NPJ Genomic Medicine最新文献

{"title":"Bridging the gap: an emerging link between tubulinopathies and ciliopathies.","authors":"Sydney Steiman, Safia Omer, Stephen Pastore, Evgueni A Ivakine","doi":"10.1038/s41525-026-00576-x","DOIUrl":"https://doi.org/10.1038/s41525-026-00576-x","url":null,"abstract":"<p><p>Genetic neurodevelopmental disorders arise from variants in genes critical for brain development, including those causing ciliopathies and tubulinopathies. Both disorders are linked to brain malformations, intellectual disability, and motor impairments. Since cilia rely on microtubules for ciliogenesis, axoneme formation, and intraflagellar transport, defects in tubulin genes can directly disrupt ciliary function. This review highlights emerging evidence connecting these two disease groups and reveals how tubulin variants impact ciliopathy mechanisms.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pleiotropic germline PTEN mutations influence gastrulation through dysregulated AKT activation.","authors":"Omer Enes Onur, Juan Andres Venegas, Arda Durmaz, Shin Chung Kang, Masahiro Hitomi, Charis Eng","doi":"10.1038/s41525-026-00574-z","DOIUrl":"https://doi.org/10.1038/s41525-026-00574-z","url":null,"abstract":"<p><p>PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, exhibits pleiotropic manifestations, including hamartomas, cancers, and neurodevelopmental disorders, posing challenges in patient management. We hypothesized that mutant PTEN allele-dependent alterations during gastrulation impact PHTS pleiotropism. We generated gastruloids from isogenic human induced pluripotent stem cells with clinically relevant heterozygous PTEN mutations, PTEN^G132D/WT found in PHTS patients with cancer, hamartoma, and autism spectrum disorder, and PTEN^M134R/WT associated with cancer-only patients. PTEN^G132D/WTgastruloids exhibited axial over-elongation driven by AKT hyperactivation, upregulation of Snail, a key regulator of epithelial-to-mesenchymal transition (EMT), and enrichments in mesoderm and endoderm-related gene signatures, compared to those with PTEN^M134R/WT or PTEN^WT/WT. Our machine-learning algorithm accurately recognized the over-elongated PTEN^G132D/WT gastruloids and morphological reversal with AKT inhibitor treatment. Our data suggest a potential link between the mutant PTEN allele-specific early developmental alterations and the clinical outcomes of PHTS, and provide a platform for pathogenic mutation and drug screening.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence in genomic medicine: dispelling three myths.","authors":"Benjamin D Solomon","doi":"10.1038/s41525-026-00575-y","DOIUrl":"https://doi.org/10.1038/s41525-026-00575-y","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"11 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777323","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 variants in Rps4x cause intellectual disability with dysmorphic features, microcephaly, and autism.","authors":"Courtney Matheny-Rabun, Lynda Holloway, Ken Corning, Raymond Louie, PoNien Lu, Thomas Smol, Simon Boussion, Emily Woods, Diana Johnson, Catherine Williams, Richard Steet, Michael Friez, Gavin Arno, Roger Stevenson, Heather Flanagan-Steet","doi":"10.1038/s41525-026-00573-0","DOIUrl":"https://doi.org/10.1038/s41525-026-00573-0","url":null,"abstract":"<p><p>X-linked intellectual disability (XLID) comprises a group of heterogeneous disorders associated with impaired cognitive function and developmental delays. It has been estimated that 10% of the genes on the X-chromosome are associated with at least one form of intellectual disability. To date, genetic variants in 172 genes have been associated with XLID. Clinically, these disorders are highly variable, with some exhibiting multi-system involvement and others limited only to intellectual impairment. Here we describe a new XLID condition caused by defects in RPS4X, which encodes a component of the small (40S) subunit of the ribosome. Genetic testing of two male siblings with dysmorphic facial features, microcephaly, global developmental delay, and autism revealed a maternally inherited missense variant in RPS4X. Studies in patient fibroblasts and zebrafish indicate this RPS4X variant is pathogenic, with functional findings consistent with the clinical presentation. Four additional individuals with intellectual disability were identified through the GeneMatcher and the 100,000 Genomes project that also bear RPS4X variants. Together, these data support RPS4X as a new XLID-associated gene, expanding the involvement of ribosomal components in genetic disease.