Meritxell Oliva, Mrinal K. Sarkar, Michael E. March, Amir Hossein Saeidian, Frank D. Mentch, Chen-Lin Hsieh, Fanying Tang, Ranjitha Uppala, Matthew T. Patrick, Qinmengge Li, Rachael Bogle, J. Michelle Kahlenberg, Deborah Watson, Joseph T. Glessner, Leila Youssefian, Hassan Vahidnezhad, Lam C. Tsoi, Hakon Hakonarson, Johann E. Gudjonsson, Kathleen M. Smith, Bridget Riley-Gillis
{"title":"Integration of GWAS, QTLs and keratinocyte functional assays reveals molecular mechanisms of atopic dermatitis","authors":"Meritxell Oliva, Mrinal K. Sarkar, Michael E. March, Amir Hossein Saeidian, Frank D. Mentch, Chen-Lin Hsieh, Fanying Tang, Ranjitha Uppala, Matthew T. Patrick, Qinmengge Li, Rachael Bogle, J. Michelle Kahlenberg, Deborah Watson, Joseph T. Glessner, Leila Youssefian, Hassan Vahidnezhad, Lam C. Tsoi, Hakon Hakonarson, Johann E. Gudjonsson, Kathleen M. Smith, Bridget Riley-Gillis","doi":"10.1038/s41467-025-58310-7","DOIUrl":"https://doi.org/10.1038/s41467-025-58310-7","url":null,"abstract":"<p>Atopic dermatitis is a highly heritable and common inflammatory skin condition affecting children and adults worldwide. Multi-ancestry approaches to atopic dermatitis genetic association studies are poised to boost power to detect genetic signal and identify loci contributing to atopic dermatitis risk. Here, we present a multi-ancestry GWAS meta-analysis of twelve atopic dermatitis cohorts from five ancestral populations totaling 56,146 cases and 602,280 controls. We report 101 genomic loci associated with atopic dermatitis, including 16 loci that have not been previously associated with atopic dermatitis or eczema. Fine-mapping, QTL colocalization, and cell-type enrichment analyses identified genes and cell types implicated in atopic dermatitis pathophysiology. Functional analyses in keratinocytes provide evidence for genes that could play a role in atopic dermatitis through epidermal barrier function. Our study provides insights into the etiology of atopic dermatitis by harnessing multiple genetic and functional approaches to unveil the mechanisms by which atopic dermatitis-associated variants impact genes and cell types.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"7 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ahmed H. Dorrah, Joon-Suh Park, Alfonso Palmieri, Federico Capasso
{"title":"Free-standing bilayer metasurfaces in the visible","authors":"Ahmed H. Dorrah, Joon-Suh Park, Alfonso Palmieri, Federico Capasso","doi":"10.1038/s41467-025-58205-7","DOIUrl":"https://doi.org/10.1038/s41467-025-58205-7","url":null,"abstract":"<p>Multi-layered meta-optics have enabled complex wavefront shaping beyond their single layer counterpart owing to the additional design variables afforded by each plane. For instance, lossless complex amplitude modulation, generalized polarization transformations, and wide field of view are key attributes that fundamentally require multi-plane wavefront matching. Nevertheless, existing embodiments of bilayer metasurfaces have relied on configurations which suffer from Fresnel reflections, low mode confinement, or undesired resonances which compromise the intended response. Here, we introduce bilayer metasurfaces made of free-standing meta-atoms working in the visible spectrum. We demonstrate their use in wavefront shaping of linearly polarized light using pure geometric phase with diffraction efficiency of 80% — expanding previous literature on Pancharatnam-Berry phase metasurfaces which rely on circularly or elliptically polarized illumination. The fabrication relies on a two-step lithography and selective development processes which yield free standing, bilayer stacked metasurfaces, of 1200 nm total thickness. The metasurfaces comprise TiO<sub>2</sub> nanofins with vertical sidewalls. Our work advances the nanofabrication of compound meta-optics and inspires new directions in wavefront shaping, metasurface integration, and polarization control.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"38 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chengxi Zang, Daniel Guth, Ann M. Bruno, Zhenxing Xu, Haoyang Li, Nariman Ammar, Robert Chew, Nick Guthe, Emily Hadley, Rainu Kaushal, Tanzy Love, Brenda M. McGrath, Rena C. Patel, Elizabeth C. Seibert, Yalini Senathirajah, Sharad Kumar Singh, Fei Wang, Mark G. Weiner, Kenneth J. Wilkins, Yiye Zhang, Torri D. Metz, Elaine Hill, Thomas W. Carton
