{"title":"Completely resolved structural variants by optical genome mapping with adaptive sampling from CNV discovery.","authors":"Li Fu, Chong Ae Kim, Masatoshi Tokita, Yohane Miyata, Nobuhiko Okamoto, Yoshio Makita, Hitoshi Osaka, Ayataka Fujimoto, Atsuro Daida, Jun Nirei, Noriko Udagawa, Seiichi Hayakawa, Kimiko Deguchi, Mitsumasa Fukuda, Hiroshi Matsumoto, Manami Akasaka, Junichiro Okada, Yohei Misumi, Jun Kido, Toshifumi Suzuki, Hiromi Aoi, Rie Seyama, Haruka Hamanoue, Satomi Mitsuhashi, Sachiko Ohori, Ken Saida, Yuta Inoue, Kohei Hamanaka, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Atsuo Itakura, Naoki Harada, Atsushi Fujita, Naomichi Matsumoto","doi":"10.1038/s41525-026-00561-4","DOIUrl":"10.1038/s41525-026-00561-4","url":null,"abstract":"<p><p>Structural variants (SVs), including duplications, deletions, inversions, translocations, and insertions, play major roles in human phenotypic diversity but remain difficult to detect because of variable size and structural complexity. Optical genome mapping (OGM) uses ultra-high molecular weight DNA (>150 kb) fluorescently labeled at a specific six-nucleotide sequence, enabling comprehensive SV detection by analyzing labeling patterns along long DNA molecules. This study aimed to fully characterize SVs using OGM. OGM was applied to 30 cases with exome sequencing-based copy number (CN) variants (16 CN losses, 7 CN gains, and 7 combined CN losses and gains). Additionally, targeted Oxford Nanopore long-read sequencing with adaptive sampling was used to determine breakpoints of SVs. This approach revealed undetected SVs in 14 cases (46.7%), and disclosed gene disruptions or CN alterations explaining clinical features in seven cases (23.3%). Even complex SVs involving numerous chromosomal segments and breakpoints were resolved efficiently, highlighting the power of combining OGM and long-read sequencing. Integrating OGM with long-read sequencing improves diagnostic resolution beyond sequencing alone and provides a robust framework for interpreting complex SVs. These findings highlight the potential clinical utility of combining OGM and long-read sequencing as a comprehensive diagnostic strategy for improved precision medicine in rare genetic diseases.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13184285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521673","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}
Suzanne E de Bruijn, Van den Born L Ingeborgh, Ronny Derks, Lonneke Haer-Wigman, Luke O'Gorman, Frans P M Cremers, Ronald van Beek, Alexander Hoischen, Susanne Roosing, Kornelia Neveling
{"title":"Publisher Correction: Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome.","authors":"Suzanne E de Bruijn, Van den Born L Ingeborgh, Ronny Derks, Lonneke Haer-Wigman, Luke O'Gorman, Frans P M Cremers, Ronald van Beek, Alexander Hoischen, Susanne Roosing, Kornelia Neveling","doi":"10.1038/s41525-026-00559-y","DOIUrl":"10.1038/s41525-026-00559-y","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"11 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13013611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513652","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}
Lamis Yehia, Lin Li, Gideon Idumah, Thomas W Frazier, Vladimir Makarov, Aritra Bose, Laxmi Parida, Antonio Hardan, Julian A Martinez-Agosto, David M Ritter, Mustafa Sahin, Charis Eng, Ying Ni
{"title":"Genomic modifiers of malignant and neurodevelopmental phenotypes in individuals with PTEN hamartoma tumor syndrome.","authors":"Lamis Yehia, Lin Li, Gideon Idumah, Thomas W Frazier, Vladimir Makarov, Aritra Bose, Laxmi Parida, Antonio Hardan, Julian A Martinez-Agosto, David M Ritter, Mustafa Sahin, Charis Eng, Ying Ni","doi":"10.1038/s41525-026-00556-1","DOIUrl":"10.1038/s41525-026-00556-1","url":null,"abstract":"<p><p>PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN variants, exhibits marked phenotypic heterogeneity, most notably cancer, neurodevelopmental disorders (NDD), or both. The basis for this divergence, even among carriers of identical PTEN variants, remains poorly defined. We