NPJ Genomic Medicine最新文献

{"title":"Exercise-induced lactic acidemia associated with a SLC16A13 biallelic variant.","authors":"Narin Intarak, Sasiprapa Prommanee, Thanakorn Theerapanon, Worawan Sirichana, Onanong Kulaputana, Vichit Supornsilchai, Atsushi Ohazama, Katsushige Kawasaki, Paul T Sharpe, Thitaya Chaiboonyarak, Vorasuk Shotelersuk, Thantrira Porntaveetus","doi":"10.1038/s41525-026-00577-w","DOIUrl":"10.1038/s41525-026-00577-w","url":null,"abstract":"<p><p>The molecular basis of impaired lactate clearance and exercise-induced lactic acidemia remains largely unknown. Here, we report a 10-year-old Thai girl, born to consanguineous parents, with growth delay and partial growth hormone deficiency. The proband underwent detailed clinical phenotyping, exercise stress testing, metabolic profiling, and genome sequencing. She presented with profound exercise-induced lactic acidemia, characterized by elevated blood lactate (3.7-fold above baseline) and severely compromised clearance. Genome sequencing identified a novel homozygous frameshift variant in the solute carrier gene SLC16A13 (c.24delC, p.Asp9Thrfs*50). To assess causality, Slc16a13 knockout mice were generated and subjected to treadmill exercise and biochemical assays, revealing impaired decline of blood lactate after exercise (p = 0.001) and altered amino acid metabolism. These findings implicate SLC16A13 as a critical regulator of lactate metabolism in humans and establish a direct link between biallelic SLC16A13 variants and exercise-induced lactic acidemia, highlighting a novel genetic mechanism underlying exercise stress and metabolic dysregulation.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006032","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":"Germline variants in cancer susceptibility genes among patients with mucosal melanoma.","authors":"Afsaneh Amouzegar, Xiaogang Wu, James P Long, Gabriela W Chen, Justin W Wong, Sabitha Prabhakaran, Latasha Little, Curtis Gumbs, Neus Bota, Jared Malke, Julie Simon, Jianhua Zhang, Priyadharsini Nagarajan, Michael A Davies, Hussein Tawbi, Rodabe N Amaria, Isabella C Glitza Oliva, Alexandra P Ikeguchi, Shirley Su, Ehab Y Hanna, Roi Weiser, Brian Bednarski, Travis T Sims, Devarati Mitra, Jennifer Wargo, Jeffrey E Gershenwald, Paul Scheet, Yao Yu, Chad Huff, Kelly C Nelson, Jennifer L McQuade, P Andrew Futreal","doi":"10.1038/s41525-026-00583-y","DOIUrl":"10.1038/s41525-026-00583-y","url":null,"abstract":"<p><p>Mucosal melanoma (MM) is a rare and aggressive melanoma subtype with poor outcomes and poorly understood risk factors, including the contribution of germline pathogenic variants (PVs). In this study, 346 MM patients treated at MD Anderson Cancer Center underwent germline sequencing of 322 known cancer susceptibility genes, with PV frequencies compared to population controls (gnomAD and TOPMed) using Fisher's exact test. The cohort had a median age at diagnosis of 64 years and was predominantly female (62%) and White (84.0%). Anatomical subtypes of MM included gastrointestinal (36%), head and neck (33%), and genitourinary (31%). Among patients with somatic testing results (n = 303), KIT mutations (26%) were most common, followed by NRAS (17%), BRAF^Non-V600 (6.6%), and BRAF^V600 (2.6%). Germline PVs were identified in 37 patients (10.7%), most frequently in CHEK2 (n = 9, 23.0%), ATM (n = 8, 20.5%), and MITF (n = 6, 15.4%). MITF p.E318K (OR 6.0; 95% CI 2.2-13.2) and CHEK2 c.1100delC (OR 6.7; 95% CI 1.8-17.5) were significantly enriched compared to population control rates. Patients with germline PVs were more likely to have two or more affected first-degree relatives (49.0% vs. 29.1%, p = 0.019). These findings highlight a meaningful germline contribution to MM risk and support the incorporation of genetic testing in this population.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13478063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006072","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 uncovers diverse genetic causes and phenotypic signatures in infantile nystagmus and albinism.","authors":"Mahmoud R Fassad, Pradeep C Vasudevan, Julian Barwell, Gail DE Maconachie, Savita Madhusudhan, David Hunt, Irene Gottlob, Mariya Moosajee, Omar A Mahroo, Andrew R Webster, Michel Michaelides, Mervyn G Thomas","doi":"10.1038/s41525-026-00580-1","DOIUrl":"10.1038/s41525-026-00580-1","url":null,"abstract":"<p><p>We combined deep phenotype data and whole-genome sequencing results from the UK 100,000 Genomes Project (100KGP) to characterize the genetic spectrum of infantile nystagmus and albinism, and to explore genotype-phenotype correlations in this cohort. Participants were enrolled in the study based on the clinical codes for albinism or infantile nystagmus. Whole genome sequencing data was retrieved and variants in known nystagmus/albinism genes (PanelApp R39 panel) were analysed alongside genome-wide findings. We ascertained 473 affected individuals (388 families). Positive genetic findings were obtained in 218 participants (46%), including 176 (37%) with definitive diagnoses. Pathogenic variants were found in 16 of 38 panel genes, most commonly in TYR (56 families) and OCA2 (21 families). Recurrent variants (24% of 103 different variants) were identified in six genes. An additional 36 off-panel genes accounted for diagnoses in 45 families, including four dual genetic diagnoses in three families. Phenotypically, refractive errors and foveal hypoplasia-related diagnoses were significantly enriched (odds ratio ~2.8 for refractive disorders). Strabismus and neurodevelopmental features were also over-represented in the cohort. We show that whole-genome sequencing provided a high diagnostic yield in infantile nystagmus/albinism and uncovered a broad allelic spectrum. Integrating comprehensive phenotype data identified distinct genotype-phenotype relationships.