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immuno-molecular features associated with exceptional recurrence-free survivorship from Ovarian Cancer in the pre-PARP era.","authors":"Félix Blanc-Durand, Elisa Yaniz Galende, Gwénaël Ferron, Marie-Christine Kaminsky, Elsa Kalbacher, Sophie Abadie-Lacourtoisie, Florence Joly, Jerome Meunier, Olivier Tredan, Coriolan Lebreton, Jerome Alexandre, Alain Zannetti, Christophe Louvet, Cyriak Blonz, Nadine Dohollou, Dominique Berton, Christophe Desauw, Elisabeth Carola, Michel Fabbro, Philippe Follana, Eric Pujade-Lauraine, Louis Mourani, Audrey Le Formal, Hortense Gaultier De Saint Basile, Catherine Genestie, Etienne Rouleau, Alexandra Leary","doi":"10.1038/s41525-026-00570-3","DOIUrl":"https://doi.org/10.1038/s41525-026-00570-3","url":null,"abstract":"<p><p>High-grade serous ovarian cancer (HGSOC) remains a leading cause of gynecological cancer mortality, with only <15% of patients achieving long-term, relapse-free survival. Using data from the VIVROVAIRE (NCT03418844) and CHIVA (NCT03418844) clinical trials, this study investigated the molecular and immunophenotypic characteristics of long-term recurrence-free survivors (LTS) compared with short-term survivors (STS). Tumor samples from 37 LTS (recurrence-free ≥3 years) and 105 STS were analyzed using next-generation sequencing, BRCA1/RAD51C promoter methylation assays, shallow whole genome and multiplex immunofluorescence. Homologous recombination deficiency (HRD) was defined by BRCA1/2 or RAD51C/D alterations, and genomic instability scores (GIS). Immune profiling included quantification of CD4⁺, CD8⁺, CD20⁺, and FOXP3⁺ cells. LTS were younger and had a lower prevalence of FIGO stage IV disease. Molecularly, LTS showed fewer TP53 mutations, enrichment of BRCA2 mutations and BRCA1 and RAD51C promoter methylation, and a strong association between RB1 loss co-occurring with a BRCA alteration. Conversely, CCNE1 amplification was underrepresented in LTS. Immune profiling demonstrated increased stromal and intraepithelial CD8⁺ T-cell infiltration and reduced FOXP3⁺ regulatory T cells in LTS. Overall, exceptional survival in HGSOC is associated with younger age, enrichment of BRCA2 mutations and BRCA1/RAD51C methylation, reduced CCNE1 amplification, and a competent antitumor immune response. These findings highlight potential biomarkers for refining risk stratification and guiding personalized therapeutic strategies in ovarian cancer management.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-penetrance TP53 variants are mainly hypomorphic: an underestimated issue with high clinical significance.","authors":"Lea Rodriguez, Bernard Leroy, Franck Toledo, Julianne Susanne Funk, Thorsten Stiewe, Panagiotis Baliakas, François Delhommeau, Thierry Soussi","doi":"10.1038/s41525-026-00568-x","DOIUrl":"10.1038/s41525-026-00568-x","url":null,"abstract":"<p><p>Missense mutations that inactivate p53 are common in cancer. LiFraumeni syndrome, which is linked to early-onset cancer, is caused by germline mutations in TP53. Full-penetrant, inactive variants have garnered great attention, whereas low-penetrant variants are less well understood despite their clinical importance. This study systematically leveraged the 2025 UMD_TP53 database to identify missense variants that exhibit a statistically skewed germline-versus-somatic ratio (GVSr). Unlike classic hotspots that are equally prevalent in somatic and germline settings, these variants were disproportionately found in the germline, suggesting they act as low-penetrance variants with insufficient