Pub Date : 2025-09-23DOI: 10.1016/j.ajhg.2025.08.012
Austin W Reynolds,Haiko Schurz,Gillian Meeks,Simon Gravel,Justin W Myrick,Stacy Edington,Fernando L Mendez,Cedric J Werely,Paul D van Helden,Eileen G Hoal,G David Poznik,Minju Kim,Caitlin Uren,Peter A Underhill,Marlo Möller,Brenna M Henn
The colonial-period arrival of Europeans in southern Africa is associated with strong sex-biased migration by which male settlers displaced Indigenous Khoekhoe and San men. Concurrently, the importation of enslaved individuals from South Asia, Indonesia, and eastern Africa likely contributed to female-biased migration. Using genetic data from over 1,400 individuals, we examine the spatial and temporal spread of sex-biased migration from the Cape to the northern edges of the historic colonial frontier. In all regions, admixture patterns were sex biased, with evidence of a greater male contribution of European ancestry and greater female contribution of Khoe-San ancestry. While admixture among Khoe-San, European, equatorial African, and Asian groups has likely been continuous from the founding of Cape Town to the present day, we find that Khoe-San groups further north experienced a single pulse of European admixture 6-8 generations ago. European admixture was followed by additional Khoe-San gene flow, potentially reflecting an aggregation of Indigenous groups due to disruption by colonial interlopers. Male migration into the northern frontier territories was not a homogenous group of expanding Afrikaners and slaves. The Nama exhibit distinct founder effects and derive 15% of their Y chromosome haplogroups from Asian lineages, a pattern absent in the ≠Khomani San. Khoe-San ancestry from the paternal line is greatly diminished in populations from Cape Town, the Cederberg Mountains, and Upington but remains more frequent in self-identified Indigenous ethnic groups. Strikingly, we estimate that Khoe-San Y chromosomes were experiencing unprecedented population growth at the time of European arrival. Our findings shed light on the patterns of admixture and population history of South Africa as the colonial frontier expanded.
{"title":"The Indian Ocean slave trade and colonial expansion resulted in strong sex-biased admixture in South Africa.","authors":"Austin W Reynolds,Haiko Schurz,Gillian Meeks,Simon Gravel,Justin W Myrick,Stacy Edington,Fernando L Mendez,Cedric J Werely,Paul D van Helden,Eileen G Hoal,G David Poznik,Minju Kim,Caitlin Uren,Peter A Underhill,Marlo Möller,Brenna M Henn","doi":"10.1016/j.ajhg.2025.08.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.08.012","url":null,"abstract":"The colonial-period arrival of Europeans in southern Africa is associated with strong sex-biased migration by which male settlers displaced Indigenous Khoekhoe and San men. Concurrently, the importation of enslaved individuals from South Asia, Indonesia, and eastern Africa likely contributed to female-biased migration. Using genetic data from over 1,400 individuals, we examine the spatial and temporal spread of sex-biased migration from the Cape to the northern edges of the historic colonial frontier. In all regions, admixture patterns were sex biased, with evidence of a greater male contribution of European ancestry and greater female contribution of Khoe-San ancestry. While admixture among Khoe-San, European, equatorial African, and Asian groups has likely been continuous from the founding of Cape Town to the present day, we find that Khoe-San groups further north experienced a single pulse of European admixture 6-8 generations ago. European admixture was followed by additional Khoe-San gene flow, potentially reflecting an aggregation of Indigenous groups due to disruption by colonial interlopers. Male migration into the northern frontier territories was not a homogenous group of expanding Afrikaners and slaves. The Nama exhibit distinct founder effects and derive 15% of their Y chromosome haplogroups from Asian lineages, a pattern absent in the ≠Khomani San. Khoe-San ancestry from the paternal line is greatly diminished in populations from Cape Town, the Cederberg Mountains, and Upington but remains more frequent in self-identified Indigenous ethnic groups. Strikingly, we estimate that Khoe-San Y chromosomes were experiencing unprecedented population growth at the time of European arrival. Our findings shed light on the patterns of admixture and population history of South Africa as the colonial frontier expanded.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"28 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134341","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 : 2025-09-23DOI: 10.1016/j.ajhg.2025.09.003
Emma P Wilson,K Alaine Broadaway,Victoria A Parsons,Swarooparani Vadlamudi,Narisu Narisu,Sarah M Brotman,Kevin W Currin,Heather M Stringham,Michael R Erdos,Ryan Welch,Jeffrey K Holtzman,Timo A Lakka,Markku Laakso,Jaakko Tuomilehto,Michael Boehnke,Heikki A Koistinen,Francis S Collins,Stephen C J Parker,Laura J Scott,Karen L Mohlke
