Pub Date : 2026-01-27DOI: 10.1016/j.ajhg.2026.01.001
Colin M Brand,John A Capra
Ancient DNA provides an extraordinary perspective on many fundamental questions in human genetics, including understanding the evolutionary history of variants that underlie human phenotypes. However, most publicly available ancient human genotypes are limited to ∼1.23 million loci genotyped in the Allen Ancient DNA Resource. Thus, variants of interest often fall outside genotyped positions, limiting the ability of ancient DNA to shed light on many loci. Here, we address this challenge by quantifying linkage disequilibrium (LD) between modern variants and ancient genotyped variants (AGVs) to generate a catalog enabling rapid identification of proxy variants. We identified 260,732,675 pairs of AGVs and modern variants with a minimum LD threshold of R2 ≥ 0.2. At R2 ≥ 0.9, ≥60% of common variants were linked to an AGV in non-African ancestry groups, as were 34% of common variants in Africans. We evaluated the accuracy of the genotypes inferred from proxy variants in two high-coverage ancient genomes; >90% of genotypes were correctly predicted, even in a 45,000-year-old individual. To illustrate the utility of the proxies, we show that they cover, on average, 5.6 times more significant genome-wide association study (GWAS) variants compared to using AGVs alone. We also demonstrate that our proxies enable tracing the frequency of trait-associated variants through time to evaluate the potential to apply polygenic prediction models to ancient individuals. Our database, called AncientProxy, enables easy identification of proxy variants genotyped in ancient humans for a modern variant of interest.
{"title":"AncientProxy: A catalog of ancient proxies for modern genetic variants.","authors":"Colin M Brand,John A Capra","doi":"10.1016/j.ajhg.2026.01.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.01.001","url":null,"abstract":"Ancient DNA provides an extraordinary perspective on many fundamental questions in human genetics, including understanding the evolutionary history of variants that underlie human phenotypes. However, most publicly available ancient human genotypes are limited to ∼1.23 million loci genotyped in the Allen Ancient DNA Resource. Thus, variants of interest often fall outside genotyped positions, limiting the ability of ancient DNA to shed light on many loci. Here, we address this challenge by quantifying linkage disequilibrium (LD) between modern variants and ancient genotyped variants (AGVs) to generate a catalog enabling rapid identification of proxy variants. We identified 260,732,675 pairs of AGVs and modern variants with a minimum LD threshold of R2 ≥ 0.2. At R2 ≥ 0.9, ≥60% of common variants were linked to an AGV in non-African ancestry groups, as were 34% of common variants in Africans. We evaluated the accuracy of the genotypes inferred from proxy variants in two high-coverage ancient genomes; >90% of genotypes were correctly predicted, even in a 45,000-year-old individual. To illustrate the utility of the proxies, we show that they cover, on average, 5.6 times more significant genome-wide association study (GWAS) variants compared to using AGVs alone. We also demonstrate that our proxies enable tracing the frequency of trait-associated variants through time to evaluate the potential to apply polygenic prediction models to ancient individuals. Our database, called AncientProxy, enables easy identification of proxy variants genotyped in ancient humans for a modern variant of interest.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"120 2 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069904","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 : 2026-01-26DOI: 10.1016/j.ajhg.2025.12.016
Nicole Bertola, Eléonore Blondiaux, Madeleine Harion, Imen Dorboz, Sandrine Passemard, Sandra Mercier, Solène Conrad, Benjamin Cogné, Julie Boyer, Sophie Uyttebroeck, Kristof Van Schil, Wim Wuyts, Nanna Dahl Rendtorff, Mette Bertelsen, Kristianna Mey, Pierre Blanc, Jerome Champ, Odile Boespflug-Tanguy, Vincent Cantagrel, Lydie Burglen, Marion Coolen
ATOH1 encodes a basic helix-loop-helix transcription factor critical for hindbrain development and mechanosensory system formation. While animal models have provided extensive functional insights, few human disease-causing variants in ATOH1 have been reported and with no clear functional validation. Here, we report three heterozygous frameshift variants identified in five unrelated families, leading to C-ter truncations of ATOH1 and consistently associated with hearing loss, subtle motor impairments, and a highly recognizable pattern of brainstem malformations. Diffusion tensor imaging in two individuals further revealed reproducible anomalies in specific fiber tracts, supporting a convergent neuroanatomical signature. We also report an early-truncating variant, which, in contrast, is recessive and causes a distinct neurodevelopmental syndrome with highly severe cerebellar and pontine hypoplasia. Functional assays demonstrate that, unlike recessive variants, C-terminal truncating variants retain transcriptional activity but display increased protein stability. In vivo modeling using zebrafish showed that C-terminal truncations of atoh1a are sufficient to disrupt hindbrain neurogenesis and lateral-line hair cell specification. Furthermore, comparisons with loss-of-function phenotypes support a gain-of-function mechanism. Altogether, our findings establish that dominant and recessive ATOH1 variants give rise to different neurodevelopmental syndromes through distinct pathological mechanisms. Our work also underscores the importance of tight temporal control of transcription factor activity during hindbrain development and demonstrates how even subtle neurological phenotypes can arise from early disruption of core developmental programs.