performed whole-genome sequencing of 599 individuals with PHTS and family members, complemented by analyses of PTEN variant carriers from the All of Us Research Program. Analyses included both targeted evaluation of genes previously implicated in cancer and NDD and agnostic genome-wide single-variant and rare-variant burden testing. The analytic cohort comprised 543 PHTS probands, including individuals with NDD (n = 171), cancer (n = 221), both phenotypes (n = 21), or neither (n = 130) at the time of enrollment. Pathogenic or likely pathogenic variants in cancer-associated genes were identified in 37 (6.8%), most frequently in MITF, DICER1, and BRCA2, while 43 (7.9%) harbored variants in NDD-related genes, including DHCR7, POLG, and ARSA. Such secondary variants were less common in PTEN variant carriers in All of Us. Genome-wide analyses identified candidate modifier loci functionally linked to PTEN, including in ZNF713, TPTE2P1, and PDPK1. These findings demonstrate that PHTS phenotypes are shaped by complex gene-gene interactions beyond PTEN alone, informing mechanisms underlying the cancer-NDD dichotomy and advancing precision risk stratification.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13172402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474489","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}
Michal Stawarski, Noa Bielopolski, Ilana Roitman, Karen Fridman, Shane Wald-Altman, Megan Eitel, Benedict Hui, Anneke Vulto-van Silfhout, Alexander P A Stegmann, Adela Chirita-Emandi, Jacqueline Eason, Kirsty Bradshaw, Lewis Darnell, Grażyna Kostrzewa, Rafal Ploski, Romane Meurs, Amandine Batté, Stylianos E Antonarakis, Martin Gassmann, Bernhard Bettler
{"title":"Functional signatures of de novo GABBR1 and GABBR2 variants associated with neurodevelopmental disorders.","authors":"Michal Stawarski, Noa Bielopolski, Ilana Roitman, Karen Fridman, Shane Wald-Altman, Megan Eitel, Benedict Hui, Anneke Vulto-van Silfhout, Alexander P A Stegmann, Adela Chirita-Emandi, Jacqueline Eason, Kirsty Bradshaw, Lewis Darnell, Grażyna Kostrzewa, Rafal Ploski, Romane Meurs, Amandine Batté, Stylianos E Antonarakis, Martin Gassmann, Bernhard Bettler","doi":"10.1038/s41525-026-00558-z","DOIUrl":"10.1038/s41525-026-00558-z","url":null,"abstract":"<p><p>GABA<sub>B</sub> receptors, the G protein-coupled receptors for the neurotransmitter GABA, are essential for regulating neuronal excitability in the brain. Monoallelic de novo missense variants in GABBR1 and GABBR2, which encode the receptor subunits, have been associated with neurodevelopmental disorders. Here, we investigated the functional impact of seven de novo missense variants in GABBR1 and GABBR2 identified in individuals with autism spectrum disorder, intellectual disability, and/or attention deficit/hyperactivity disorder. In vitro functional characterization of these variants revealed a range of gain- and loss-of-function alterations: (i) increased constitutive activity, leading to a corresponding decrease in GABA efficacy; (ii) a significant reduction in GABA potency at the receptor; and (iii) reduced surface expression, resulting in decreased GABA efficacy. While computational predictions indicated pathogenicity for all variants, our study emphasizes the importance of functional studies in clarifying the nature and scope of pharmacological changes-an essential step toward advancing targeted therapies in precision medicine.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390689","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}
Sung Kyung Kim, Joowon Jang, Yeseul Kim, Hobin Sung, Hyesu Lee, Hara Yim, Sung Im Cho, Jee-Soo Lee, Moon-Woo Seong
