NPJ Genomic Medicine最新文献

{"title":"Biallelic variants in BBOX1 cause L-Carnitine deficiency and elevated γ-butyrobetaine.","authors":"Xiao Li, Mehdi Yeganeh, Graham Sinclair, Jill Mwenifumbo, Karen J Jacob, Laura Arbour, Anna Lehman, Bojana Rakic, Frédéric M Vaz, Gabriella Horvath, Maja Tarailo-Graovac, Sylvia Stockler-Ipsiroglu","doi":"10.1038/s41525-025-00523-2","DOIUrl":"10.1038/s41525-025-00523-2","url":null,"abstract":"<p><p>Gamma-butyrobetaine hydroxylase (BBOX1) catalyses the last step of carnitine biosynthesis, converting γ-butyrobetaine (γ-BB) into L-carnitine. Here we show, for the first time, that biallelic variants in BBOX1 are associated with decreased levels of L-carnitine and increased plasma levels of γ-BB in three patients from two unrelated families presenting with myopathic, neurodevelopmental, and late-onset psychiatric manifestations. Using a knockout C. elegans model of BBOX1 homolog, gbh-1, and strains harboring patient-derived variants (gbh-1(D72G) for p.Asp59Gly, gbh-1(G283R) for p.Gly263Arg, and gbh-1(G247Vfs6) for p.Gly227Valfs*6), we show very low L-carnitine levels and significantly elevated γ-BB in c.675delA and c.787G>A mutants, and moderately elevated γ-BB in c.176A>G. Furthermore, we observed a lethal embryonic phenotype for the gbh-1 loss-of-function strains, which was rescued upon L-carnitine supplementation. Our study provides novel insights into the clinical and biochemical consequences of BBOX1-related L-carnitine biosynthesis deficiency and establishes C. elegans as a model to study the effects of BBOX1 deficiency.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"64"},"PeriodicalIF":4.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12480863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: A founder BRCA1 exonic duplication involving breakpoint in T2T reference genome-specific region results in constitutional fusion transcript.","authors":"Mathias Schwartz, Mathilde Filser, Kevin Merchadou, Elisa Lemaitre, Khadija Abidallah, Henrique Tenreiro, Catherine Dubois D'enghien, Audrey Rapinat, Elise Pierre-Noel, Voreak Suybeng, Marion Espenel, Sylvain Baulande, Séverine Adams, Audrey Remenieras, Crystal Renaud, Camille Aucouturier, Capucine Delnatte, Céline Garrec, Victor Renault, Lisa Golmard, Emmanuelle Fourme, Julien Masliah-Planchon, Sandrine M Caputo","doi":"10.1038/s41525-025-00522-3","DOIUrl":"10.1038/s41525-025-00522-3","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"62"},"PeriodicalIF":4.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PopPK modeling supports BW band dosing of lacosamide for pediatric epilepsy.","authors":"Yue Li, Hong-Li Guo, Lin Fan, Jie Wang, Ya-Hui Hu, Yuan-Yuan Zhang, Jin-Chun Qiu, Jing Chen, Chun-Feng Wu, Gang Zhang, Xiao-Peng Lu, Feng Chen","doi":"10.1038/s41525-025-00519-y","DOIUrl":"10.1038/s41525-025-00519-y","url":null,"abstract":"<p><p>Personalized precision dosing remains an unmet clinical need. This study used population pharmacokinetic (PopPK) modeling to evaluate transitioning lacosamide (LCM) in children with epilepsy from body weight (BW)-based (mg/kg) to simplified BW-band or fixed-dose (mg) regimens. Real-world data from 190 patients were analyzed using nonlinear mixed-effects modeling program, comparing a BW-based model (Model I) and a genotype-guided model (Model II); the latter showed superior predictive performance. Monte Carlo simulations confirmed comparable LCM exposure across regimens, with >78% target attainment in external validation. A fixed 100 mg dose for patients ≥10 kg achieved equivalent exposure to BW-adjusted dosing, with consistent results in 1-4 years and obese patients. These findings enabled BW-band dosing as a clinically viable alternative to mg/kg regimens, while CYP2C19 genotyping further enhanced precision. This PopPK-based strategy simplifies LCM therapy without compromising efficacy, offering a practical approach to personalized epilepsy management in children.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"61"},"PeriodicalIF":4.