{"title":"Dominant and recessive ATOH1 variants cause distinct neurodevelopmental disorders with hearing loss","authors":"Nicole Bertola, Eléonore Blondiaux, Madeleine Harion, Imen Dorboz, Sandrine Passemard, Sandra Mercier, Solène Conrad, Benjamin Cogné, Julie Boyer, Sophie Uyttebroeck, Kristof Van Schil, Wim Wuyts, Nanna Dahl Rendtorff, Mette Bertelsen, Kristianna Mey, Pierre Blanc, Jerome Champ, Odile Boespflug-Tanguy, Vincent Cantagrel, Lydie Burglen, Marion Coolen","doi":"10.1016/j.ajhg.2025.12.016","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.016","url":null,"abstract":"<ce:italic>ATOH1</ce:italic> encodes a basic helix-loop-helix transcription factor critical for hindbrain development and mechanosensory system formation. While animal models have provided extensive functional insights, few human disease-causing variants in <ce:italic>ATOH1</ce:italic> have been reported and with no clear functional validation. Here, we report three heterozygous frameshift variants identified in five unrelated families, leading to C-ter truncations of ATOH1 and consistently associated with hearing loss, subtle motor impairments, and a highly recognizable pattern of brainstem malformations. Diffusion tensor imaging in two individuals further revealed reproducible anomalies in specific fiber tracts, supporting a convergent neuroanatomical signature. We also report an early-truncating variant, which, in contrast, is recessive and causes a distinct neurodevelopmental syndrome with highly severe cerebellar and pontine hypoplasia. Functional assays demonstrate that, unlike recessive variants, C-terminal truncating variants retain transcriptional activity but display increased protein stability. <ce:italic>In vivo</ce:italic> modeling using zebrafish showed that C-terminal truncations of atoh1a are sufficient to disrupt hindbrain neurogenesis and lateral-line hair cell specification. Furthermore, comparisons with loss-of-function phenotypes support a gain-of-function mechanism. Altogether, our findings establish that dominant and recessive <ce:italic>ATOH1</ce:italic> variants give rise to different neurodevelopmental syndromes through distinct pathological mechanisms. Our work also underscores the importance of tight temporal control of transcription factor activity during hindbrain development and demonstrates how even subtle neurological phenotypes can arise from early disruption of core developmental programs.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"1 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047950","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 : 2026-01-21DOI: 10.1016/j.ajhg.2025.12.015
Heba Morsy, Hyeonho Kim, Gyubin Jang, Maha S. Zaki, Mariasavina Severino, Ibrahim M. Abdelrazek, Haytham Hussien, Eleanor Self, Raidah Saleem Albaradie, Khadijah Bakur, Zahra Firoozfar, Stephanie Efthymiou, Mahmoud M. Noureldeen, Amira Nabil, Javeria Raza Alvi, Fateme Molavi, Shahryar Alavi, Reza Alibakhshi, Vehap Topcu, Hanifenur Mancilar, Eyyup Uctepe, Ahmet Yesilyurt, Hesham Aldhalaan, Ehab Salah Showki Tous, Bader Alhaddad, Hasnaa M. Elbendary, Annarita Scardamaglia, David Murphy, Vicente A. Yépez, Julien Gagneur, Tarek I. Omar, Marwa Abd Elmaksoud, Jana Vandrovocova, Ebtessam Abdalla, Mary M. Reilly, Tipu Sultan, Fowzan S. Alkuraya, Joseph G. Gleeson, Ji Won Um, Henry Houlden, Jaewon Ko, Reza Maarofian