Identifying genetic variants that regulate gene expression can help uncover mechanisms underlying complex traits. We performed a meta-analysis of skeletal muscle expression quantitative trait locus (eQTL) using data from 1,002 individuals from two studies. A stepwise analysis identified 18,818 conditionally distinct signals for 12,283 genes, and 35% of these genes contained two or more signals. Colocalization of these eQTL signals with 26 muscular and cardiometabolic trait genome-wide association studies (GWASs) identified 2,252 GWAS-eQTL colocalizations that nominated 1,342 candidate genes. Notably, 22% of the GWAS-eQTL colocalizations involved non-primary eQTL signals. Additionally, 37% of the colocalized GWAS-eQTL signals corresponded to the closest protein-coding gene, while 44% were located >50 kb from the transcription start site of the nominated gene. To assess tissue specificity for a heterogeneous trait, we compared colocalizations with type 2 diabetes (T2D) signals across muscle, adipose, liver, and islet eQTLs; we identified 551 candidate genes for 309 T2D signals representing 36% of T2D signals tested and over 100 more than were detected with any one tissue alone. We then functionally validated the allelic regulatory effect of an eQTL variant for INHBB linked to T2D in both muscle and adipose tissue. Together, these results further demonstrate the value of skeletal muscle eQTLs in elucidating mechanisms underlying complex traits.
{"title":"Skeletal muscle eQTL meta-analysis implicates genes in the genetic architecture of muscular and cardiometabolic traits.","authors":"Emma P Wilson,K Alaine Broadaway,Victoria A Parsons,Swarooparani Vadlamudi,Narisu Narisu,Sarah M Brotman,Kevin W Currin,Heather M Stringham,Michael R Erdos,Ryan Welch,Jeffrey K Holtzman,Timo A Lakka,Markku Laakso,Jaakko Tuomilehto,Michael Boehnke,Heikki A Koistinen,Francis S Collins,Stephen C J Parker,Laura J Scott,Karen L Mohlke","doi":"10.1016/j.ajhg.2025.09.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.09.003","url":null,"abstract":"Identifying genetic variants that regulate gene expression can help uncover mechanisms underlying complex traits. We performed a meta-analysis of skeletal muscle expression quantitative trait locus (eQTL) using data from 1,002 individuals from two studies. A stepwise analysis identified 18,818 conditionally distinct signals for 12,283 genes, and 35% of these genes contained two or more signals. Colocalization of these eQTL signals with 26 muscular and cardiometabolic trait genome-wide association studies (GWASs) identified 2,252 GWAS-eQTL colocalizations that nominated 1,342 candidate genes. Notably, 22% of the GWAS-eQTL colocalizations involved non-primary eQTL signals. Additionally, 37% of the colocalized GWAS-eQTL signals corresponded to the closest protein-coding gene, while 44% were located >50 kb from the transcription start site of the nominated gene. To assess tissue specificity for a heterogeneous trait, we compared colocalizations with type 2 diabetes (T2D) signals across muscle, adipose, liver, and islet eQTLs; we identified 551 candidate genes for 309 T2D signals representing 36% of T2D signals tested and over 100 more than were detected with any one tissue alone. We then functionally validated the allelic regulatory effect of an eQTL variant for INHBB linked to T2D in both muscle and adipose tissue. Together, these results further demonstrate the value of skeletal muscle eQTLs in elucidating mechanisms underlying complex traits.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"13 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134391","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 : 2025-09-22DOI: 10.1016/j.ajhg.2025.09.001
Johnny Bou-Rouphael,Auriane Cospain,Thomas Courtin,Boris Keren,Corentine Marie,Marion Lesieur-Sebellin,Delphine Heron,Jean-Madeleine de Sainte Agathe,Solveig Heide,Elodie Lejeune,Chloe Quelin,François Lecoquierre,Mathilde Nizon,Bertrand Isidor,Thomas Besnard,Benjamin Cogne,Xenia Latypova,Jonathan Levy,Pascal Joset,Katharina Steindl,Maria Palomares-Bralo,Fernando Santos-Simarro,Mary Ann Thomas,Amina Abubakar,Sally Ann Lynch,Amelie J Müller,Tobias B Haack,Martin Zenker,Michael Parker,Emma Clossick,Michael Spiller,Renarta Crookes,Muriel Holder-Espinasse,Allan Bayat,Rikke S Møller,Tomasz Stanislaw Mieszczanek,Pierre de la Grange,Julien Buratti,Pierre Marijon,Sabir Ataf,Ryan Gavin,Carlos Parras,Bassem A Hassan,Cyril Mignot,Laïla El Khattabi
