NPJ Genomic Medicine最新文献

{"title":"A ciliopathy combining Joubert syndrome and Oro-Facial-Digital syndrome caused by bi-allelic 5'-UTR loss-of-function CEP83 variant.","authors":"Matan M Jean, Anan Yunis, Tzofit Elbaz-Biton, Vadim Dolgin, Ginat Narkis, Analia Michaelovsky, Marina Eskin-Schwartz, Alexandra A Tsitrina, Nadav Agam, Tomer Poleg, Amit Safran, Ofek Freund, Noam Hadar, Dan Levy, Ilan Shelef, Khalil El Amour, Hagit Flusser, Ohad S Birk","doi":"10.1038/s41525-025-00514-3","DOIUrl":"10.1038/s41525-025-00514-3","url":null,"abstract":"<p><p>Oro-Facial-Digital Syndrome (OFDS) and Joubert syndrome are ciliary disorders. Fifteen individuals of consanguineous Bedouin kindred presented with global developmental delay with no speech, and a clear OFDS phenotype, combined with Joubert syndrome, with MRI showing hypoplastic corpus callosum and molar tooth sign. Renal and liver function tests and ultrasound were unremarkable. Within a 0.5 Mb disease-associated locus (LOD score 6.2), whole genome sequencing identified a single variant: CEP83 NG_051825.2:g.5774dupG, (NM_016122.3):c.-278dupG. Patient fibroblasts showed aberrantly long cilia, and alternative splicing of CEP83 5'UTR, skipping most of exon 1 of the canonical transcript, and frameshift, abrogating CEP83 mRNA and protein expression. CEP83 acts in primary cilium assembly. CEP83 biallelic missense or in-frame deletions, with presumed residual function, were previously associated with early-onset nephronophthisis culminating in end-stage renal disease. We now demonstrate that a biallelic complete loss-of-function CEP83 variant culminates in elongated primary cilia, causing OFDS with Joubert-like features without evident renal involvement.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"66"},"PeriodicalIF":4.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12514222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275415","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":"Whole genome sequencing in adolescent idiopathic scoliosis cohort implicates multiple biological pathways.","authors":"Islam Oguz Tuncay, Eun Kyoung Lee, Anxhela Gustafson, Yoonsuh Lee, Dawoon Jung, June-Young Koh, Wonchul Lee, Sangmoon Lee, Kamran Shazand","doi":"10.1038/s41525-025-00520-5","DOIUrl":"10.1038/s41525-025-00520-5","url":null,"abstract":"<p><p>Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder. This study used whole-genome sequencing (WGS) to investigate the genetic basis of AIS in 119 patients from 103 families. Our WGS analysis identified known pathogenic or protein-truncating variants in 15 probands, and other strong or moderate candidate variants in 69 additional patients. We found both coding and non-coding mutations, including structural variants. Candidate genes included known AIS genes (e.g., COL11A2, FBN1) and genes linked to other musculoskeletal disorders with scoliosis (e.g., RYR1). Association analysis confirmed four known AIS single-nucleotide polymorphisms in our cohort. Gene set enrichment analysis revealed four gene clusters related to skeletal muscle contraction, extracellular matrix, and gene expression regulation. This WGS-based approach identified clinically relevant genetic variations and biological pathways in AIS patients, offering valuable insights into its complex development.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"67"},"PeriodicalIF":4.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12514243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275420","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":"Meta-analysis reveals transcription factors and DNA binding domain variants associated with congenital heart defect and orofacial cleft.","authors":"Raehoon Jeong, Martha L Bulyk","doi":"10.1038/s41525-025-00525-0","DOIUrl":"10.1038/s41525-025-00525-0","url":null,"abstract":"<p><p>Many congenital anomaly patients lack genetic diagnoses because there are many disease genes as yet to be discovered. We applied a gene burden test incorporating de novo predicted-loss-of-function (pLoF) and likely damaging missense variants together with inherited pLoF variants to a collection of congenital heart defect (CHD) and orofacial cleft (OFC) parent-offspring trio cohorts (n = 3835 and 1844, respectively). We identified 17 novel candidate CHD genes and 8 novel candidate OFC genes, of which many were known developmental disorder genes. TFs were enriched among the significant genes; 14 and 8 transcription factor (TF) genes showed significant variant burden for CHD and OFC, respectively. In total, 30 affected children had a de novo missense variant in a DNA binding domain of a known CHD, OFC, and other developmental disorder TF genes. Our results suggest candidate pathogenic variants in CHD and OFC and their potentially pleiotropic effects in other developmental disorders.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"63"},"PeriodicalIF":4.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192171","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":"Genetic analyses across cardiovascular traits: leveraging genetic correlations to empower locus discovery and prediction in common cardiovascular diseases.","authors":"Paloma Jordà, Yiwei Lai, Amélie Jeuken, Louis-Philippe Lemieux Perreault, Elisabeth Goulet, Najim Lahrouchi, Anna Nozza, Michael W Tanck, Peter Guerra, Julia Cadrin-Tourigny, Simon de Denus, Connie R Bezzina, Guillaume Lettre, David Busseuil, Marie-Pierre Dubé, Jean-Claude Tardif, Rafik Tadros","doi":"10.1038/s41525-025-00515-2","DOIUrl":"10.1038/s41525-025-00515-2","url":null,"abstract":"<p><p>Common genetic variation detected by genome-wide association studies (GWAS) partially explains variability in the spectrum of cardiac phenotypes. In this work, we explore genetic correlations among 58 cardiac-related traits/diseases, detecting novel ones. We subsequently employ multi-trait analysis of GWAS (MTAG), which meta-analyzes genetically correlated traits, to improve genomic loci discovery and prediction in atrial fibrillation (AF), coronary artery disease (CAD), and heart failure (HF). We identify 19 novel loci specific for AF, 131 for CAD, and 141 for HF. Polygenic scores (PGS) in 15,177 Canadian individuals show similar results when PGS are derived from conventional GWAS versus MTAG summary statistics, although MTAG-PGS improve prediction and discrimination of CAD in females [∆R² 1.735% (95% Confidence Interval (CI): 0.609-2.856); Net reclassification index 0.208 (95%CI: 0.139-0.277)]. This work describes new relevant genetic correlations among cardiac-related traits/diseases and supports MTAG to improve loci discovery in common cardiovascular diseases and potentially improve the prediction of CAD in females.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"65"},"PeriodicalIF":4.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12480102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192136","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":"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}