{"title":"MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy","authors":"Heba Morsy, Hyeonho Kim, Gyubin Jang, Maha S. Zaki, Mariasavina Severino, Ibrahim M. Abdelrazek, Haytham Hussien, Eleanor Self, Raidah Saleem Albaradie, Khadijah Bakur, Zahra Firoozfar, Stephanie Efthymiou, Mahmoud M. Noureldeen, Amira Nabil, Javeria Raza Alvi, Fateme Molavi, Shahryar Alavi, Reza Alibakhshi, Vehap Topcu, Hanifenur Mancilar, Eyyup Uctepe, Ahmet Yesilyurt, Hesham Aldhalaan, Ehab Salah Showki Tous, Bader Alhaddad, Hasnaa M. Elbendary, Annarita Scardamaglia, David Murphy, Vicente A. Yépez, Julien Gagneur, Tarek I. Omar, Marwa Abd Elmaksoud, Jana Vandrovocova, Ebtessam Abdalla, Mary M. Reilly, Tipu Sultan, Fowzan S. Alkuraya, Joseph G. Gleeson, Ji Won Um, Henry Houlden, Jaewon Ko, Reza Maarofian","doi":"10.1016/j.ajhg.2025.12.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.015","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"6 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014533","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 : 2026-01-21DOI: 10.1016/j.ajhg.2025.12.012
Abdulai I. Rashid, Nicole A. Rincon, Nathan Rihani, Jennifer K. Wagner
{"title":"Competition in human genetic technologies: The current US legal landscape","authors":"Abdulai I. Rashid, Nicole A. Rincon, Nathan Rihani, Jennifer K. Wagner","doi":"10.1016/j.ajhg.2025.12.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.012","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"1 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.ajhg.2025.12.014
Yanyu Liang, Festus Nyasimi, Hae Kyung Im
{"title":"A gene-specific variance-control approach corrects polygenicity-driven inflation observed in transcriptome-wide association studies","authors":"Yanyu Liang, Festus Nyasimi, Hae Kyung Im","doi":"10.1016/j.ajhg.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.014","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"63 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.ajhg.2025.12.011
Jesse M Levine,Daniel G Calame,Riccardo Sangermano,Haowei Du,Ahmed Saad,Jasmin Lisfeld,Tatjana Bierhals,Jonas Denecke,Eyyup Uctepe,Merve Yoldas Celik,Ahmet Yesilyurt,Hilal Yildiz Er,Elif Yilmaz Gulec,Aziza Mushiba,Naif Almontashiri,Pawel Gawlinski,Wojciech Wiszniewski,Ender Karaca,Lama Alabdi,Davut Pehlivan,Dana Marafi,Maha S Zaki,Fowzan S Alkuraya,Joseph G Gleeson,Shalini N Jhangiani,Richard A Gibbs,Jennifer E Posey,Kinga M Bujakowska,James R Lupski
ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2. We expand the clinical phenotypic descriptions of ASTN1-related NDDs, which range from mild to profound developmental delay or intellectual disability and can be associated with autism, attention-deficient hyperactivity disorder (ADHD), and epilepsy. Other recurrent abnormalities include dysmorphic facial features, hypotonia, spasticity, and ataxia. Additionally, we add to the neuroradiographic phenotype of this condition, which can be normal, mildly dysmorphic (a thin corpus callosum and cerebellar dysgenesis), or severely dysmorphic (polymicrogyria and lissencephaly). Remarkably, three genetic models of multilocus pathogenic variation (MPV), including tri-allelic, double heterozygous, and double homozygous due to distributive absence of heterozygosity (AOH), were observed. This ASTN1 allelic series characterizes the consequences of perturbations in radial-glia-guided neuronal migration in humans, the phenotypic spectrum of ASTN1-related NDDs, and the contribution of MPV to the genetic basis of NDDs.