potency to drive tumorigenesis as single somatic events. To define the biological basis of LPVs, we integrated functional data from multiplexed assays of variant effects, tumor cell transcriptome analyses and computational predictive tools. This characterization revealed that these high-GVSr p53 variants consistently retain intermediate transcriptional activity and growth-suppressive function, classifying them distinctively as hypomorphic alleles rather than loss-of-function mutants. Our findings highlight the complexity of TP53 variant effects and underscore the importance of refined functional classification. Recognizing and accurately characterizing hypomorphic variants associated with low-penetrance cancer risk are essential for precision oncology, as they will improve genetic counseling, risk stratification, and tailored surveillance strategies for individuals with TP53 mutations.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717595","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":"Clinical validation of a high-performance somatic exome sequencing assay: from target-enrichment strategy to variant calling.","authors":"Junko Tsuji, Micah Rickles-Young, Justin Abreu, Alyssa Friedman, Caroline Petersen, J Bryan, Konrad Scheffler, Taylor O'Connell, Theo Heyns, Edyta Malolepsza, Mark Fleharty, Katie Larkin, Kenneth J Livak, Shuqiang Li, David A Reardon, Catherine J Wu, Patrick A Ott, Fanny Dao, Heidi Rehm, Max Jan, Chip Stewart, Gad Getz, Varun Jain, Severine Catreux, Carrie Cibulskis, Niall Lennon","doi":"10.1038/s41525-026-00569-w","DOIUrl":"10.1038/s41525-026-00569-w","url":null,"abstract":"<p><p>Clinical whole-exome sequencing (WES) has revolutionized clinical diagnostics by enabling scalable, cost-effective molecular profiling to detect somatic variants and identify novel therapeutic targets. In particular, the clinical evaluation of somatic variants relies on both high-quality sequencing data and robust variant detection with rapid turnaround times. We developed an updated WES workflow utilizing a co-developed Twist Bioscience targeting panel and the DRAGEN (Dynamic Read Analysis for GENomics) platform, benchmarked with cell line mixtures containing >40,000 simulated variants and a clinical cohort of FFPE tumor specimens. Our assay, the Broad Clinical Somatic Whole Exome Assay V6.0, demonstrated high sensitivity (96.9% for SNVs with variant allele fraction [VAF] >10% at ≥125X; 93.5% for InDels with VAF > 20% at ≥125X) and low false positive rates (0.04 and 0.01 per Mb, respectively). The assay meets clinical requirements and enables large-scale, accurate variant profiling of cancers, expanding opportunities for molecular diagnostics across diverse clinical settings.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147654641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variants in the ciliopathy gene SCLT1 are associated with non-syndromic and syndromic retinal degeneration of variable severity.","authors":"Riccardo Sangermano, Kaoru Fujinami, Suk Ho Byeon, Emily M Place, Julien Navarro, Johanna Valensi, Samer Khateb, Eyal Banin, Christel Condroyer, Stephanie DiTroia, Dror Sharon, Christina Zeitz, Isabelle Audo, Kinga M Bujakowska, Jinu Han","doi":"10.1038/s41525-026-00566-z","DOIUrl":"10.1038/s41525-026-00566-z","url":null,"abstract":"<p><p>Inherited retinal degenerations (IRDs) are a group of clinically and genetically heterogeneous blinding disorders. In this study, we describe five families clearly or which were presumed to be diagnosed with autosomal recessive non-syndromic IRD and one with mild syndromic IRD, in which affected probands carried rare bi-allelic variants in SCLT1, a gene previously associated with multiple autosomal recessive ciliopathies. Eight of the ten variants identified were novel; five variants affected splicing, including the known missense p.