{"title":"Integrative analysis of in silico predictions and clinical evidence to delineate the capability of HiFi long-read sequencing in paralogous genes.","authors":"Sung Kyung Kim, Joowon Jang, Yeseul Kim, Hobin Sung, Hyesu Lee, Hara Yim, Sung Im Cho, Jee-Soo Lee, Moon-Woo Seong","doi":"10.1038/s41525-026-00555-2","DOIUrl":"10.1038/s41525-026-00555-2","url":null,"abstract":"<p><p>Paralogous genes challenge short-read sequencing (SRS) due to high sequence similarity. Although long-read sequencing (LRS) improves resolution, the extent to which it resolves paralogous genes remains unclear. This study evaluates the capability of LRS by integrating in silico mappability-based predictions with clinical data to generate SRS- and LRS-unresolved gene lists, and by assessing whether a paralog-specific phasing, Paraphase, can overcome remaining limitations. Mappability was simulated across read lengths (250 bp to 14 kb) to predict unresolved regions and validated against mapping quality (MQ) from 66 high-fidelity LRS samples. Paraphase was applied to 79 paralog groups. Among 645 medically relevant (MR) genes unresolved by SRS, 419 (65.0%) were predicted to be resolved by LRS, while 226 (35.0%) remained unresolved. These predictions correlated with clinical MQ (χ² = 92.43, p < 2.2 × 10<sup>-16</sup>; κ = 0.37), with significant differences between LRS-resolved and LRS-unresolved MR genes (W = 63,656, p < 2.2 × 10<sup>-16</sup>; r = 0.36). Paraphase resolved 61 groups (77.2%), providing additional resolution beyond LRS. LRS improves paralogous gene resolution but cannot fully eliminate paralog blind spots. Curated gene lists define boundaries of LRS utility for clinical interpretation, while Paraphase adds complementary resolution, supporting an integrated framework combining predictive modeling with algorithmic strategies.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347748","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":"Variants in MTNAP1 underlie a neurodegenerative disorder by impairing mitochondrial stability.","authors":"Abhishek Kumar, Smita Saha, Nazim Nasir, Vishal Gaurav, Yogendra Pratap Mathuria, Shailesh Kumar Gupta, Akash Ranjan, Debasish Kumar Ghosh","doi":"10.1038/s41525-026-00554-3","DOIUrl":"10.1038/s41525-026-00554-3","url":null,"abstract":"<p><p>Mutations in genes encoding mitochondrial proteins are increasingly recognized as a major cause of neurodegenerative disorders, owing to the role of mitochondria in neuronal energy metabolism and signaling. Here, we investigate MTNAP1 (mitochondrial nucleoid-associated protein 1) as a novel gene associated with an autosomal recessive neurodevelopmental disorder characterized by progressive cerebral and cerebellar atrophy. Three affected probands from two unrelated families presented with global developmental delay, ataxia, spasticity, seizures, and progressive neurological decline, with MRI revealing generalized cerebral and cerebellar volume loss and thinning of the corpus callosum. Trio-based exome sequencing uncovered two ultra-rare, biallelic loss-of-function variants in MTNAP1: a homozygous missense variant (p.G553R) in two siblings and a homozygous nonsense variant (p.Y13X) in an unrelated proband. Functional studies in proband-derived fibroblasts and MTNAP1-silenced neuronal cells implicated profound mitochondrial fragmentation, reduced oxidative phosphorylation capacity, increased reactive oxygen species accumulation, and premature senescence-like stress responses. Structural modeling and biophysical analyses revealed that the p.G553R variant destabilizes the MTNAP1 fold, disrupts its DNA- and membrane-binding interfaces, and induces aberrant aggregation, leading to loss of mitochondrial integrity. Collectively, our findings suggest MTNAP1 as a crucial regulator of mitochondrial homeostasis and identify pathogenic MTNAP1 variants as the cause of a novel, progressive neurodegenerative disorder.