Alternative splicing is highly prevalent in the brain where it orchestrates key processes such as neurogenesis and synaptogenesis, both essential for the nervous system's complexity and plasticity. Dysregulation of splicing has increasingly been linked to neurodevelopmental disorders. Here, we describe unrelated individuals carrying de novo, likely deleterious heterozygous variants in Splicing Factor 1 (SF1), all presenting with neurodevelopmental disorders of variable severity, frequently accompanied by autistic traits and other non-specific features. SF1 is a core component of pre-mRNA processing, facilitating early spliceosome assembly at the 3' splice site and regulating alternative splicing. We conducted functional studies in neural progenitor cells, which showed that SF1 downregulation alters gene expression and alternative splicing programs, particularly in genes involved in neuronal differentiation, synaptic transmission, and axonal guidance, processes fundamental to brain development. Together, these findings establish SF1 dysfunction as an additional spliceosomopathy contributing to neurodevelopmental disorders and underscore its essential role in human neurodevelopment and disease.
{"title":"Heterozygous pathogenic variants in the splicing factor SF1 lead to a large spectrum of neurodevelopmental disorders.","authors":"Johnny Bou-Rouphael,Auriane Cospain,Thomas Courtin,Boris Keren,Corentine Marie,Marion Lesieur-Sebellin,Delphine Heron,Jean-Madeleine de Sainte Agathe,Solveig Heide,Elodie Lejeune,Chloe Quelin,François Lecoquierre,Mathilde Nizon,Bertrand Isidor,Thomas Besnard,Benjamin Cogne,Xenia Latypova,Jonathan Levy,Pascal Joset,Katharina Steindl,Maria Palomares-Bralo,Fernando Santos-Simarro,Mary Ann Thomas,Amina Abubakar,Sally Ann Lynch,Amelie J Müller,Tobias B Haack,Martin Zenker,Michael Parker,Emma Clossick,Michael Spiller,Renarta Crookes,Muriel Holder-Espinasse,Allan Bayat,Rikke S Møller,Tomasz Stanislaw Mieszczanek,Pierre de la Grange,Julien Buratti,Pierre Marijon,Sabir Ataf,Ryan Gavin,Carlos Parras,Bassem A Hassan,Cyril Mignot,Laïla El Khattabi","doi":"10.1016/j.ajhg.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.09.001","url":null,"abstract":"Alternative splicing is highly prevalent in the brain where it orchestrates key processes such as neurogenesis and synaptogenesis, both essential for the nervous system's complexity and plasticity. Dysregulation of splicing has increasingly been linked to neurodevelopmental disorders. Here, we describe unrelated individuals carrying de novo, likely deleterious heterozygous variants in Splicing Factor 1 (SF1), all presenting with neurodevelopmental disorders of variable severity, frequently accompanied by autistic traits and other non-specific features. SF1 is a core component of pre-mRNA processing, facilitating early spliceosome assembly at the 3' splice site and regulating alternative splicing. We conducted functional studies in neural progenitor cells, which showed that SF1 downregulation alters gene expression and alternative splicing programs, particularly in genes involved in neuronal differentiation, synaptic transmission, and axonal guidance, processes fundamental to brain development. Together, these findings establish SF1 dysfunction as an additional spliceosomopathy contributing to neurodevelopmental disorders and underscore its essential role in human neurodevelopment and disease.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"2 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127151","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}
Allele-specific silencing by RNA interference offers a promising therapeutic approach for dominant inherited diseases through specific silencing of the mRNA produced by the mutated allele. Here, we report the development of such a strategy for Schuurs-Hoeijmakers syndrome (SHMS), a rare neurodevelopmental disorder characterized by intellectual disability, abnormal craniofacial features, and congenital malformations without available treatment. Most cases of SHMS are caused by a recurrent de novo heterozygous missense mutation (c.607C>T [p.Arg203Trp]) in the PACS1 gene, which encodes PACS1 (phosphofurin acid cluster sorting 1), a multifunctional sorting protein. Through an in vitro screening of fibroblasts derived from affected individuals, we identified several small interfering RNA (siRNA) sequences that specifically silence the PACS1 transcript harboring the recurrent PACS1 mutation while sparing the wild-type mRNA. Furthermore, transcriptomic analysis of SHMS fibroblasts revealed alterations in extracellular matrix organization in mutant cells, including elevated COL8A1 expression and extracellular deposition. Treatment with the best selected allele-specific siRNA corrected the COL8A1 dysregulation. Altogether, this study provides the proof of concept of allele-specific RNA interference therapeutic for SHMS in cells derived from affected individuals and highlights a pathophysiological mechanism involving extracellular matrix dysfunction in this disorder. These results strengthen the allele-specific silencing approach as a robust, safe, and efficient therapy for dominant inherited diseases.
