker relationship to scores. This suggests that improving confidence, not just providing knowledge, is an important part of increasing uptake of genetics in various applications. Further, we found that multiple self-described beliefs had mixed predictive effects on all three of our genetic literacy subscales. These findings demonstrate the complexity inherent in endeavors to raise genetic literacy in the US population as an example, as well as the importance of context-specific genetics communication.
{"title":"Interaction of identity and beliefs with genetic literacy.","authors":"Gabriela M Ramírez Renta,India D Little,Laura M Koehly,Anna J Hilliard,Kaylee L Foor,Jessica Butts,Jordan Lundeen,Chris Gunter","doi":"10.1016/j.ajhg.2025.11.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.014","url":null,"abstract":"Genetic literacy goes beyond knowledge of genetic terms, as it requires sufficient skills and understanding to effectively facilitate health-related decision-making and participation in social discussions about genetic issues. Personal identity and beliefs have been shown to affect how individuals interact with new information, but rarely in the context of genetic literacy. In 2021, we created and disseminated a survey to two separate samples: 2,050 members of the US general public and 2,023 participants in a large genetic research study. We assessed genetic literacy through three components: subjective knowledge (Familiarity), objective knowledge (Knowledge), and knowledge comprehension (Skills), making this one of the only large-scale surveys to assess comprehension as a part of genetic literacy. We hypothesized that additional measures of identity and belief factors would enable a better understanding of how individuals process and retain genetic information. We found that confidence in one's genetic knowledge was the strongest predictor of positive scores in all three components, controlling nearly 25% of the variance in scores, while perceived importance of genetic information had a positive but weaker relationship to scores. This suggests that improving confidence, not just providing knowledge, is an important part of increasing uptake of genetics in various applications. Further, we found that multiple self-described beliefs had mixed predictive effects on all three of our genetic literacy subscales. These findings demonstrate the complexity inherent in endeavors to raise genetic literacy in the US population as an example, as well as the importance of context-specific genetics communication.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"23 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813553","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}
Pub Date : 2025-12-22DOI: 10.1016/j.ajhg.2025.11.015
Kirill Zaslavsky,Liyin Chen,Chloe Park,Emily M Place,Daniel Navarro-Gomez,Seyedeh M Zekavat,Christopher F Barile,Kinga M Bujakowska,Elizabeth J Rossin,Eric A Pierce
Inherited retinal degenerations (IRDs) are the leading cause of blindness in working-age adults and are thought to be monogenic with near-complete penetrance. However, traditional variant discovery based on phenotypic ascertainment may inflate penetrance estimates and obscure the true genotype-phenotype spectrum. We used large biobanks with linked genomic and clinical data to quantify the population-level penetrance of IRD-associated variants. We screened 317,964 All of Us (AoU) participants for loss-of-function or pathogenic IRD variants to curate a cohort with definite IRD-compatible genotypes. We defined three nested International Classification of Diseases (ICD)-9/10 code sets ("IRD," "retinopathy," and "screening") to derive lower- and upper-bound penetrance estimates via disease annotation frequencies (DAFs). Within a cohort of 481 AoU participants with definite IRD-compatible genotypes, DAFs ranged from 9.4% (IRD) to 28.1% (screening), which were enriched relative to the prevalence of the code sets in AoU (p < 0.001). For validation, we examined retinal imaging of UK Biobank (UKB) participants who shared variants with the AoU cohort. In the UKB, 16.1%-27.9% of participants with shared variants exhibited definite or possible IRD features, concordant with AoU estimates. Participant demographics, smoking, socioeconomic status, and comorbidities did not predict penetrance. These results show that the population penetrance of IRD-associated genotypes is markedly lower than traditionally assumed. This suggests that genetic or environmental modifiers are required to manifest disease and that IRD genotypes are more prevalent (0.7%-2.1%) than expected. These findings inform our understanding of the genetic causality of IRDs, impact the clinical use of genetic testing, and have implications for the development of therapies for IRDs.
