Pub Date : 2025-12-04DOI: 10.1016/j.ajhg.2025.10.009
Bruce R Korf
{"title":"Transitions in interesting times.","authors":"Bruce R Korf","doi":"10.1016/j.ajhg.2025.10.009","DOIUrl":"10.1016/j.ajhg.2025.10.009","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 12","pages":"2815-2816"},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12808940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686805","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 : 2025-12-04DOI: 10.1016/j.ajhg.2025.11.005
Paul W. Hook, Alyson B. Barnes
{"title":"This month in The Journal","authors":"Paul W. Hook, Alyson B. Barnes","doi":"10.1016/j.ajhg.2025.11.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.005","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"2 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689938","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 : 2025-12-04DOI: 10.1016/j.ajhg.2025.11.001
Teri A Manolio, Alauna Rupert, Jahnavi Narula, Carol J Bult, Rex L Chisholm, Geoffrey S Ginsburg, Gillian W Hooker, Gail P Jarvik, George A Mensah, Dan M Roden, Robb Rowley, Casey Overby Taylor, Simona Volpi, Marc S Williams
{"title":"Genomic medicine year in review: 2025.","authors":"Teri A Manolio, Alauna Rupert, Jahnavi Narula, Carol J Bult, Rex L Chisholm, Geoffrey S Ginsburg, Gillian W Hooker, Gail P Jarvik, George A Mensah, Dan M Roden, Robb Rowley, Casey Overby Taylor, Simona Volpi, Marc S Williams","doi":"10.1016/j.ajhg.2025.11.001","DOIUrl":"10.1016/j.ajhg.2025.11.001","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 12","pages":"2822-2825"},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12808944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686740","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 : 2025-12-04DOI: 10.1016/j.ajhg.2025.11.011
James Fasham,Julia Rankin,Rachel Schot,Susan M White,Katrina M Bell,Matthew N Wakeling,Lucy J Mallin,Alex Shah,Michelle G de Silva,David I Francis,Maie Walsh,Emily E Jones,Kayal Vijayakumar,Katie Johnson,Francis H Sansbury,Johann Te Water Naudé,Paola Giunti,Marios Hadjivassiliou,Andrea H Nemeth,George K Tofaris,Carlo Rinaldi,Benito Banos-Pinero,Marianna Selikhva,Nishanka Ubeyratna,Anneke Kievit,Frank Sleutels,Joey van Giessen,Tahsin Stefan Barakat,Timothy S Hall,Alan Whone,Eleanor Thomas,Joseph S Leslie,Rosemary A Bamford,Aaron R Jeffries,Jenny Lord,Susan Walker,Tjakko J van Ham,Sue L Hill,Lucy McGavin,Andrew Parrish,Andrew H Crosby,Emma L Baple,Alistair T Pagnamenta
Complex neurodegenerative conditions have occasionally been associated with copy-number gains. Using microarray and genome sequencing on DNA samples from eleven individuals from nine unrelated families, we show that copy-number gains at 16p13.3 cause a severe, recognizable disorder characterized by early-onset progressive ataxia and cognitive decline (9-32 years). Most affected individuals also displayed peripheral neuropathy and scoliosis. Optic atrophy, nystagmus, and dystonia were more variable features. The neuroradiological phenotype comprises a distinctive combination of atrophy of the cerebellum and caudate nuclei. Co-segregation data showed that the structural variant (SV) had occurred de novo in 5 individuals and, for one other individual, had been inherited from a mosaic, unaffected parent. Triplicated segments of 16p13.3 were identified within the duplications. Although these varied in size (30-811 kb), the minimal region of overlap included a single gene (ATP6V0C) that is highly expressed in the cerebellum. RNA sequencing (RNA-seq) using whole-blood and fibroblast/lymphoblast cultures indicated increased expression of several genes within the SV, with ATP6V0C showing the most significant increase (up to 4-fold). In most cases, the central segment of the SV was proven to be inverted and lay immediately distal to a 144 kb palindrome. Across 500,000 individuals from the UK Biobank, we identified 19 duplications but no triplications at this locus. Further analysis of the consequences of ATP6V0C overexpression on the stoichiometry within the vacuolar H+-ATPase heteromer and on neurological function will provide valuable pathomechanistic insights. Together, our findings define palindrome-mediated triplication on 16p13.3 as the cause of a clinically distinct childhood-onset neurodegenerative disorder.