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13035927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146258576","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":"Inherited burden for disease predisposition in diverse populations.","authors":"Barış Kayaalp, Meltem Ece Kars, Yuval Itan, Ayşe Nazlı Başak, Jean-Laurent Casanova, Tayfun Özçelik","doi":"10.1038/s41525-026-00552-5","DOIUrl":"10.1038/s41525-026-00552-5","url":null,"abstract":"<p><p>We leveraged allele frequencies from gnomAD, Regeneron Genetics Center Million Exome and Turkish Variome for 4591 disease genes from PanelApp and OMIM, and identified 97,135 pathogenic and 478,263 likely pathogenic variants using an American College of Medical Genetics and Genomics-based classifier. This expanded pathogenic and likely pathogenic variants nearly six-fold. On average, an individual is born with 4.70 pathogenic or likely pathogenic variants, of which 1.66 are compatible with a Mendelian condition at the genotype level; 1 in 11 has an actionable genotype, and 382 genes are candidates for carrier screening. A genome-first approach revealed the likelihood of having a genotype compatible with disease in 13 ICD-10 disease groups, for example, congenital (1 in 2.70), musculoskeletal/connective (1 in 3.00) and blood/immune (1 in 3.07 individuals). Evidence-based genetic epidemiology demonstrates the potential of personalized medicine for the implementation of early preventive measures and incentivization of lifestyle changes to enhance healthspan and lifespan.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13031552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220552","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}
Lilian Downie, Jade Caruana, Nathasha Kugenthiran, Anaita Kanga-Parabia, Erin Tutty, Yvonne Bombard, Marc Clausen, Sophie Bouffler, Clara Gaff, Alison D Archibald, Sebastian Lunke, Zornitza Stark
{"title":"Supporting decisions about genomic newborn screening at scale in the digital age: the BabyScreen+ study.","authors":"Lilian Downie, Jade Caruana, Nathasha Kugenthiran, Anaita Kanga-Parabia, Erin Tutty, Yvonne Bombard, Marc Clausen, Sophie Bouffler, Clara Gaff, Alison D Archibald, Sebastian Lunke, Zornitza Stark","doi":"10.1038/s41525-026-00551-6","DOIUrl":"10.1038/s41525-026-00551-6","url":null,"abstract":"<p><p>Digital platforms hold promise to scale implementation of population screening. We tailored the Genetics Adviser platform to provide education, decision support, consent, and result return in a genomic newborn screening (gNBS) study, BabyScreen + . Participants were surveyed and interviewed on the usability and value of Genetics Adviser. Genetics Adviser was used by 1048 participants and 1007 (96%) provided feedback. The majority (96%, n = 963) found the platform easy to navigate, with 85% (n = 851) spending <20 min online. Participants demonstrated excellent understanding, over 80% answering at least 6/8 knowledge questions correctly. Only 7% (12/173) of participant-initiated contacts with the study team were for genetic counselling. Interview participants valued the online process. We demonstrate the successful use of a digital platform for a genomic screening program. This model is streamlined, providing consistent, user-friendly education to support decision-making with minimal input from healthcare practitioners. Further evaluation in diverse populations will be essential for future use.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197829","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}
Ayesha Chowdhury, Shashikanth Marri, Lucy Anastasi, Alex Ashenden, Tomas Rozek, Jinghua Feng, Lucas DeJong, Rosalie Kenyon, Dominik Kaczorowski, Hung Nguyen, Khoa Lam, Kirsty Stallard, Tracy Merlin, Enzo Ranieri, Sunita De Sousa, Nicholas Smith, Abhi Kulkarni, Benjamin Saxon, Drago Bratkovic, Christopher Barnett, Carol Wai-Kwan Siu, Hamish S Scott, Jovanka King, Karin S Kassahn
{"title":"Semi-automated genomic newborn screening highlights complexities in reporting.","authors":"Ayesha Chowdhury, Shashikanth Marri, Lucy Anastasi, Alex Ashenden, Tomas Rozek, Jinghua Feng, Lucas DeJong, Rosalie Kenyon, Dominik Kaczorowski, Hung Nguyen, Khoa Lam, Kirsty Stallard, Tracy Merlin, Enzo Ranieri, Sunita De Sousa, Nicholas Smith, Abhi Kulkarni, Benjamin Saxon, Drago Bratkovic, Christopher Barnett, Carol Wai-Kwan Siu, Hamish S Scott, Jovanka King, Karin S Kassahn","doi":"10.1038/s41525-026-00553-4","DOIUrl":"10.1038/s41525-026-00553-4","url":null,"abstract":"<p><p>Newborn screening programs are instrumental in the early detection of treatable conditions in the first days of life. By integrating genomic approaches, there is