{"title":"Long COVID after SARS-CoV-2 during pregnancy in the United States","authors":"Chengxi Zang, Daniel Guth, Ann M. Bruno, Zhenxing Xu, Haoyang Li, Nariman Ammar, Robert Chew, Nick Guthe, Emily Hadley, Rainu Kaushal, Tanzy Love, Brenda M. McGrath, Rena C. Patel, Elizabeth C. Seibert, Yalini Senathirajah, Sharad Kumar Singh, Fei Wang, Mark G. Weiner, Kenneth J. Wilkins, Yiye Zhang, Torri D. Metz, Elaine Hill, Thomas W. Carton","doi":"10.1038/s41467-025-57849-9","DOIUrl":"https://doi.org/10.1038/s41467-025-57849-9","url":null,"abstract":"<p>Pregnancy alters immune responses and clinical manifestations of COVID-19, but its impact on Long COVID remains uncertain. This study investigated Long COVID risk in individuals with SARS-CoV-2 infection during pregnancy compared to reproductive-age females infected outside of pregnancy. A retrospective analysis of two U.S. databases, the National Patient-Centered Clinical Research Network (PCORnet) and the National COVID Cohort Collaborative (N3C), identified 29,975 pregnant individuals (aged 18–50) with SARS-CoV-2 infection in pregnancy from PCORnet and 42,176 from N3C between March 2020 and June 2023. At 180 days after infection, estimated Long COVID risks for those infected during pregnancy were 16.47 per 100 persons (95% CI, 16.00–16.95) in PCORnet using the PCORnet computational phenotype (CP) model and 4.37 per 100 persons (95% CI, 4.18–4.57) in N3C using the N3C CP model. Compared to matched non-pregnant individuals, the adjusted hazard ratios for Long COVID were 0.86 (95% CI, 0.83–0.90) in PCORnet and 0.70 (95% CI, 0.66–0.74) in N3C. The observed risk factors for Long COVID included Black race/ethnicity, advanced maternal age, first- and second-trimester infection, obesity, and comorbid conditions. While the findings suggest a high incidence of Long COVID among pregnant individuals, their risk was lower than that of matched non-pregnant females.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"103 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural insights into the dual Ca2+-sensor-mediated activation of the PPEF phosphatase family","authors":"Jia Liu, Cang Wu, Yuyang Liu, Qiangou Chen, Yuzhen Ding, Zhiqiao Lin, Lifeng Pan, Kang Xiao, Jianchao Li, Zhongmin Liu, Wei Liu","doi":"10.1038/s41467-025-58261-z","DOIUrl":"https://doi.org/10.1038/s41467-025-58261-z","url":null,"abstract":"<p>Serine/threonine-protein phosphatases with EF-hands (PPEFs) are a family of highly conserved proteins implicated in cancer and neuronal degeneration. The initially characterized member, <i>Drosophila melanogaster</i> retinal degeneration C (RDGC) contains a calmodulin (CaM)-interacting extended-IQ motif and a Ca<sup>2+</sup>-binding EF-like/EF-hand tandem. However, the molecular regulation of PPEF is poorly understood. In this study, we use cryogenic-electron microscopy to delineate the structures of the RDGC/CaM holoenzyme. In the absence of Ca<sup>2+</sup>, CaM and the EF-like/EF-hand tandem allow the extended-IQ motif to block substrate access to the catalytic sites, constituting an auto-inhibitory mechanism. Upon Ca<sup>2+</sup> binding, CaM and the EF-like/EF-hand tandem drive drastic conformational changes in the extended-IQ motif to unlock the catalytic sites. This dual Ca<sup>2+</sup>-sensor-mediated activation is evolutionarily conserved in mammals. This study provides mechanistic insight into the molecular activation of PPEFs, paving the way for the development of therapeutic strategies for PPEF-related human diseases.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"216 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuanyuan Qu, Wanbo Tai, Enhao Ma, Qiwei Jiang, Miao Fan, Wangcheng Xiao, Chongyu Tian, Yang Liu, Jianying Liu, Xinquan Wang, Jiwan Ge, Gong Cheng