{"title":"Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia.","authors":"James Fasham,Julia Rankin,Rachel Schot,Susan M White,Katrina M Bell,Matthew N Wakeling,Lucy J Mallin,Alex Shah,Michelle G de Silva,David I Francis,Maie Walsh,Emily E Jones,Kayal Vijayakumar,Katie Johnson,Francis H Sansbury,Johann Te Water Naudé,Paola Giunti,Marios Hadjivassiliou,Andrea H Nemeth,George K Tofaris,Carlo Rinaldi,Benito Banos-Pinero,Marianna Selikhva,Nishanka Ubeyratna,Anneke Kievit,Frank Sleutels,Joey van Giessen,Tahsin Stefan Barakat,Timothy S Hall,Alan Whone,Eleanor Thomas,Joseph S Leslie,Rosemary A Bamford,Aaron R Jeffries,Jenny Lord,Susan Walker,Tjakko J van Ham,Sue L Hill,Lucy McGavin,Andrew Parrish,Andrew H Crosby,Emma L Baple,Alistair T Pagnamenta","doi":"10.1016/j.ajhg.2025.11.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.011","url":null,"abstract":"Complex neurodegenerative conditions have occasionally been associated with copy-number gains. Using microarray and genome sequencing on DNA samples from eleven individuals from nine unrelated families, we show that copy-number gains at 16p13.3 cause a severe, recognizable disorder characterized by early-onset progressive ataxia and cognitive decline (9-32 years). Most affected individuals also displayed peripheral neuropathy and scoliosis. Optic atrophy, nystagmus, and dystonia were more variable features. The neuroradiological phenotype comprises a distinctive combination of atrophy of the cerebellum and caudate nuclei. Co-segregation data showed that the structural variant (SV) had occurred de novo in 5 individuals and, for one other individual, had been inherited from a mosaic, unaffected parent. Triplicated segments of 16p13.3 were identified within the duplications. Although these varied in size (30-811 kb), the minimal region of overlap included a single gene (ATP6V0C) that is highly expressed in the cerebellum. RNA sequencing (RNA-seq) using whole-blood and fibroblast/lymphoblast cultures indicated increased expression of several genes within the SV, with ATP6V0C showing the most significant increase (up to 4-fold). In most cases, the central segment of the SV was proven to be inverted and lay immediately distal to a 144 kb palindrome. Across 500,000 individuals from the UK Biobank, we identified 19 duplications but no triplications at this locus. Further analysis of the consequences of ATP6V0C overexpression on the stoichiometry within the vacuolar H+-ATPase heteromer and on neurological function will provide valuable pathomechanistic insights. Together, our findings define palindrome-mediated triplication on 16p13.3 as the cause of a clinically distinct childhood-onset neurodegenerative disorder.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"138 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680627","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 : 2025-12-02DOI: 10.1016/j.ajhg.2025.11.009
Abdalla A. Alkhawaja, Kevin W. Currin, Hannah J. Perrin, Swarooparani Vadlamudi, Amy S. Etheridge, K. Alaine Broadaway, Gabrielle H. Cannon, Carlton W. Anderson, Anne H. Moxley, Alina C. Iuga, Erin G. Schuetz, Federico Innocenti, Terrence S. Furey, Karen L. Mohlke
{"title":"Liver single-nucleus multiome profiling reveals cell-type mechanisms for cardiometabolic traits","authors":"Abdalla A. Alkhawaja, Kevin W. Currin, Hannah J. Perrin, Swarooparani Vadlamudi, Amy S. Etheridge, K. Alaine Broadaway, Gabrielle H. Cannon, Carlton W. Anderson, Anne H. Moxley, Alina C. Iuga, Erin G. Schuetz, Federico Innocenti, Terrence S. Furey, Karen L. Mohlke","doi":"10.1016/j.ajhg.2025.11.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.009","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"13 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657121","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 : 2025-12-02DOI: 10.1016/j.ajhg.2025.11.008
Qing Li, Qingyuan Song, Zhishan Chen, Jungyoon Choi, Victor Moreno, Jie Ping, Wanqing Wen, Chao Li, Xiang Shu, Jun Yan, Xiao-ou Shu, Qiuyin Cai, Jirong Long, Jeroen R. Huyghe, Rish Pai, Stephen B. Gruber, Yaohua Yang, Graham Casey, Xusheng Wang, Adetunji T. Toriola, Li Li, Bhuminder Singh, Ken S. Lau, Li Zhou, Zichen Zhang, Chong Wu, Ulrike Peters, Wei Zheng, Quan Long, Zhijun Yin, Xingyi Guo