遗传性视网膜变性（IRDs）是导致工作年龄成年人失明的主要原因，被认为是单基因的，几乎完全外显。然而，传统的基于表型确定的变异发现可能会夸大外显率估计并模糊真正的基因型-表型谱。我们使用具有相关基因组和临床数据的大型生物库来量化ird相关变异的人群水平外显率。我们筛选了317,964名All Us （AoU）参与者的功能丧失或致病性IRD变异，以建立一个明确的IRD相容基因型的队列。我们定义了三个嵌套的国际疾病分类(ICD)-9/10代码集（“IRD”、“视网膜病变”和“筛查”），通过疾病注释频率（daf）得出下限和上限外显率估计。在481名具有明确的IRD相容基因型的AoU参与者中，daf范围从9.4% （IRD）到28.1%（筛选），相对于AoU中代码集的流行程度（p < 0.001）。为了验证，我们检查了与AoU队列共享变异的UK Biobank （UKB）参与者的视网膜成像。在英国，16.1%-27.9%具有共同变异的参与者表现出明确或可能的IRD特征，与AoU估计一致。参与者的人口统计、吸烟、社会经济地位和合并症不能预测外显率。这些结果表明，ird相关基因型的群体外显率明显低于传统的假设。这表明需要遗传或环境修饰因子来表现疾病，并且IRD基因型比预期更普遍（0.7%-2.1%）。这些发现使我们了解了IRDs的遗传因果关系，影响了基因检测的临床应用，并对IRDs的治疗方法的发展产生了影响。
{"title":"Low population penetrance of variants associated with inherited retinal degenerations.","authors":"Kirill Zaslavsky,Liyin Chen,Chloe Park,Emily M Place,Daniel Navarro-Gomez,Seyedeh M Zekavat,Christopher F Barile,Kinga M Bujakowska,Elizabeth J Rossin,Eric A Pierce","doi":"10.1016/j.ajhg.2025.11.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.015","url":null,"abstract":"Inherited retinal degenerations (IRDs) are the leading cause of blindness in working-age adults and are thought to be monogenic with near-complete penetrance. However, traditional variant discovery based on phenotypic ascertainment may inflate penetrance estimates and obscure the true genotype-phenotype spectrum. We used large biobanks with linked genomic and clinical data to quantify the population-level penetrance of IRD-associated variants. We screened 317,964 All of Us (AoU) participants for loss-of-function or pathogenic IRD variants to curate a cohort with definite IRD-compatible genotypes. We defined three nested International Classification of Diseases (ICD)-9/10 code sets (\"IRD,\" \"retinopathy,\" and \"screening\") to derive lower- and upper-bound penetrance estimates via disease annotation frequencies (DAFs). Within a cohort of 481 AoU participants with definite IRD-compatible genotypes, DAFs ranged from 9.4% (IRD) to 28.1% (screening), which were enriched relative to the prevalence of the code sets in AoU (p < 0.001). For validation, we examined retinal imaging of UK Biobank (UKB) participants who shared variants with the AoU cohort. In the UKB, 16.1%-27.9% of participants with shared variants exhibited definite or possible IRD features, concordant with AoU estimates. Participant demographics, smoking, socioeconomic status, and comorbidities did not predict penetrance. These results show that the population penetrance of IRD-associated genotypes is markedly lower than traditionally assumed. This suggests that genetic or environmental modifiers are required to manifest disease and that IRD genotypes are more prevalent (0.7%-2.1%) than expected. These findings inform our understanding of the genetic causality of IRDs, impact the clinical use of genetic testing, and have implications for the development of therapies for IRDs.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"22 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813552","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}
Pub Date : 2025-12-19DOI: 10.1016/j.ajhg.2025.11.010
Jessica I. Gold, Yehuda Elkaim, Nina B. Gold, Stephanie Asher, Anna Raper, Courtney Condit, Zoe Bogus, Isaac Elysee, Laura Hennessy, Emma Kennedy, Lauren C. Briere, David A. Sweetser, Colleen Kripke, Anurag Verma, Hojjat Salmasian, Latrice Landry, Katherine L. Nathanson, Staci Kallish, Theodore G. Drivas
{"title":"Racial and socioeconomic disparities in genetic evaluation and testing in the adult patient population","authors":"Jessica I. Gold, Yehuda Elkaim, Nina B. Gold, Stephanie Asher, Anna Raper, Courtney Condit, Zoe Bogus, Isaac Elysee, Laura Hennessy, Emma Kennedy, Lauren C. Briere, David A. Sweetser, Colleen Kripke, Anurag Verma, Hojjat Salmasian, Latrice Landry, Katherine L. Nathanson, Staci Kallish, Theodore G. Drivas","doi":"10.1016/j.ajhg.2025.11.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.010","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"11 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784776","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}
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