{"title":"Allele-specific RNAi therapy corrects an extracellular matrix defect in Schuurs-Hoeijmakers syndrome.","authors":"Lylia Mekzine,Natalia Pinzón,Kamel Mamchaoui,Maria Kondili,Bruno Cadot,Marc Bitoun,Delphine Trochet","doi":"10.1016/j.ajhg.2025.07.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.07.010","url":null,"abstract":"Allele-specific silencing by RNA interference offers a promising therapeutic approach for dominant inherited diseases through specific silencing of the mRNA produced by the mutated allele. Here, we report the development of such a strategy for Schuurs-Hoeijmakers syndrome (SHMS), a rare neurodevelopmental disorder characterized by intellectual disability, abnormal craniofacial features, and congenital malformations without available treatment. Most cases of SHMS are caused by a recurrent de novo heterozygous missense mutation (c.607C>T [p.Arg203Trp]) in the PACS1 gene, which encodes PACS1 (phosphofurin acid cluster sorting 1), a multifunctional sorting protein. Through an in vitro screening of fibroblasts derived from affected individuals, we identified several small interfering RNA (siRNA) sequences that specifically silence the PACS1 transcript harboring the recurrent PACS1 mutation while sparing the wild-type mRNA. Furthermore, transcriptomic analysis of SHMS fibroblasts revealed alterations in extracellular matrix organization in mutant cells, including elevated COL8A1 expression and extracellular deposition. Treatment with the best selected allele-specific siRNA corrected the COL8A1 dysregulation. Altogether, this study provides the proof of concept of allele-specific RNA interference therapeutic for SHMS in cells derived from affected individuals and highlights a pathophysiological mechanism involving extracellular matrix dysfunction in this disorder. These results strengthen the allele-specific silencing approach as a robust, safe, and efficient therapy for dominant inherited diseases.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"6 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089909","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}
Genomic sequencing is essential for both biomedical research and clinical practice. While single-cell RNA sequencing (scRNA-seq) provides insights into biological processes at the cellular level, bulk RNA sequencing remains widely used for its scalability and cost-effectiveness. To explore biological heterogeneity, research efforts have been made toward inferring single-cell-like cellular compositions from bulk samples, i.e., deconvolving bulk samples into multiple cell types. However, existing deconvolution methods face two major limitations: (1) reliance on predefined gene signature matrices without accounting for inter-sample variability and (2) susceptibility to noise within biological systems. Here, we propose a cellular-component analysis (CCA) framework by leveraging a genomic-interaction-encoded image representation of RNA-seq data for substantially improved pattern discovery. The framework incorporates sample-specific gene-expression variability and derives signature patterns by utilizing a convolutional variational autoencoder and Gaussian mixture model. An image-domain linear decomposition of bulk RNA-seq data based on these sample-specific, interpretable gene-signature patterns is then performed for CCA and other downstream tasks, such as cancer subtype classification and biomarker discovery. We demonstrate that the proposed technique improves decomposition accuracy by over 14.1% in average Pearson correlation compared to existing techniques by using both simulation and experimental datasets. This approach offers an effective solution for tissue heterogeneity analysis and lays a foundation for a range of clinical and biological applications.