potential to expand the range of conditions included in these programs. As part of a research study, NewbornsInSA, we validated a genomic newborn screening workflow. Analysis of whole-genome sequencing data was restricted to a virtual panel of 613 genes, selected through engagement with local clinical teams. We assessed the workflow's performance using retrospective samples with known variant status. To reduce manual curation time, bioinformatics scripts were developed to auto-classify cases into those with no findings and those requiring manual review. We report on early findings from applying this workflow to a prospectively recruited cohort in which five reportable findings have been made to date. We discuss reporting challenges encountered in genes associated with multiple conditions, with incomplete penetrance, or variants associated with only mild phenotypes.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12960665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156187","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}
Giovanni Spirito, Sara Trova, Gaia Treves, Khudayar Farmanli, Mariacristina Franzese Canonico, Agata Fant, Stefano Marangoni, Federica Furia, Debora Charrance, Nicola Locci, Sara Gottardo, Francesca Groppo, Vittoria Perseghin, Martina Toscano, Erika Bibbò, Serena Donetti Dontin, Cecilia Cargnelutti, Mélody Colliard, Alessandro Rosina, Anna Maria Beoni, Cristina Bérard, Alessandro Coppe, Paolo Serravalle, Fabio Landuzzi, Francesco Musacchia, Antonio Amoroso, Remo Sanges, Andrea Cavalli, Manuela Vecchi, Laure Obino, Stefano Gustincich
{"title":"New insights into neurodevelopmental disorders by whole genome sequencing of 100 families from Italy.","authors":"Giovanni Spirito, Sara Trova, Gaia Treves, Khudayar Farmanli, Mariacristina Franzese Canonico, Agata Fant, Stefano Marangoni, Federica Furia, Debora Charrance, Nicola Locci, Sara Gottardo, Francesca Groppo, Vittoria Perseghin, Martina Toscano, Erika Bibbò, Serena Donetti Dontin, Cecilia Cargnelutti, Mélody Colliard, Alessandro Rosina, Anna Maria Beoni, Cristina Bérard, Alessandro Coppe, Paolo Serravalle, Fabio Landuzzi, Francesco Musacchia, Antonio Amoroso, Remo Sanges, Andrea Cavalli, Manuela Vecchi, Laure Obino, Stefano Gustincich","doi":"10.1038/s41525-025-00547-8","DOIUrl":"10.1038/s41525-025-00547-8","url":null,"abstract":"<p><p>Neurodevelopmental disorders (NDDs) have a strong but largely unexplained genetic basis. Moreover, the genetic architecture of these complex disorders in under-represented communities is poorly studied. We analyzed 110 probands from 100 families (for a total of 298 individuals), using whole genome sequencing (WGS) to identify genetic contributors to NDDs. This study is part of the '5000genomi@VdA' project characterizing Valle d'Aosta (Italy) genomic landscape in health and disease. Probands were stratified into three diagnostic categories: ASD (autism spectrum disorder without intellectual disability), ID (intellectual disability without ASD), and ASD-ID (autism spectrum disorder with comorbid intellectual disability). Following the ACMG guidelines, we identified 32 likely phenotype-causing variants in known NDD-associated genes in 26.4% of the probands. We observed a diagnostic yield gradient, lowest in ASD, intermediate in ASD-ID, and highest in ID. We also identified 42 variants of uncertain significance, 14 of which were located in genes not previously linked to NDDs but relevant to neurodevelopment, and may thus represent new NDD candidate genes. Furthermore, we used Evo 2, an evolutionary constraint-based model, to refine variant interpretation and identify VUS with pathogenic-like signatures. These findings highlight the utility of WGS in exploring the genetic heterogeneity within stratified NDD clinical groups.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":"11"},"PeriodicalIF":5.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12886966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106550","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}
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