{"title":"Large-scale integration of omics and electronic health records to identify potential risk protein biomarkers and therapeutic drugs for cancer prevention","authors":"Qing Li, Qingyuan Song, Zhishan Chen, Jungyoon Choi, Victor Moreno, Jie Ping, Wanqing Wen, Chao Li, Xiang Shu, Jun Yan, Xiao-ou Shu, Qiuyin Cai, Jirong Long, Jeroen R. Huyghe, Rish Pai, Stephen B. Gruber, Yaohua Yang, Graham Casey, Xusheng Wang, Adetunji T. Toriola, Li Li, Bhuminder Singh, Ken S. Lau, Li Zhou, Zichen Zhang, Chong Wu, Ulrike Peters, Wei Zheng, Quan Long, Zhijun Yin, Xingyi Guo","doi":"10.1016/j.ajhg.2025.11.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.008","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"25 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657145","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 : 2025-12-01DOI: 10.1016/j.ajhg.2025.11.007
Simone Martinelli,Hélène Cavé,Alessandro De Luca,Marina DiStefano,Rachel Karchin,Ana Clara Lugones,Anne O'Donnell-Luria,Deborah I Ritter,David Tamborero,Michael Y Tolstorukov,Paulo Vidal Campregher,Marco Tartaglia,Dmitriy Sonkin
Genetic alterations influence biological function through a variety of molecular mechanisms. While common functional descriptions (such as loss of function and gain of function) are useful, they may fail to capture mechanistic complexity, particularly in cases of pleiotropy and context-dependent variant effects. To improve variant interpretation and classification, we propose a framework incorporating "context qualifiers" to address mechanistic specificity. This perspective explores the limitations of common functional descriptors and discusses the criteria needed to implement context qualifiers in variant interpretation frameworks to enhance precision medicine applications.
{"title":"Interpreting the functional impact of genetic variants: The need for context qualifiers.","authors":"Simone Martinelli,Hélène Cavé,Alessandro De Luca,Marina DiStefano,Rachel Karchin,Ana Clara Lugones,Anne O'Donnell-Luria,Deborah I Ritter,David Tamborero,Michael Y Tolstorukov,Paulo Vidal Campregher,Marco Tartaglia,Dmitriy Sonkin","doi":"10.1016/j.ajhg.2025.11.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.007","url":null,"abstract":"Genetic alterations influence biological function through a variety of molecular mechanisms. While common functional descriptions (such as loss of function and gain of function) are useful, they may fail to capture mechanistic complexity, particularly in cases of pleiotropy and context-dependent variant effects. To improve variant interpretation and classification, we propose a framework incorporating \"context qualifiers\" to address mechanistic specificity. This perspective explores the limitations of common functional descriptors and discusses the criteria needed to implement context qualifiers in variant interpretation frameworks to enhance precision medicine applications.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"359 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656982","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 : 2025-11-24DOI: 10.1016/j.ajhg.2025.11.002
David R. Blair, Neil Risch
{"title":"Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks","authors":"David R. Blair, Neil Risch","doi":"10.1016/j.ajhg.2025.11.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.002","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"16 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583814","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 : 2025-11-20DOI: 10.1016/j.ajhg.2025.11.003
{"title":"Collaborative science in genomics: The value of data sharing and thoughtful stewardship","authors":"","doi":"10.1016/j.ajhg.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.003","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"18 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559759","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 : 2025-11-19DOI: 10.1016/j.ajhg.2025.10.016
Diane Xue, Elizabeth E. Blue, Stephanie M. Fullerton, Nora B. Henrikson, Sarah Knerr, Anne-Marie Laberge, Lisa S. Parker, Maya Sabatello, Nirupama Nini Shridhar, Jennifer A. Smith, Benjamin S. Wilfond, Genevieve L. Wojcik, Joon-Ho Yu, Alison E. Fohner
{"title":"Training competencies and recommendations for the next generation of public health genetics: Reflections from current leaders in the field","authors":"Diane Xue, Elizabeth E. Blue, Stephanie M. Fullerton, Nora B. Henrikson, Sarah Knerr, Anne-Marie Laberge, Lisa S. Parker, Maya Sabatello, Nirupama Nini Shridhar, Jennifer A. Smith, Benjamin S. Wilfond, Genevieve L. Wojcik, Joon-Ho Yu, Alison E. Fohner","doi":"10.1016/j.ajhg.2025.10.016","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.016","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"5 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553838","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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