{"title":"Unveiling tissue heterogeneity through genomic interaction-encoded image representation of RNA-sequencing data.","authors":"Junyan Liu,Zixia Zhou,Yizheng Chen,Md Tauhidul Islam,Lei Xing","doi":"10.1016/j.ajhg.2025.08.021","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.08.021","url":null,"abstract":"Genomic sequencing is essential for both biomedical research and clinical practice. While single-cell RNA sequencing (scRNA-seq) provides insights into biological processes at the cellular level, bulk RNA sequencing remains widely used for its scalability and cost-effectiveness. To explore biological heterogeneity, research efforts have been made toward inferring single-cell-like cellular compositions from bulk samples, i.e., deconvolving bulk samples into multiple cell types. However, existing deconvolution methods face two major limitations: (1) reliance on predefined gene signature matrices without accounting for inter-sample variability and (2) susceptibility to noise within biological systems. Here, we propose a cellular-component analysis (CCA) framework by leveraging a genomic-interaction-encoded image representation of RNA-seq data for substantially improved pattern discovery. The framework incorporates sample-specific gene-expression variability and derives signature patterns by utilizing a convolutional variational autoencoder and Gaussian mixture model. An image-domain linear decomposition of bulk RNA-seq data based on these sample-specific, interpretable gene-signature patterns is then performed for CCA and other downstream tasks, such as cancer subtype classification and biomarker discovery. We demonstrate that the proposed technique improves decomposition accuracy by over 14.1% in average Pearson correlation compared to existing techniques by using both simulation and experimental datasets. This approach offers an effective solution for tissue heterogeneity analysis and lays a foundation for a range of clinical and biological applications.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"17 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083354","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 : 2025-09-09DOI: 10.1016/j.ajhg.2025.08.015
Hammad Yousaf,Maayke A de Koning,Kamal Khan,Kelly L Gilmore,Mariëtte J V Hoffer,Georgios Kellaris,Sophie Lanone,Maylis Dagouassat,Farid Ullah,Phebe N Adama van Scheltema,Delphine Heron,Yline Capri,Alma Kuechler,Bernd Schweiger,Monique C Haak,Boris Keren,Frederic Tran Mau Them,Cacha M P C D Peeters-Scholte,Frank J Kaiser,Tamara T Koopmann,Hailiang Mei,Binnaz Yalcin,Christel Depienne,Neeta L Vora,Gijs W E Santen,Erica E Davis
Fetal brain anomalies identified by prenatal ultrasound and/or magnetic resonance imaging represent a considerable healthcare burden with ∼1-2/1,000 live births. To identify the underlying etiology, trio prenatal exome sequencing or genome sequencing (ES/GS) has emerged as a comprehensive diagnostic paradigm with a reported diagnostic rate up to ∼32%. Here, we report five unrelated families with six affected individuals that presented neuroanatomical, craniofacial, and skeletal anomalies, all harboring rare, bi-allelic deleterious variants in SNAPIN, which encodes SNARE-associated protein. SNAPIN is a ubiquitously expressed component of the autophagy-lysosomal pathway that catalyzes retrograde axonal transport and synaptic transmission. To investigate the role of SNAPIN in brain development, we generated zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes. Two independent, genetically stable snapin mutants exhibited pre-adulthood lethality, reduced overall length, disproportionately smaller head size, and altered brain morphology. Transcriptomic profiling of snapin mutant zebrafish heads revealed an early and progressive transcriptomic shift marked by autophagy activation with concomitant downregulation of structural and neurodevelopmental genes. Assessment of brain cellular ultrastructure with electron microscopy and light chain 3 (LC3)-II immunoblotting revealed retrograde vesicle transport defects, with an accumulation of late endosomes and autophagosomes. Together, these findings support bi-allelic pathogenic variants in SNAPIN as a likely cause for a severe neurodevelopmental syndrome and expand the growing list of autophagy-lysosome pathway regulators essential for human brain development.