(Lys544Arg), detected in compound heterozygosity in three East Asian probands, and the novel, hypomorphic, deep-intronic variant c.290+2732A>G, leading to the inclusion of a 45-bp cryptic exon containing a premature termination codon. Analysis of the genomic data also revealed a large in-frame tandem duplication spanning exons 3-10, which was subsequently validated. Although no clear correlation was found between the severity of the SCLT1-associated phenotypes and the identified causal variants, this report expands the current knowledge of SCLT1-associated disease by enriching its mutational landscape and clearly supports its association with autosomal recessive non-syndromic IRD.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147654663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the genetic architecture of non-Huntington chorea: a biobank-scale study of rare variants and repeat expansions.","authors":"Fulya Akçimen, Monica Diez-Fairen, Ignacio Alvarez, Victor Puente, Spencer Grant, Jorge Hernandez-Vara, Marzieh Khani, Mariateresa Buongiorno, Félix Javier Jiménez-Jiménez, José A G Agúndez, Miquel Aguilar, Esther Cubo, Jesus Perez, Javier Pagonabarraga, Núria Caballol, Asuncion Avila, Jinhui Ding, Elena García-Martín, Hortensia Alonso-Navarro, Yaroslau Compta, Carlos Cruchaga, Katrin Beyer, J Raphael Gibbs, Andrew Singleton, Sara Bandres-Ciga, Pau Pastor","doi":"10.1038/s41525-026-00567-y","DOIUrl":"https://doi.org/10.1038/s41525-026-00567-y","url":null,"abstract":"<p><p>Chorea can arise from genetic, metabolic, pharmacologic, and autoimmune causes. In clinical practice, however, non-genetic causes are rare. The most common genetic cause is a CAG repeat expansion in HTT, leading to Huntington's disease (HD). Beyond HD, systematic studies have been lacking and many individuals with non-HD chorea remain without a molecular diagnosis. We conducted whole-exome and genome sequencing analysis on 190 non-HD chorea cases, leveraging data from the All of Us Research Program (n = 134), UK Biobank (n = 26), and a clinically ascertained multicenter Spanish cohort recruited by the Spanish Study Group for Genetics of Chorea (SSGGC) (n = 30). Variant calling was performed without pre-filtering based on a disease or gene list, and variants were clinically contextualized using OMIM, ClinVar, and in silico predictions. We identified thirteen protein-altering variants, including six previously described as pathogenic or likely pathogenic. Notably, we identified a pathogenic JPH3 expansion in a patient of Black race and c9orf72 expansions in individuals of European and South Asian ancestry. These findings explained 23% of cases in the SSGGC, 12% in UK Biobank, and 4% in All of Us. Our results broaden the genetic architecture of non-HD chorea and highlight the value of multi-ancestry genomic approaches for rare movement disorders.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proof-of-concept study for the detection of somatic structural variant driver alterations using HiFi long-read sequencing in a pediatric leukemia cohort.","authors":"Lisa A Lansdon, Byunggil Yoo, Ayse Keskus, Irina Pushel, Chengpeng Bi, Tanveer Ahmad, Asher Bryant, Adam Walter, Margaret Gibson, Mary Rindler, Weijie Li, Sultan M Habeebu, Linda D Cooley, John Herriges, Elena Repnikova, Lei Zhang, Keith J August, Terrie G Flatt, Alan S Gamis, Erin M Guest, J Allyson Hays, Maxine Hetherington, Karen Lewing, Tomi Pastinen, Mikhail Kolmogorov, Midhat S Farooqi","doi":"10.1038/s41525-026-00560-5","DOIUrl":"https://doi.org/10.1038/s41525-026-00560-5","url":null,"abstract":"<p><p>Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variants (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort. We show that this methodology successfully determined all known crSVs (n = 5/5) detected through routine clinical testing. This approach also identified crSVs that resulted in the classification of a leukemia genetic subtype for four additional patients (n = 4/12), such as an ins(11;10)(q23.3;p12p12) forming a KMT2A::MLLT10 fusion, that were missed by routine clinical approaches. This study demonstrates the diagnostic potential of lrSeq as an assay for SV detection in pediatric leukemia and supports lrSeq as a valuable tool for the accurate detection of crSVs.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}