European Journal of Human Genetics最新文献

{"title":"The potential of whole genome sequencing in pharmacogenetics: a retrospective health record study in rare disease patients.","authors":"Madeline Gorny, Katja S Just, Tim Krüger, Matthias Begemann, Florian Kraft, Thomas Eggermann, Jeremias Krause, Miriam Elbracht","doi":"10.1038/s41431-026-02025-w","DOIUrl":"https://doi.org/10.1038/s41431-026-02025-w","url":null,"abstract":"<p><p>The clinical relevance of pharmacogenetics (PGx) is becoming increasingly evident as knowledge in this field expands. As of May 2025, 209 clinical guideline annotations are already listed on the internationally recognized ClinPGx website. Nevertheless, except for a few indications, the implementation of PGx in clinical practice currently remains limited in most countries. At the same time, whole genome sequencing (WGS) is increasingly applied in clinical diagnostics, particularly for rare and oncological diseases. These data could also be used for simultaneous PGx analysis. In a retrospective study, we analysed short-read WGS data from 1,000 individuals, including index patients with suspected rare disorders and their relatives. For a subset of 359 individuals, medical reports were reviewed to document drug prescriptions. Guidelines published by PGx consortia on ClinPGx were used for phenotype assignment and interpretation. Clinically relevant PGx variants were detected in 97% (n = 970) of the cohort. Among patients with drug prescriptions (n = 359), 30% (n = 111) had been prescribed at least one medication for which their PGx profile would recommend therapy adjustment. Additionally, CNVs and rare variants were detected, which in 28% (n = 8) resulted in modified therapeutic recommendations. While the most (cost)-efficient strategy for broad PGx implementation remains subject of future research, our findings demonstrate that existing WGS data, such as those generated in the context of rare disease patients, could provide substantial benefits for PGx diagnostics with minimal additional effort.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating direct-to-consumer genetic testing: experiences, decisions and perspectives of Dutch users","authors":"Danny Bruins,&nbsp;Esther A. M. Bührman,&nbsp;Martina C. Cornel,&nbsp;Marc H. W. van Mil,&nbsp;Margreet G. E. M. Ausems,&nbsp;Olga C. Damman,&nbsp;Tessel Rigter","doi":"10.1038/s41431-026-02022-z","DOIUrl":"10.1038/s41431-026-02022-z","url":null,"abstract":"Insights into the perspectives, decision-making and experiences of non-US consumers regarding health-related direct-to-consumer genetic testing (DTC-GT) are currently lacking. These insights are essential to allow the implementation of consumer-tailored approaches that facilitate responsible use of DTC-GT. To fill this knowledge gap, the present study employed interviews to examine the consumer journeys of twenty Dutch health-related DTC-GT consumers. Overall, participants appeared quite satisfied with their DTC-GT consumer journeys. Participants’ initial contacts with DTC-GT, as well as their pre-test information acquisition, occurred via a diversity of sources. Participants’ pre-test expectations revealed considerable presumed clinical utility of DTC-GT. Feeling unheard within the regular healthcare system supported multiple participants’ decisions to undergo health-related DTC-GT. Participants mentioned a modifying effect of price on their decision-making, and several participants stated not having considered potential negative consequences of DTC-GT prior to DTC-GT usage. Several potentially adverse consequences of undergoing DTC-GT were identified that could affect individual consumers, the regular healthcare system, and society as a whole. Three considerations to potentially stimulate responsible use of DTC-GT aligning with participants’ needs and preferences were derived, namely improving pre-test information provision, implementing adequate post-test support systems for consumers, and development, implementation and enforcement of cross-border regulation and legislation. Based on these findings, we advocate for stakeholder discussions to further explore the feasibility and desirability of translating these considerations into deliverables. Ultimately, these deliverables could aid in empowering (potential) consumers for responsible use of health-related DTC-GT.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 4","pages":"480-490"},"PeriodicalIF":4.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02022-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature","authors":"Fatimah Albuainain,&nbsp;Myrrhe Venema,&nbsp;Rachel Schot,&nbsp;Gideon Huigen,&nbsp;Grazia M. S. Mancini,&nbsp;Tjakko J. van Ham,&nbsp;Tahsin Stefan Barakat","doi":"10.1038/s41431-026-02023-y","DOIUrl":"10.1038/s41431-026-02023-y","url":null,"abstract":"Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by bi-allelic pathogenic variants in CCDC32. So far, CFNDS has only been described in four living individuals and one terminated fetus from four families, and the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar hypoplasia, and cardiac anomalies. We present a family with two affected individuals who were diagnosed through clinical RNA sequencing (RNA-seq) after conventional DNA diagnostics did not yield a molecular cause. Skipping of two exons in CCDC32 transcript was identified, consistent with a bi-allelic deletion including exons 3 and 4 of CCDC32. This deletion was not detected in previous SNP array analyses and trio exome sequencing focusing on genes related to intellectual disability and congenital malformations, highlighting the complementary value of RNA-seq. Furthermore, we review the clinical phenotype of this rare disorder and its potential disease mechanisms.