{"title":"Bi-allelic deleterious variants in SNAPIN, which encodes a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder.","authors":"Hammad Yousaf,Maayke A de Koning,Kamal Khan,Kelly L Gilmore,Mariëtte J V Hoffer,Georgios Kellaris,Sophie Lanone,Maylis Dagouassat,Farid Ullah,Phebe N Adama van Scheltema,Delphine Heron,Yline Capri,Alma Kuechler,Bernd Schweiger,Monique C Haak,Boris Keren,Frederic Tran Mau Them,Cacha M P C D Peeters-Scholte,Frank J Kaiser,Tamara T Koopmann,Hailiang Mei,Binnaz Yalcin,Christel Depienne,Neeta L Vora,Gijs W E Santen,Erica E Davis","doi":"10.1016/j.ajhg.2025.08.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.08.015","url":null,"abstract":"Fetal brain anomalies identified by prenatal ultrasound and/or magnetic resonance imaging represent a considerable healthcare burden with ∼1-2/1,000 live births. To identify the underlying etiology, trio prenatal exome sequencing or genome sequencing (ES/GS) has emerged as a comprehensive diagnostic paradigm with a reported diagnostic rate up to ∼32%. Here, we report five unrelated families with six affected individuals that presented neuroanatomical, craniofacial, and skeletal anomalies, all harboring rare, bi-allelic deleterious variants in SNAPIN, which encodes SNARE-associated protein. SNAPIN is a ubiquitously expressed component of the autophagy-lysosomal pathway that catalyzes retrograde axonal transport and synaptic transmission. To investigate the role of SNAPIN in brain development, we generated zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes. Two independent, genetically stable snapin mutants exhibited pre-adulthood lethality, reduced overall length, disproportionately smaller head size, and altered brain morphology. Transcriptomic profiling of snapin mutant zebrafish heads revealed an early and progressive transcriptomic shift marked by autophagy activation with concomitant downregulation of structural and neurodevelopmental genes. Assessment of brain cellular ultrastructure with electron microscopy and light chain 3 (LC3)-II immunoblotting revealed retrograde vesicle transport defects, with an accumulation of late endosomes and autophagosomes. Together, these findings support bi-allelic pathogenic variants in SNAPIN as a likely cause for a severe neurodevelopmental syndrome and expand the growing list of autophagy-lysosome pathway regulators essential for human brain development.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"12 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031927","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 : 2025-09-08DOI: 10.1016/j.ajhg.2025.08.014
Charlie F Rowlands,Sophie Allen,Alice Garrett,Miranda Durkie,George J Burghel,Rachel Robinson,Alison Callaway,Joanne Field,Bethan Frugtniet,Sheila Palmer-Smith,Jonathan Grant,Judith Pagan,Trudi McDevitt,Katie Snape,Helen Hanson,Terri McVeigh,Clare Turnbull,
Multiplex assays of variant effect (MAVEs) provide promising new sources of functional evidence, potentially empowering improved classification of germline genomic variants, particularly rare missense variants, which are commonly assigned as variants of uncertain significance (VUSs). However, paradoxically, quantification of clinically applicable evidence strengths for MAVEs requires construction of "truthsets" comprising missense variants already robustly classified as pathogenic and benign. In this study, we demonstrate how benign truthset size is the primary driver of applicable functional evidence toward pathogenicity (PS3). We demonstrate, when using existing ClinVar classifications as a source of benign missense truthset variants, that only 19.8% (23/116) of established cancer susceptibility genes had a PS3 evidence strength of "strong" attainable when simulating validation for a hypothetical new MAVE (also applying favorable assumption of perfect concordance). We describe a systematic framework for benign truthset construction in which all possible missense variants in a gene of interest are concurrently assessed for assignation of (likely) benignity via established ACMG/AMP combination rules, including population frequency, in silico evidence codes, and case-control signal. We apply this framework to eight hereditary breast and ovarian cancer genes, demonstrating that systematically generated benign missense truthsets allow maximum application of PS3 at greater (or equivalent) strength-reaching "moderate" for CHEK2 and "strong" for the other seven genes-than those derived from ClinVar ≥2∗ classifications alone. We propose, given many genes have few existing benign-classified missense variants, that the application of this systematic framework to disease genes more broadly will be important for leveraging full value from MAVEs.