{"title":"Generation and characterization of neutralizing antibodies against M1R and B6R proteins of monkeypox virus","authors":"Yuanyuan Qu, Wanbo Tai, Enhao Ma, Qiwei Jiang, Miao Fan, Wangcheng Xiao, Chongyu Tian, Yang Liu, Jianying Liu, Xinquan Wang, Jiwan Ge, Gong Cheng","doi":"10.1038/s41467-025-58180-z","DOIUrl":"https://doi.org/10.1038/s41467-025-58180-z","url":null,"abstract":"<p>The global outbreak of monkeypox virus (MPXV), combined with the termination of smallpox vaccination and the lack of specific antiviral treatments, raises increasing concerns. The surface proteins M1R and B6R of MPXV are crucial for virus transmission and serve as key targets for vaccine development. In this study, a panel of human antibodies targeting M1R and B6R is isolated from a human antibody library using phage display technology. Among these antibodies, A138 against M1R and B026 against B6R show the most potent broad-spectrum neutralizing activities against MPXV and Vaccinia virus (VACV). When used in combination, A138 and B026 exhibit complementary neutralizing activity against both viruses in vitro. X-ray crystallography reveales that A138 binds to the loop regions of M1R, similar to the vulnerable epitope of 7D11 on VACV L1R. By contrast, A129 targets a more cryptic epitope, primarily comprising the β-strands of M1R. Moreover, prophylactic and therapeutic administration of A138 or B026 alone provides partial protection, while combining these two antibodies results in enhanced protection against VACV in male C57BL/6 mice. This study demonstrates of a dual-targeting strategy using two different components of the virion for the prevention and treatment of MPXV infection.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"133 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Transcriptomic and spatial GABAergic neuron subtypes in zona incerta mediate distinct innate behaviors","authors":"Mengyue Zhu, Jieqiao Peng, Mi Wang, Shan Lin, Huiying Zhang, Yu Zhou, Xinyue Dai, Huiying Zhao, Yan-qin Yu, Li Shen, Xiao-Ming Li, Jiadong Chen","doi":"10.1038/s41467-025-57896-2","DOIUrl":"https://doi.org/10.1038/s41467-025-57896-2","url":null,"abstract":"<p>Understanding the anatomical connection and behaviors of transcriptomic neuron subtypes is critical to delineating cell type-specific functions in the brain. Here we integrated single-nucleus transcriptomic sequencing, in vivo circuit mapping, optogenetic and chemogenetic approaches to dissect the molecular identity and function of heterogeneous GABAergic neuron populations in the zona incerta (ZI) in mice, a region involved in modulating various behaviors. By microdissecting ZI for transcriptomic and spatial gene expression analyses, our results revealed two non-overlapping <i>Ecel1-</i> and <i>Pde11a</i>-expressing GABAergic neurons with dominant expression in the rostral and medial zona incerta (ZIr<sup>Ecel1</sup> and ZIm<sup>Pde11a</sup>), respectively. The GABAergic projection from ZIr<sup>Ecel1</sup> to periaqueductal gray mediates self-grooming, while the GABAergic projection from ZIm<sup>Pde11a</sup> to the oral part of pontine reticular formation promotes transition from sleep to wakefulness. Together, our results revealed the molecular markers, spatial organization and specific neuronal circuits of two discrete GABAergic projection neuron populations in segregated subregions of the ZI that mediate distinct innate behaviors, advancing our understanding of the functional organization of the brain.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"32 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenkai Wang, Zhuo Cheng, Miao Yu, Ke Liu, Hongli Duan, Yang Zhang, Xinle Huang, Menghuan Li, Changqing Li, Yan Hu, Zhong Luo, Minghan Liu