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 4","pages":"574-579"},"PeriodicalIF":4.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic exploration of the relationship between liability to psychiatric disorders and acne vulgaris","authors":"Brittany L. Mitchell,&nbsp;Michelle K. Lupton,&nbsp;Miguel E. Rentería,&nbsp;Michael A. Simpson,&nbsp;William R. Reay","doi":"10.1038/s41431-026-02028-7","DOIUrl":"10.1038/s41431-026-02028-7","url":null,"abstract":"Observational epidemiology suggests a link between the dermatological disorder acne vulgaris and several psychiatric disorders. However, the biological mechanisms that underlie the relationship between acne and mental health are poorly characterised. Here, we employed a genetic approach using large-scale genome-wide association studies of acne and ten psychiatric disorders to both estimate causal effects and uncover potential shared genetic risk factors. Multiple psychiatric disorders displayed evidence of small-to-moderate genetic correlations with acne. However, only genetic liability to schizophrenia displayed some evidence of a causal effect on the risk of acne, though horizontal pleiotropy cannot be fully excluded. Using a Gaussian mixture-model based approach, we then identified a cluster of schizophrenia-associated variants with distinct effects on acne liability, refining the molecular mechanisms that may link schizophrenia and acne. Shared genetic risk architecture between schizophrenia and acne was also investigated using Bayesian approaches. This revealed a subset of genetic loci associated with both acne and schizophrenia via shared or different causal variants, implicating biological processes including glutamatergic signalling. Finally, we found that genetic risk for schizophrenia was also associated with increased acne severity using a population-based cohort. In summary, we revealed genetic support for a biological relationship between acne and schizophrenia that may at least partially drive the elevated rates of acne amongst people living with schizophrenia.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 4","pages":"565-573"},"PeriodicalIF":4.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02028-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing genomic medicine: Guidelines, risk scores, and disease discovery","authors":"Alisdair McNeill","doi":"10.1038/s41431-026-02021-0","DOIUrl":"10.1038/s41431-026-02021-0","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"165-166"},"PeriodicalIF":4.6,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02021-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive screening in hereditary cancer: a randomized controlled trial to test cell-free DNA-based early detection in the CHARM consortium.","authors":"Kirsten M Farncombe, Julia A Sobotka, Melyssa Aronson, Mark Basik, Yvonne Bombard, Leslie Born, Rona Cheifetz, Marc Clausen, Natalie Coburn, Lesa Dawson, Andrea S Doria, Khaled Y Elbanna, Holly Etchegary, William D Foulkes, Chiquita Hessels, Angela Hyde, Karineh Kazazian, Adam Kinnaird, C Anne Koch, Stephane Laframboise, Jordan Lerner-Ellis, Stephanie Lheureux, David Malkin, Ur Metser, Lynette S Penney, Sarah Ridd, Kasmintan A Schrader, Teresa Tiano, Alicia A Tone, Patrick Veit-Haibach, Stephanie Wong, Wei Xu, Trevor J Pugh, Raymond H Kim","doi":"10.1038/s41431-026-02014-z","DOIUrl":"https://doi.org/10.1038/s41431-026-02014-z","url":null,"abstract":"<p><p>Individuals with hereditary cancer syndromes are born with germline genetic variants that significantly increase their lifetime risk of developing multiple cancers. Cancer rates and overall mortality can be reduced with intensive surveillance to facilitate early cancer detection. However, participating in diagnostic imaging and endoscopy surveillance programs is often time-consuming, overwhelming, inconvenient, and anxiety-inducing. To improve this, multi-cancer early detection tests are being developed using cell-free DNA (cfDNA) sequencing analysis to detect cancers with more sensitivity than conventional screening methods. Our community (the CHARM consortium: Cell-free DNA in Hereditary And high-Risk Malignancies) has been exploring the use of cfDNA sequencing in hereditary cancer, and has launched the CHARM2 prospective randomized controlled trial, which is enrolling 1000 participants with Hereditary Breast and Ovarian Cancer, Lynch syndrome, Li-Fraumeni syndrome, Neurofibromatosis type 1 and Hereditary Diffuse Gastric Cancer to improve equitable access, early detection and surveillance for high-risk individuals. All participants will have screening as per conventional syndrome-specific surveillance recommendations. Half the participants (experimental cohort) will also have cfDNA analysis at least three times a year, with abnormal results triggering dedicated clinical imaging and diagnostic evaluation, and heightened surveillance. Vetted by our patient advisors, validated patient-reported outcome and experience measures assessing participant psychosocial outcomes, engagement, and test preferences will be administered to both arms. Our goal is to inform if and how cfDNA analysis could be implemented into routine clinical care and offer a path to equitable and more convenient cancer screening for all high-risk Canadians.