{"title":"Bi-allelic variants in neuronal adhesion molecule astrotactin 1 gene ASTN1 cause diverse neurodevelopmental disorders.","authors":"Jesse M Levine,Daniel G Calame,Riccardo Sangermano,Haowei Du,Ahmed Saad,Jasmin Lisfeld,Tatjana Bierhals,Jonas Denecke,Eyyup Uctepe,Merve Yoldas Celik,Ahmet Yesilyurt,Hilal Yildiz Er,Elif Yilmaz Gulec,Aziza Mushiba,Naif Almontashiri,Pawel Gawlinski,Wojciech Wiszniewski,Ender Karaca,Lama Alabdi,Davut Pehlivan,Dana Marafi,Maha S Zaki,Fowzan S Alkuraya,Joseph G Gleeson,Shalini N Jhangiani,Richard A Gibbs,Jennifer E Posey,Kinga M Bujakowska,James R Lupski","doi":"10.1016/j.ajhg.2025.12.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.011","url":null,"abstract":"ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2. We expand the clinical phenotypic descriptions of ASTN1-related NDDs, which range from mild to profound developmental delay or intellectual disability and can be associated with autism, attention-deficient hyperactivity disorder (ADHD), and epilepsy. Other recurrent abnormalities include dysmorphic facial features, hypotonia, spasticity, and ataxia. Additionally, we add to the neuroradiographic phenotype of this condition, which can be normal, mildly dysmorphic (a thin corpus callosum and cerebellar dysgenesis), or severely dysmorphic (polymicrogyria and lissencephaly). Remarkably, three genetic models of multilocus pathogenic variation (MPV), including tri-allelic, double heterozygous, and double homozygous due to distributive absence of heterozygosity (AOH), were observed. This ASTN1 allelic series characterizes the consequences of perturbations in radial-glia-guided neuronal migration in humans, the phenotypic spectrum of ASTN1-related NDDs, and the contribution of MPV to the genetic basis of NDDs.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"36 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1016/j.ajhg.2025.12.008
Xinyu Yan, Amy L. Roberts, Julia S. El-Sayed Moustafa, Sergio Villicaña, Maryam Al-Hilal, Max Tomlinson, Cristina Menni, Thomas A.B. Sanders, Maxim B. Freidin, Jordana T. Bell, Kerrin S. Small
{"title":"Genetic regulation of fatty acid content in adipose tissue","authors":"Xinyu Yan, Amy L. Roberts, Julia S. El-Sayed Moustafa, Sergio Villicaña, Maryam Al-Hilal, Max Tomlinson, Cristina Menni, Thomas A.B. Sanders, Maxim B. Freidin, Jordana T. Bell, Kerrin S. Small","doi":"10.1016/j.ajhg.2025.12.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.008","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"46 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1016/j.ajhg.2026.01.005
Julie-Alexia Dias, Tony Chen, Hua Xing, Xiaoyu Wang, Alex A Rodriguez, Ravi K Madduri, Peter Kraft, Haoyu Zhang
{"title":"Evaluating multi-ancestry genome-wide association methods: Statistical power, population structure, and practical implications.","authors":"Julie-Alexia Dias, Tony Chen, Hua Xing, Xiaoyu Wang, Alex A Rodriguez, Ravi K Madduri, Peter Kraft, Haoyu Zhang","doi":"10.1016/j.ajhg.2026.01.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.01.005","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987731","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 : 2026-01-12DOI: 10.1016/j.ajhg.2025.12.007
Nataliya Di Donato, NMA Consortium, Andrew Thom, Andreas Rump, Johannes N. Greve, Juan Cadiñanos, Salvatore Calabro, Sara Cathey, Brian Chung, Heidi Cope, Maria Costales, Sara Cuvertino, Philine Dinkel, Kalliopi Erripi, Andrew E. Fry, Livia Garavelli, Sabine Hoffjan, Wibke G. Janzarik, Insa Kreimer, Grazia Mancini, Purificacion Marin-Reina, Andrea Meinhardt, Indra Niehaus, Daniela Pilz, Ivana Ricca, Fernando Santos Simarro, Evelin Schrock, Anja Marquardt, Manuel H. Taft, Kamer Tezcan, Sofia Thunström, Judith Verhagen, Alain Verloes, Bernd Wollnik, Peter Krawitz, Tzung-Chien Hsieh, Michael Seifert, Michael Heide, Catherine B. Lawrence, Neil A. Roberts, Dietmar J. Manstein, Adrian S. Woolf, Siddharth Banka
Recent advances in Mendelian genomics reveal the importance of variant-level characterization of allelic disorders. Non-muscle actin isoforms, encoded by the genes ACTB and ACTG1, are the most abundant intracellular proteins, but historically, they are often regarded as merely being “housekeeping” molecules. Here, we illuminate the extraordinary clinical heterogeneity and complex pathobiology of genetic non-muscle actinopathies. To do this, we combine human genomics studies with molecular biology. Strikingly, variants in ACTB and ACTG1 isoforms generate at least eight distinct clinical disorders. A subset of disease-associated missense variants causes dysregulated actin polymerization-depolymerization and neuronal migration defects. In contrast, nonsense, frameshift, and missense variants enhancing protein degradation cause milder phenotypes or are benign. These results emphasize the essential functional aspects of the non-muscle actin isoforms. Critically, they additionally constitute a template for the personalized genetic variant-level-driven management of the pleiotropic allelic single-gene disorders.