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12394691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome sequencing provides high diagnostic yield and new etiological insights for intellectual disability and developmental delay.","authors":"Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Kazuharu Misawa, Eriko Koshimizu, Yuri Uchiyama, Naomi Tsuchida, Rie Seyama, Masamune Sakamoto, Kazuhiro Iwama, Naoto Nishimura, Yasuhiro Utsuno, Li Fu, Marina Takizawa, Qiaowei Liang, Toshiyuki Itai, Ken Saida, Sachiko Ohori, Shinichi Kameyama, Hiromi Fukuda, Yukina Hayashi, Yuta Inoue, Tomohide Goto, Kazushi Ichikawa, Ichiro Kuki, Masataka Fukuoka, Kiyohiro Kim, Tadashi Shiohama, Konomi Shimoda, Kosuke Otsuka, Yuki Ueda, Kazutoshi Cho, Kotaro Yuge, Nobutada Tachi, Masaki Yoshida, Atsuro Daida, Kyoko Hirasawa, Tomoe Yanagishita, Toshiyuki Yamamoto, Kentaro Shirai, Tammar Fixler Mehr, Aviva Fattal-Valevski, Dorit Lev, Haruna Yokoyama, Emi Iwabuchi, Yoshihiko Saito, Masaki Miura, Kenji Sugai, Akihiko Ishiyama, Masayuki Sasaki, Yoshihiro Watanabe, Jun-Ichi Takanashi, Chong Ae Kim, Kenji Yokochi, Jun Tohyama, Tatsuo Mori, Yuishin Izumi, Yuiko Hasegawa, Nobuhiko Okamoto, Takahiro Ikeda, Hitoshi Osaka, Yosuke Kawai, Yosuke Omae, Katsushi Tokunaga, Mitsuhiro Kato, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s41525-025-00521-4","DOIUrl":"10.1038/s41525-025-00521-4","url":null,"abstract":"<p><p>Short-read genome sequencing (GS) is a powerful technique for investigating the genetic etiologies of rare diseases, capturing diverse genetic variations that are challenging to approach with exome sequencing (ES). We performed GS on 260 families with intellectual disability/developmental delay. GS detected potentially disease-related variants in 55 of the 260 families, with structural resolution by long-read sequencing or optical genome mapping, and functional assessment by RNA sequencing. Excluding 31 theoretically ES-resolvable cases, GS yielded likely pathogenic variants in 17 of 229 as well as variants of unknown significance in 7 of 229, totaling 10.5%. These variants implicated several new etiological mechanisms: a microduplication syndrome involving ATP6V0C; disturbed interactions of TBL1XR1 and NR2F1 with putative cis-regulatory elements by chromosomal rearrangements; and a CCG repeat expansion near the CHD3 transcription start site. This study highlights the critical role of GS in clinical diagnostics and its potential to advance understanding of genetic disorders.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"60"},"PeriodicalIF":4.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid generation of a sdhb loss-of-function zebrafish model for secreting pheochromocytomas and paragangliomas.","authors":"S Parisien-La Salle, F Nobilleau, A da Silva Babinet, J Lamontagne, M Labrecque, B Rampal, C Mas, M Liao, V A Barragan Torres, G Corbeil, L Chatel-Chaix, M Dona, M Tétreault, I Bourdeau, É Samarut","doi":"10.1038/s41525-025-00518-z","DOIUrl":"10.1038/s41525-025-00518-z","url":null,"abstract":"<p><p>Genotype plays a central role in the comprehensive management of pheochromocytomas and paragangliomas, highlighting the critical need for specific in vivo genetic models. Yet, animal models fall short of fully recapitulating the biological complexity of these tumours. We generated first-generation loss-of-function zebrafish models for sdhb, a canonical PPGL-associated gene, using CRISPR/Cas9. Sdhb-CRISPants exhibit increased heart rates, reduced swimming activity and premature death. In whole fish extracts, normetanephrine (NM), metanephrine (MN), and dopamine (DA) levels were about three times higher in sdhb CRISPants than in control larvae. In the bathing medium, NM and MN were also significantly elevated, along with 3-MT. Complementary metabolic and transcriptomic profiling revealed that sdhb CRISPants exhibit a clear signature of Complex II dysfunction and upregulation of genes involved in the hypoxia response, angiogenesis, stress response, and glycolysis. Our work validates the relevance of CRISPant zebrafish models to study the pathogenicity of PPGL-causing genetic variants in vivo.