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Results of a multigene panel testing approach targeting patients with suspected genetic predisposition to pancreatic ductal adenocarcinoma.","authors":"Bruno Buecher, Mathilde Warcoin, Emilie Rolland, Rukhshona Abdullazoda, Aurélia Le Guillevic, Chrystelle Colas, Lisa Golmard","doi":"10.1038/s41431-026-02020-1","DOIUrl":"https://doi.org/10.1038/s41431-026-02020-1","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma occur in the context of a suspected or proven genetic predisposition in 5-10% of cases. While universal germline multigene panel testing is currently recommended by NCCN and ASCO, this approach was previously limited to patients with personal and/or family criteria suggestive of hereditary predisposition. We report the results of this « selective » approach applied in our institution from January 2018 to June 2023. Germline testing of a panel of 13 « clinically actionable » genes (APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51C, RAD51D, STK11) was performed in 496 patients with pancreatic ductal adenocarcinoma and suspected genetic predisposition based on the validation of prespecified clinical criteria. A germline pathogenic/likely pathogenic variant of one of these genes was identified in 49 patients corresponding to 9.9% of the study population. ATM and BRCA2 were the two most frequently implicated genes (18 and 16 cases, respectively) and the prevalence of pathogenic/likely pathogenic variants of these genes was significantly higher than in gnomAD controls. The overall contribution of core and non-core genes of the Homologous Recombination DNA repair system was 83.7% while the contribution of the Mismatch Repair system was 10.2%. An exploratory approach consisting of unmasking the results of the NGS analysis of 123 « research » genes involved in the carcinogenesis was applied to the 447 patients tested negative for the different genes of our diagnostic panel. This approach failed to identify other susceptibility genes to pancreatic adenocarcinoma.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De novo heterozygous variants of the RSF1 gene are responsible for a syndromic neurodevelopmental disorder","authors":"Céline Jost,&nbsp;Tiffany Busa,&nbsp;Daniel Wegner,&nbsp;Marwan Shinawi,&nbsp;Elise Schaefer,&nbsp;Amélie Piton,&nbsp;Caroline Schluth-Bolard,&nbsp;Perrine Charles,&nbsp;Boris Keren,&nbsp;Katharina Mayerhanser,&nbsp;Theresa Brunet,&nbsp;Ulrich Schatz,&nbsp;Jennifer E. Neil,&nbsp;Christopher A. Walsh,&nbsp;Kathleen Sisco,&nbsp;Alexander J. Paul,&nbsp;Undiagnosed Diseases Network,&nbsp;Chung Lee,&nbsp;Natalie Dykzeul,&nbsp;Devon Bonner,&nbsp;Jonathan A. Bernstein,&nbsp;Erin Sutcliffe,&nbsp;Ingrid M. Wentzensen,&nbsp;Catherine Froehlich,&nbsp;Kaleigh Liebler,&nbsp;Patricia Galvin Parton,&nbsp;Jody Weiss-Burns,&nbsp;Chloé Sagnol,&nbsp;Julian Delanne,&nbsp;Caroline Racine,&nbsp;Christel Thauvin-Robinet,&nbsp;Hana Safraou,&nbsp;Frédéric Tran Mau-Them,&nbsp;Yannis Duffourd,&nbsp;Ange-Line Bruel,&nbsp;Laurence Faivre","doi":"10.1038/s41431-026-02017-w","DOIUrl":"10.1038/s41431-026-02017-w","url":null,"abstract":"Neurodevelopmental disorders (NDD) are a wide and heterogenous group of conditions due to impaired brain development, orchestrated by the crosstalk between genome and environment. Dynamic chromatin regulation during cortical development is fundamental, and chromatin remodelers are critical determinants of this process. Recently, numerous chromatin remodeling genes have been implicated in NDDs. By altering genes’ epigenetic state, mutated chromatin remodelers disrupt the spatiotemporal regulation of gene expression during development, potentially leading to severe consequences. The Remodeling and Spacing Factor 1 (RSF1) gene encodes a ubiquitous nuclear protein involved in chromatin remodeling, crucial for processes such as DNA transcription, replication, and repair. In this study, we identified by gene matching (n = 7) and literature search (n = 4) eleven unrelated individuals harboring de novo or inherited from a symptomatic parent heterozygous variants in RSF1. All individuals had an NDD, whether intellectual disability, autism spectrum disorder or developmental delay. From the seven individuals with detailed clinical information, unspecific and inconsistent associated features were described, including cranio-facial morphological features, musculoskeletal, digestive, vision, tone, epilepsy and brain MRI anomalies. Our data support the hypothesis that RSF1 is important for brain development and a novel candidate gene for syndromic NDDs.