{"title":"Availability of benign missense variant \"truthsets\" for validation of functional assays: Current status and a systematic approach.","authors":"Charlie F Rowlands,Sophie Allen,Alice Garrett,Miranda Durkie,George J Burghel,Rachel Robinson,Alison Callaway,Joanne Field,Bethan Frugtniet,Sheila Palmer-Smith,Jonathan Grant,Judith Pagan,Trudi McDevitt,Katie Snape,Helen Hanson,Terri McVeigh,Clare Turnbull, ","doi":"10.1016/j.ajhg.2025.08.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.08.014","url":null,"abstract":"Multiplex assays of variant effect (MAVEs) provide promising new sources of functional evidence, potentially empowering improved classification of germline genomic variants, particularly rare missense variants, which are commonly assigned as variants of uncertain significance (VUSs). However, paradoxically, quantification of clinically applicable evidence strengths for MAVEs requires construction of \"truthsets\" comprising missense variants already robustly classified as pathogenic and benign. In this study, we demonstrate how benign truthset size is the primary driver of applicable functional evidence toward pathogenicity (PS3). We demonstrate, when using existing ClinVar classifications as a source of benign missense truthset variants, that only 19.8% (23/116) of established cancer susceptibility genes had a PS3 evidence strength of \"strong\" attainable when simulating validation for a hypothetical new MAVE (also applying favorable assumption of perfect concordance). We describe a systematic framework for benign truthset construction in which all possible missense variants in a gene of interest are concurrently assessed for assignation of (likely) benignity via established ACMG/AMP combination rules, including population frequency, in silico evidence codes, and case-control signal. We apply this framework to eight hereditary breast and ovarian cancer genes, demonstrating that systematically generated benign missense truthsets allow maximum application of PS3 at greater (or equivalent) strength-reaching \"moderate\" for CHEK2 and \"strong\" for the other seven genes-than those derived from ClinVar ≥2∗ classifications alone. We propose, given many genes have few existing benign-classified missense variants, that the application of this systematic framework to disease genes more broadly will be important for leveraging full value from MAVEs.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"72 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025701","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 : 2025-09-04Epub Date: 2025-08-11DOI: 10.1016/j.ajhg.2025.08.001
Pomme M F Rigter, Charlotte de Konink, Matthew J Dunn, Martina Proietti Onori, Jennifer B Humberson, Matthew Thomas, Caitlin Barnes, Carlos E Prada, K Nicole Weaver, Thomas D Ryan, Oana Caluseriu, Jennifer Conway, Emily Calamaro, Chin-To Fong, Wim Wuyts, Marije Meuwissen, Eva Hordijk, Carsten N Jonkers, Lucas Anderson, Berfin Yuseinova, Sarah Polonia, Diane Beysen, Zornitza Stark, Elena Savva, Cathryn Poulton, Fiona McKenzie, Elizabeth Bhoj, Caleb P Bupp, Stéphane Bézieau, Sandra Mercier, Amy Blevins, Ingrid M Wentzensen, Fan Xia, Jill A Rosenfeld, Tzung-Chien Hsieh, Peter M Krawitz, Miriam Elbracht, Danielle C M Veenma, Howard Schulman, Margaret M Stratton, Sébastien Küry, Geeske M van Woerden
{"title":"Role of CAMK2D in neurodevelopment and associated conditions.","authors":"Pomme M F Rigter, Charlotte de Konink, Matthew J Dunn, Martina Proietti Onori, Jennifer B Humberson, Matthew Thomas, Caitlin Barnes, Carlos E Prada, K Nicole Weaver, Thomas D Ryan, Oana Caluseriu, Jennifer Conway, Emily Calamaro, Chin-To Fong, Wim Wuyts, Marije Meuwissen, Eva Hordijk, Carsten N Jonkers, Lucas Anderson, Berfin Yuseinova, Sarah Polonia, Diane Beysen, Zornitza Stark, Elena Savva, Cathryn Poulton, Fiona McKenzie, Elizabeth Bhoj, Caleb P Bupp, Stéphane Bézieau, Sandra Mercier, Amy Blevins, Ingrid M Wentzensen, Fan Xia, Jill A Rosenfeld, Tzung-Chien Hsieh, Peter M Krawitz, Miriam Elbracht, Danielle C M Veenma, Howard Schulman, Margaret M Stratton, Sébastien Küry, Geeske M van Woerden","doi":"10.1016/j.ajhg.2025.08.001","DOIUrl":"10.1016/j.ajhg.2025.08.001","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2247"},"PeriodicalIF":8.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833735","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 : 2025-09-04Epub Date: 2025-07-29DOI: 10.1016/j.ajhg.2025.07.005
Shelby L Hemker, Ashley Marsh, Felicia Hernandez, Elena Glick, Grace Clark, Alyssa Bashir, Krystal Jiang, Jacob O Kitzman
Variants of uncertain significance (VUSs) limit the actionability of genetic testing. A prominent example is MUTYH, a DNA repair factor underlying colorectal cancer with a pathogenic variant carrier rate of ∼1:50. To systematically interrogate MUTYH variant function, we coupled deep mutational scanning to DNA repair reporters containing its lesion substrate, 8OG:A. Our variant-to-function map covers 96.6% of possible MUTYH point variants (n = 10,941) and achieves 100% accuracy on known clinical variants (n = 247). Leveraging a large clinical registry, we observe significant associations with colorectal polyps and cancer, with more severely impaired missense variants conferring greater risk. We recapitulate functional differences between pathogenic founder alleles and highlight sites of complete missense intolerance, including residues that intercalate DNA and coordinate essential Zn2+ or Fe-S clusters. This map provides a resource to resolve the >1,100 existing missense VUSs in MUTYH and demonstrates a scalable strategy to interrogate other clinically relevant DNA repair factors.