{"title":"Injectable ECM-mimetic dynamic hydrogels abolish ferroptosis-induced post-discectomy herniation through delivering nucleus pulposus progenitor cell-derived exosomes","authors":"Wenkai Wang, Zhuo Cheng, Miao Yu, Ke Liu, Hongli Duan, Yang Zhang, Xinle Huang, Menghuan Li, Changqing Li, Yan Hu, Zhong Luo, Minghan Liu","doi":"10.1038/s41467-025-58447-5","DOIUrl":"https://doi.org/10.1038/s41467-025-58447-5","url":null,"abstract":"<p>Discectomy-induced ferroptosis of nucleus pulposus cells (NPCs) contributes to postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). We discover that nucleus pulposus progenitor cells (NPPCs) could imprint ferroptosis resistance into NPCs through exosome-dependent intercellular transmission of miR-221-3p. Based on these findings, we first develop synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity, which are integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enables marked ferroptosis inhibition in NPCs that not only prevents LDH recurrence but also reverses the IDD symptoms, leading to robust restoration of NP structure and functions. In summary, this study offers a promising approach for treating disc herniation.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"23 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Analysis of allohexaploid wheatgrass genome reveals its Y haplome origin in Triticeae and high-altitude adaptation","authors":"Yi Xiong, Shuai Yuan, Yanli Xiong, Lizuiyue Li, Jinghan Peng, Jin Zhang, Xing Fan, Chengzhi Jiang, Li-na Sha, Zhaoting Wang, Xue Peng, Zecheng Zhang, Qingqing Yu, Xiong Lei, Zhixiao Dong, Yingjie Liu, Junming Zhao, Guangrong Li, Zujun Yang, Shangang Jia, Daxu Li, Ming Sun, Shiqie Bai, Jianquan Liu, Yongzhi Yang, Xiao Ma","doi":"10.1038/s41467-025-58341-0","DOIUrl":"https://doi.org/10.1038/s41467-025-58341-0","url":null,"abstract":"<p>Phylogenetic origin of the Y haplome present in allopolyploid Triticeae species remains unknown. Here, we report the 10.47 Gb chromosome-scale genome of allohexaploid <i>Elymus nutans</i> (StStYYHH). Phylogenomic analyses reveal that the Y haplome is sister to the clade comprising V and Jv haplomes from <i>Dasypyrum</i> and <i>Thinopyum</i>. In addition, H haplome from the <i>Hordeum</i>-like ancestor, St haplome from the <i>Pseudoroegneria</i>-like ancestor and Y haplome are placed in the successively diverged clades. Resequencing data reveal the allopolyploid origins with St, Y, and H haplome combinations in <i>Elymus</i>. Population genomic analyses indicate that <i>E. nutans</i> has expanded from medium to high/low-altitude regions. Phenotype/environmental association analyses identify <i>MAPKKK18</i> promoter mutations reducing its expression, aiding UV-B adaptation in high-altitude populations. These findings enhance understanding of allopolyploid evolution and aid in breeding forage and cereal crops through intergeneric hybridization within Triticeae.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"12 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Florian Malard, Kristen Dias, Margaux Baudy, Stéphane Thore, Brune Vialet, Philippe Barthélémy, Sébastien Fribourg, Fedor V. Karginov, Sébastien Campagne