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 4","pages":"554-564"},"PeriodicalIF":4.6,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02017-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the genetic landscape of inherited metabolic diseases using long-read sequencing and transcriptomic profiling","authors":"Alejandro Soriano-Sexto,&nbsp;Obdulia Sánchez-Lijarcio,&nbsp;Leonardo Beccari,&nbsp;Natalia Castejón-Fernández,&nbsp;Fátima Leal,&nbsp;Patricia Alcaide,&nbsp;Belén de la Morena-Barrio,&nbsp;María del Pilar Bahíllo-Curieses,&nbsp;Patricia Correcher,&nbsp;Rafael Hencke-Tresbach,&nbsp;Laura López,&nbsp;Elena Martín-Hernández,&nbsp;Raquel Yahyaoui,&nbsp;Magdalena Ugarte,&nbsp;Pilar Rodríguez-Pombo,&nbsp;Belén Pérez","doi":"10.1038/s41431-025-01995-7","DOIUrl":"10.1038/s41431-025-01995-7","url":null,"abstract":"Although next-generation sequencing has emerged as a powerful tool for diagnosing rare diseases (RD), many cases of inherited metabolic diseases (IMD) remain unsolved, hindering the diagnosis, clinical and therapeutic management of the patients. The primary aim of this study is to address the most elusive cases by applying long-read sequencing (LRS) targeted to the gene of interest on seven patients (FARS2, GYS2, PEX1, SLC2A1, AGL, ACAT1, and ACADM), identifying six novel pathogenic variants including two intronic variants, a structural variant and three transposable elements (TE) insertions. In addition, we have demonstrated the effect on splicing of an exonic variant previously reported as missense. Functional genetic tests specific for the expected effect of each variant of uncertain significance were designed, such as minigenes analysis or chromatin conformation capture assay. From the TE insertions, two were located in the genomic region of GYS2 or PEX1, causing a reduction in their mRNA expression. The third was located 7.6 kb downstream of SLC2A1; it alters the interaction between the SLC2A1 promoter and its distal regulatory element via the establishment of a loop with the 3’ border of the native topologically associating domain. This study shows that the combination of LRS and functional genetic assays confers a powerful approach for expanding the mutational spectrum of IMD, adding data to improve the diagnosis of this large group of RD.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 4","pages":"543-553"},"PeriodicalIF":4.6,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01995-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146051011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic diagnosis of CYP21A2-related CAH: adaptive sampling long-read sequencing is an accurate and scalable solution","authors":"Dorte Launholt Lildballe,&nbsp;Morten Reiffenstein Huno,&nbsp;Lukas Ochsner Reynaud Ridder,&nbsp;Camilla Mains Balle,&nbsp;Simon Opstrup Drue,&nbsp;Agnethe Berglund,&nbsp;Morten Dunø,&nbsp;Ebbe Norskov Bak,&nbsp;Mette Hansen Viuff,&nbsp;Laura Skak Rasmussen,&nbsp;Claus Højbjerg Gravholt","doi":"10.1038/s41431-026-02019-8","DOIUrl":"10.1038/s41431-026-02019-8","url":null,"abstract":"Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, commonly caused by variants in CYP21A2 (chr6p21.33), which encodes the 21-hydroxylase enzyme. Genetic diagnosis is challenging due to the high homology between CYP21A2 and its nearby pseudogene CYP21A1P. The current gold standard, PCR-based Sanger sequencing combined with multiplex ligation-dependent probe amplification (MLPA), is labor-intensive, costly, and amenable to PCR bias. Furthermore, it is not reliable in detecting complex structural variants, and it provides no information on whether variants are located on the same allele or not. The purpose of this study was to develop a method based on long-read sequencing (LRS) for accurate diagnostics of CYP21A2 variants and their phasing. Adaptive sampling (AS-)-LRS with chromosome 6 as region-of-interest was applied to DNA from 34 patients clinically diagnosed with CAH. To overcome mapping challenges in the highly homologous regions, we developed NanoCAH, a custom bioinformatic tool that accurately distinguishes between CYP21A2 and CYP21A1P reads. Using AS-LRS and NanoCAH, we genetically confirmed CYP21A2-associated CAH in 32 (94%) of the patients, including reliable phasing of the variants without the need for parental testing. AS-LRS clarified previously ambiguous findings, including the detection of chimeric genes, deletions, and missed variants. Compared to current gold standard methods, AS-LRS proved to be faster and more scalable, while providing greater accuracy in detecting variants within the CYP21A2 region. This makes AS-LRS a promising tool not only for CAH diagnosis but also for genetic testing in other regions with complex genomic architecture.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 4","pages":"535-542"},"PeriodicalIF":4.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02019-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}