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13454288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147973944","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":"Multimodal characterisation of the SMN locus in SMA: copy number quantification and hybrid gene identification.","authors":"Alba Berzal-Serrano, Sonia González-Alvaredo, Iván Lesende, Lidón Carretero-Vilarroig, Teresa Jaijo, Ignacio Onsurbe, Karolina Aragon-Gawinska, Nancy Carolina Ñungo-Garzón, Inmaculada Pitarch-Castellano, Juan Francisco Vázquez-Costa, Elena Aller, José María Millán, Gema García-García","doi":"10.1038/s41525-026-00579-8","DOIUrl":"10.1038/s41525-026-00579-8","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic disruption of the Survival Motor Neuron 1 (SMN1) gene. Accurate quantification of Survival Motor Neuron 2 (SMN2) copy number is essential for patient stratification, prognosis, and treatment decisions, yet remains challenging at high copy numbers and does not fully explain phenotypic variability. We compared complementary molecular approaches in 78 Spanish patients with genetically confirmed SMA. Multiplex ligation-dependent probe amplification (MLPA) and digital PCR (dPCR) showed complete concordance, supporting their reliability for SMN2 quantification. In contrast, the AmplideX PCR/CE SMN1/2 Plus Kit showed discrepancies in seven patients, mainly at clinically relevant thresholds (three vs. four SMN2 copies), indicating higher sensitivity to technical variability. Notably, dPCR resolved a case with >5 SMN2 copies, demonstrating superior resolution. Long-read sequencing (LRS) in ten patients with MLPA-detected rearrangements enabled high-resolution reconstruction of the SMN locus and revealed six previously undescribed SMN hybrid structures. Structural haplotype architecture, rather than copy number alone, may further determine SMN variability and contribute to phenotype heterogeneity. Overall, our findings support an integrated diagnostic strategy in which copy-number quantification is complemented by structural characterisation in complex cases, improving molecular resolution of the SMN locus.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13458669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982097","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":"AI-genomics synergy for drug repurposing in breast cancer: an interpretability-driven framework.","authors":"Rahaf M Ahmad, Salahdein Aburuz, Bassam R Ali, Noura AlDhaheri","doi":"10.1038/s41525-026-00578-9","DOIUrl":"10.1038/s41525-026-00578-9","url":null,"abstract":"<p><p>Breast cancer's genomic heterogeneity complicates drug discovery, making repurposing an attractive but challenging strategy. Advances in artificial intelligence now enable integration of multi-omics data to reveal drug-gene-disease relationships and generate subtype-specific repurposing hypotheses. In this Review, we examine AI-driven computational approaches from signature-based to multi-modal frameworks and propose an integrated interpretability-driven framework linking mechanistic validation with clinical translation toward more transparent and actionable precision oncology.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982153","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":"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":"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":5.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13351064/pdf/","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":"OA","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":"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":5.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13328305/pdf/","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":"OA","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":"10.1038/s41525-026-00575-y","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"11 1","pages":""},"PeriodicalIF":5.3,"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":"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":5.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282477/pdf/","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":"OA","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":"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":5.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13314978/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}