{"title":"Molecular basis for the calcium-dependent activation of the ribonuclease EndoU","authors":"Florian Malard, Kristen Dias, Margaux Baudy, Stéphane Thore, Brune Vialet, Philippe Barthélémy, Sébastien Fribourg, Fedor V. Karginov, Sébastien Campagne","doi":"10.1038/s41467-025-58462-6","DOIUrl":"https://doi.org/10.1038/s41467-025-58462-6","url":null,"abstract":"<p>Ribonucleases (RNases) are ubiquitous enzymes that process or degrade RNA, essential for cellular functions and immune responses. The EndoU-like superfamily includes endoribonucleases conserved across bacteria, eukaryotes, and certain viruses, with an ancient evolutionary link to the ribonuclease A-like superfamily. Both bacterial EndoU and animal RNase A share a similar fold and function independently of cofactors. In contrast, the eukaryotic EndoU catalytic domain requires divalent metal ions for catalysis, possibly due to an N-terminal extension near the catalytic core. In this study, we use biophysical and computational techniques along with in vitro assays to investigate the calcium-dependent activation of human EndoU. We determine the crystal structure of EndoU bound to calcium and find that calcium binding remote from the catalytic triad triggers water-mediated intramolecular signaling and structural changes, activating the enzyme through allostery. Calcium binding involves residues from both the catalytic core and the N-terminal extension, indicating that the N-terminal extension interacts with the catalytic core to modulate activity in response to calcium. Our findings suggest that similar mechanisms may be present across all eukaryotic EndoUs, highlighting a unique evolutionary adaptation that connects endoribonuclease activity to cellular signaling in eukaryotes.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"89 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anton Safonov, Tomoki T. Nomakuchi, Elizabeth Chao, Carrie Horton, Jill S. Dolinsky, Amal Yussuf, Marcy Richardson, Virginia Speare, Shuwei Li, Zoe C. Bogus, Maria Bonanni, Anna Raper, Trust Odia, Bradley S. Wubbenhorst, Elsa Faulders, Elisabeth M. Schuth, Kate Loranger, Jingwen Zhang, Carly Bess Scalise, Adam ElNaggar, Youbao Sha, Stephanie A. Felker, Jeffrey Weitzel, Staci Kallish, Marylyn D. Ritchie, Katherine L. Nathanson, Theodore G. Drivas
{"title":"A genotype-first approach identifies high incidence of NF1 pathogenic variants with distinct disease associations","authors":"Anton Safonov, Tomoki T. Nomakuchi, Elizabeth Chao, Carrie Horton, Jill S. Dolinsky, Amal Yussuf, Marcy Richardson, Virginia Speare, Shuwei Li, Zoe C. Bogus, Maria Bonanni, Anna Raper, Trust Odia, Bradley S. Wubbenhorst, Elsa Faulders, Elisabeth M. Schuth, Kate Loranger, Jingwen Zhang, Carly Bess Scalise, Adam ElNaggar, Youbao Sha, Stephanie A. Felker, Jeffrey Weitzel, Staci Kallish, Marylyn D. Ritchie, Katherine L. Nathanson, Theodore G. Drivas","doi":"10.1038/s41467-025-57077-1","DOIUrl":"https://doi.org/10.1038/s41467-025-57077-1","url":null,"abstract":"<p>Loss of function variants in the <i>NF1</i> gene cause neurofibromatosis type 1, a genetic disorder characterized by complete penetrance, characteristic physical exam findings, and a substantially increased risk for malignancy. However, our understanding of the disorder is based on patients ascertained through phenotype-first approaches, which estimate prevalence at 1 in 3000. Leveraging a genotype-first approach in multiple large patient cohorts including over one million individuals, we demonstrate an unexpectedly high prevalence (1 in 1,286) of <i>NF1</i> pathogenic variants. Half are identified in individuals lacking clinical features of NF1, with many appearing to have post-zygotic mosaicism for the identified variant. Incidentally discovered variants are not associated with classic neurofibromatosis features but are associated with an increased incidence of malignancy compared to control populations. Our findings suggest that <i>NF1</i> pathogenic variants are substantially more common than previously thought, often characterized by somatic mosaicism and reduced penetrance, and are important contributors to cancer risk in the general population.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"38 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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