{"title":"Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies","authors":"Nataliya Di Donato, NMA Consortium, Andrew Thom, Andreas Rump, Johannes N. Greve, Juan Cadiñanos, Salvatore Calabro, Sara Cathey, Brian Chung, Heidi Cope, Maria Costales, Sara Cuvertino, Philine Dinkel, Kalliopi Erripi, Andrew E. Fry, Livia Garavelli, Sabine Hoffjan, Wibke G. Janzarik, Insa Kreimer, Grazia Mancini, Purificacion Marin-Reina, Andrea Meinhardt, Indra Niehaus, Daniela Pilz, Ivana Ricca, Fernando Santos Simarro, Evelin Schrock, Anja Marquardt, Manuel H. Taft, Kamer Tezcan, Sofia Thunström, Judith Verhagen, Alain Verloes, Bernd Wollnik, Peter Krawitz, Tzung-Chien Hsieh, Michael Seifert, Michael Heide, Catherine B. Lawrence, Neil A. Roberts, Dietmar J. Manstein, Adrian S. Woolf, Siddharth Banka","doi":"10.1016/j.ajhg.2025.12.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.007","url":null,"abstract":"Recent advances in Mendelian genomics reveal the importance of variant-level characterization of allelic disorders. Non-muscle actin isoforms, encoded by the genes <ce:italic>ACTB</ce:italic> and <ce:italic>ACTG1</ce:italic>, are the most abundant intracellular proteins, but historically, they are often regarded as merely being “housekeeping” molecules. Here, we illuminate the extraordinary clinical heterogeneity and complex pathobiology of genetic non-muscle actinopathies. To do this, we combine human genomics studies with molecular biology. Strikingly, variants in <ce:italic>ACTB</ce:italic> and <ce:italic>ACTG1</ce:italic> isoforms generate at least eight distinct clinical disorders. A subset of disease-associated missense variants causes dysregulated actin polymerization-depolymerization and neuronal migration defects. In contrast, nonsense, frameshift, and missense variants enhancing protein degradation cause milder phenotypes or are benign. These results emphasize the essential functional aspects of the non-muscle actin isoforms. Critically, they additionally constitute a template for the personalized genetic variant-level-driven management of the pleiotropic allelic single-gene disorders.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"259 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human height is a complex trait regulated by genetic and environmental factors. Several components of chondrocyte proliferation and differentiation regulatory pathways are implicated in short-stature disorders; one such component is natriuretic peptide receptor 2 (NPR2), the receptor for C-type natriuretic peptide. We developed a high-throughput GFP reporter assay to evaluate the functional impact of NPR2 missense variants on receptor activity, which was utilized alongside a commercially available CatchPoint assay, and previously published data. Measurements from these sources were integrated and annotated, providing an "activity score" for each variant, based on reduced or increased receptor activity. Unlike variant effect prediction tools that assign scores from benign to pathogenic, our method enabled us to distinguish loss-of-function and gain-of-function variants, categorizing 245 NPR2 missense variants, including 47 loss-of-function, 34 partial loss-of-function, and 14 gain-of-function variants, across the functional domains of NPR2. Activity scores showed a near-linear association with standing height (Pearson's correlation R2 = 0.438, p = 5.8 × 10-10), with the effects additive and apparent across polygenic backgrounds. Moreover, phenome-wide association analysis demonstrated that NPR2 activity was significantly associated only with height and height-associated traits, suggesting that modulating NPR2 activity may modulate height only. To summarize, the relationship between NPR2 activity and height resembles a dimmer switch, whereby subtle variations in activity cause subtle variations in height. We demonstrate the therapeutic potential of modulating NPR2 activity in short-stature conditions, owing to both its strong association with height and its lack of association with traits unrelated to height.
人类身高是一个复杂的性状，受遗传和环境因素的影响。软骨细胞增殖和分化调控途径的几个组成部分与矮小障碍有关；其中一种成分是利钠肽受体2 (NPR2)，即c型利钠肽的受体。我们开发了一种高通量GFP报告基因检测方法来评估NPR2错义变异体对受体活性的功能影响，该方法与市售的CatchPoint检测方法和先前发表的数据一起使用。对这些来源的测量结果进行整合和注释，根据受体活性的降低或增加，为每个变体提供“活性评分”。与将评分从良性到致病性的变异效应预测工具不同，我们的方法使我们能够区分功能丧失和功能获得变异，对245个NPR2错义变异进行分类，包括47个功能丧失，34个部分功能丧失和14个功能获得变异，横跨NPR2的功能域。活动得分与站立高度呈近似线性相关（Pearson相关系数R2 = 0.438, p = 5.8 × 10-10），且在多基因背景下具有可加性和显著性。此外，全表型关联分析表明，NPR2活性仅与身高和身高相关性状显著相关，表明调节NPR2活性可能仅调节身高。总而言之，NPR2活动与身高之间的关系类似于一个调光开关，因此活动的细微变化会导致身高的细微变化。我们证明了调节NPR2活性在矮个子条件下的治疗潜力，因为它与身高有很强的相关性，而与身高无关的特征缺乏相关性。
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