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"59"},"PeriodicalIF":4.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12339709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A founder BRCA1 exonic duplication involving breakpoint in T2T reference genome-specific region results in constitutional fusion transcript.","authors":"Mathias Schwartz, Mathilde Filser, Kevin Merchadou, Elisa Lemaitre, Khadija Abidallah, Henrique Tenreiro, Catherine Dubois D'enghien, Audrey Rapinat, Elise Pierre-Noel, Voreak Suybeng, Marion Espenel, Sylvain Baulande, Séverine Adams, Audrey Remenieras, Crystal Renaud, Camille Aucouturier, Capucine Delnatte, Céline Garrec, Victor Renault, Lisa Golmard, Emmanuelle Fourme, Julien Masliah-Planchon, Sandrine M Caputo","doi":"10.1038/s41525-025-00517-0","DOIUrl":"10.1038/s41525-025-00517-0","url":null,"abstract":"<p><p>Pathogenicity assessment of genetic variants is the cornerstone of genetic counselling. Copy gains of exons are challenging, as pathogenicity depends on the localization of the additional exons. Eight patients form six families carried copy gains of BRCA1 exons 8-20. For appropriate characterization, long-read sequencing aligned on three distinct reference genome assemblies, optical genomic mapping, short-read and long-read RNA sequencing were performed. All patients shared the same pathogenic structural variant, involving a large segment located downstream in the genome. One breakpoint occurred in a region incorrectly annotated in GRCh37/hg19 and GRCh38/hg38. Alignment to the T2T-CHM13/hs1 assembly was therefore necessary for accurate characterization. This rearrangement caused various BRCA1 transcriptomic abnormalities: back-splicing, forward genomic strand transcription by insertion of an ectopic promoter, fusion transcripts with the \"Next to BRCA1\" gene 1 (NBR1). Our findings underscore the need to combine advanced technologies with the latest genome references to resolve complex rearrangements with significant medical implications.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"58"},"PeriodicalIF":4.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomics on FHIR - a feasibility study to support a National Strategy for Genomic Medicine.","authors":"Nina Haffer, Caroline Stellmach, Julian Sass, Michael R Muzoora, Adam S L Graefe, Sylvia Thun, Carina N Vorisek","doi":"10.1038/s41525-025-00516-1","DOIUrl":"10.1038/s41525-025-00516-1","url":null,"abstract":"<p><p>The German National Strategy for Genomic Medicine (genomDE) aims to integrate genome sequencing into standard healthcare. However, integrating genomics data from research and healthcare remains challenging. This study analyzed how the genomDE dataset could be mapped to international standards: the Genomics Reporting Fast Healthcare Interoperability Resources® (FHIR®) Implementation Guide (IG) 2.0.0, the Global Alliance for Genomics and Health (GA4GH)'s Phenopacket Schema, and the German national molecular genomics report IG of the Medical Informatics Initiative (MII). Sample FHIR® bundles and necessary search queries were created and validated. Most dataset elements could be represented using existing FHIR profiles, while unmapped elements were addressed through profiling and extensions. The study highlights that the genomDE dataset can largely be mapped to existing international standards, with the potential to extend these standards to accommodate missing elements, thereby improving genomic data interoperability in healthcare.