{"title":"Saturation mapping of MUTYH variant effects using DNA repair reporters.","authors":"Shelby L Hemker, Ashley Marsh, Felicia Hernandez, Elena Glick, Grace Clark, Alyssa Bashir, Krystal Jiang, Jacob O Kitzman","doi":"10.1016/j.ajhg.2025.07.005","DOIUrl":"10.1016/j.ajhg.2025.07.005","url":null,"abstract":"<p><p>Variants of uncertain significance (VUSs) limit the actionability of genetic testing. A prominent example is MUTYH, a DNA repair factor underlying colorectal cancer with a pathogenic variant carrier rate of ∼1:50. To systematically interrogate MUTYH variant function, we coupled deep mutational scanning to DNA repair reporters containing its lesion substrate, 8OG:A. Our variant-to-function map covers 96.6% of possible MUTYH point variants (n = 10,941) and achieves 100% accuracy on known clinical variants (n = 247). Leveraging a large clinical registry, we observe significant associations with colorectal polyps and cancer, with more severely impaired missense variants conferring greater risk. We recapitulate functional differences between pathogenic founder alleles and highlight sites of complete missense intolerance, including residues that intercalate DNA and coordinate essential Zn<sup>2+</sup> or Fe-S clusters. This map provides a resource to resolve the >1,100 existing missense VUSs in MUTYH and demonstrates a scalable strategy to interrogate other clinically relevant DNA repair factors.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2010-2026"},"PeriodicalIF":8.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752062","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 : 2025-09-04Epub Date: 2025-07-29DOI: 10.1016/j.ajhg.2025.07.004
Julian Stamp, Samuel Pattillo Smith, Daniel Weinreich, Lorin Crawford
The lack of computational methods capable of detecting epistasis in biobanks has led to uncertainty about the role of non-additive genetic effects on complex trait variation. The marginal epistasis framework is a powerful approach because it estimates the likelihood of a SNP being involved in any interaction, thereby reducing the multiple testing burden. Current implementations of this approach have failed to scale genome wide in large human studies. To address this, we present the sparse marginal epistasis (SME) test, which concentrates the scans for epistasis to regions of the genome that have known functional enrichment for a quantitative trait of interest. By leveraging the sparse nature of this modeling setup, we develop a statistical algorithm that allows SME to run 10-90 times faster than state-of-the-art epistatic mapping methods. In a study of complex traits measured in 349,411 individuals from the UK Biobank, we show that reducing searches of epistasis to variants in functionally enriched regions facilitates the identification of genetic interactions associated with regulatory genomic elements.
{"title":"Sparse modeling of interactions enables fast detection of genome-wide epistasis in biobank-scale studies.","authors":"Julian Stamp, Samuel Pattillo Smith, Daniel Weinreich, Lorin Crawford","doi":"10.1016/j.ajhg.2025.07.004","DOIUrl":"10.1016/j.ajhg.2025.07.004","url":null,"abstract":"<p><p>The lack of computational methods capable of detecting epistasis in biobanks has led to uncertainty about the role of non-additive genetic effects on complex trait variation. The marginal epistasis framework is a powerful approach because it estimates the likelihood of a SNP being involved in any interaction, thereby reducing the multiple testing burden. Current implementations of this approach have failed to scale genome wide in large human studies. To address this, we present the sparse marginal epistasis (SME) test, which concentrates the scans for epistasis to regions of the genome that have known functional enrichment for a quantitative trait of interest. By leveraging the sparse nature of this modeling setup, we develop a statistical algorithm that allows SME to run 10-90 times faster than state-of-the-art epistatic mapping methods. In a study of complex traits measured in 349,411 individuals from the UK Biobank, we show that reducing searches of epistasis to variants in functionally enriched regions facilitates the identification of genetic interactions associated with regulatory genomic elements.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2198-2212"},"PeriodicalIF":8.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752063","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}
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