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"57"},"PeriodicalIF":4.8,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sequencing validates deep learning models for EHR-based detection of Noonan syndrome in pediatric patients.","authors":"Zeyu Yang, Amy Shikany, Ammar Husami, Xinjian Wang, Eneida Mendonca, K Nicole Weaver, Jing Chen","doi":"10.1038/s41525-025-00512-5","DOIUrl":"10.1038/s41525-025-00512-5","url":null,"abstract":"<p><p>Despite advanced diagnostic tools, early detection of rare genetic conditions like Noonan syndrome (NS) remains challenging. We evaluated a deep learning model's real-world performance in identifying potential NS cases using electronic health record (EHR) data, validated through genetic sequencing and clinical assessment. The model analyzed 92,428 patients, identifying 171 high-risk individuals (score > 0.8) who underwent comprehensive review. Among these, 86 had prior genetic diagnoses, including three NS cases diagnosed during the study period. Genetic sequencing of remaining patients identified two additional NS cases with pathogenic variants. The model achieved 2.92% precision and 99.82% specificity. While precision was lower than prior validation (33.3%), this reflected expected differences in disease prevalence rather than model degradation. NS-associated phenotypes were enriched among high-risk patients, and trajectory analysis showed potential for earlier identification, highlighting both promise and limitations of EHR-based computational screening tools.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"56"},"PeriodicalIF":5.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12280026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum microRNA expression quantitative trait loci in children with asthma colocalize with asthma-related GWAS results.","authors":"Julian Hecker, Anshul Tiwari, Rinku Sharma, Kevin Mendez, Jiang Li, Sofina Begum, Qingwen Chen, Albert Smith, Juan C Celedón, Scott T Weiss, Rachel S Kelly, Jessica A Lasky-Su, Kelan G Tantisira, Michael McGeachie","doi":"10.1038/s41525-025-00510-7","DOIUrl":"10.1038/s41525-025-00510-7","url":null,"abstract":"<p><p>Asthma poses a significant public health burden. Despite identifying more than a hundred genetic risk loci in genome-wide association studies (GWAS), the underlying functional mechanisms remain poorly understood. Studying omics, especially microRNAs (miRNAs), is a promising approach to facilitate our understanding of the biological pathways of asthma. Here, we performed miRNA expression quantitative trait loci (miRNA-QTL) analyses using whole-genome sequencing and serum-based miRNA expression data from two independent cohorts of children with asthma (Genetic Epidemiology of Asthma in Costa Rica Study (GACRS), (NCT00021840, 2005-06-23) (N = 980, Discovery) and the Childhood Asthma Management Program (CAMP) (NCT00000575, 2005-06-23) (N = 354, Replication)). Our robust discovery analysis identified 28 significant cis-miRNA-QTL associations, where 12 were not reported in three independent miRNA-QTL studies. Three of these 12 signals were replicated in CAMP. The QTLs colocalize with expression and splicing QTL in asthma-relevant tissues and cells, and overlap with asthma-related and blood cell trait GWAS hits.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"55"},"PeriodicalIF":4.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A narrative review of research advancements in pharmacogenetics of cardiovascular disease and impact on clinical implications.","authors":"Ayat Shorbaji, Peter Natesan Pushparaj, Ayat B Al-Ghafari, Loubna Siraj Mira, Mohammad Abdullah Basabrain, Muhammad Imran Naseer, Farid Ahmed, Muhammad Abu-Elmagd, Mahmood Rasool, Sherin Bakhashab","doi":"10.1038/s41525-025-00511-6","DOIUrl":"10.1038/s41525-025-00511-6","url":null,"abstract":"<p><p>Pharmacogenetics can enhance cardiovascular disease (CVD) treatment by tailoring drug therapy to genetic profiles and minimising trial-and-error approaches. Genetic variability influences responses to common CVD drugs, including antiplatelet drugs (clopidogrel and aspirin), anticoagulants (warfarin), statins, and antihypertensives (ACE inhibitors and β-blockers). Understanding genetic polymorphisms can improve efficacy and safety. Despite this progress, further research is needed to optimise pharmacogenomic applications and advance personalised medicine to improve CVD treatment outcomes.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"54"},"PeriodicalIF":4.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12246195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}