European Journal of Human Genetics最新文献

{"title":"Patient views on receiving a pharmacogenetic passport - a mixed methods study exploring experiences and use after an opportunistic offer.","authors":"Eva Meier, Danny Bruins, Marieke A R Bak, Pierre M Bet, Mariette A van den Hoven, Martina Cornel, Tessel Rigter","doi":"10.1038/s41431-026-02226-3","DOIUrl":"https://doi.org/10.1038/s41431-026-02226-3","url":null,"abstract":"<p><p>Genomic data plays an increasingly important role in clinical care, yet how it can be appropriately integrated into standard practice remains debated. One emerging approach is the opportunistic use of whole-exome sequencing (WES) data to offer pharmacogenetic (PGx) information. While initiatives providing PGx prescribing recommendations ahead of actual prescriptions are growing, little is known about how recipients of such information use it in practice or how it shapes their perceived roles and responsibilities. Using a mixed-methods design combining a quantitative survey with qualitative interviews, we explored the experiences and use of an opportunistic PGx passport, that was offered to parents who had undergone a trio-WES in pursuit of a genetic diagnosis for their child's developmental delay. We examined how they experienced and used the passport in practice and how it influenced their perceived role and responsibilities in a care setting. A total of 44 respondents were included in this study. The passport was used by only a minority of participants, partly due to the absence of a current medication need, but primarily due to limited ability to understand and apply the PGx information. The PGx passport shifted responsibilities away from the digital healthcare information systems onto the individual recipient. Without adequate support, this shift risks responsibilizing recipients rather than genuinely empowering them with access to their PGx profiles. Based on these findings, we offer recommendations for the implementation of similar opportunistic PGx offers and for policy focussing on the appropriate integration of PGx into standard healthcare practice.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976356","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":"Genomic and computational analysis of variants in telomere regulatory genes in subjects with bone marrow failure.","authors":"Anjali Shah, Anchal Yadav, Merin George, Somprakash Dhangar, Aruna Rajendran, Chandrakala Shanmukhaiah, Sujata Sharma, Susan Idicula-Thomas, Babu Rao Vundinti","doi":"10.1038/s41431-026-02233-4","DOIUrl":"https://doi.org/10.1038/s41431-026-02233-4","url":null,"abstract":"<p><p>Telomere Biology Disorders (TBDs) are a genetically heterogeneous and often under-recognized cause of Bone Marrow Failure Syndromes (BMFS), driven by defective telomere maintenance and progressive telomere attrition. We performed an integrated genomic, telomeric and computational analysis in 118 subjects presenting clinical features of BMFS to delineate the contribution of Telomere Regulatory Genes (TRGs) variants to disease pathogenesis. Whole exome sequencing (WES) identified pathogenic (18.18%), likely pathogenic (27.27%) and rare variants of uncertain significance (54.54%) in 27 subjects (22.9%) across five TRGs: RTEL1, TERT, TINF2, NOP10, and WRAP53. Telomere Length (TL) assessment revealed significant telomere shortening in TRG variant-positive subjects compared with age-matched controls, with the most profound attrition observed in individuals harboring de novo TINF2 gene variants. RTEL1 emerged as the most frequently affected gene, with recurrent clustering of variants within its C-terminal regulatory region. A familial NOP10 variant, Asp12His, segregated with cutaneous pigmentation and hematological abnormalities consistent with the established role of NOP10 in dyskeratosis congenita, further broadening the known mutational spectrum of the gene. Structure-guided in-silico analyses predicted that both novel and recurrent variants disrupt protein stability, telomerase assembly or trafficking and shelterin complex integrity. Reduced TERT expression and a significant inverse correlation between telomere length and clinical severity further underscored the functional impact of TRG defects. Collectively, this study provides the first comprehensive characterization of TRG variants in the Indian BMFS cohort and highlights the utility of integrating genomic sequencing, telomere length measurement and computational modeling to improve diagnostic precision, variant interpretation and clinical stratification in TBDs.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148967396","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":"Long-read sequencing reveals a hidden Alu-mediated splice defect in CPLANE1, causing orofaciodigital syndrome type VI.","authors":"Jelena Pozojevic, Henrike Lisa Sczakiel, Saranya Balachandran, Nathalie Kruse, Martin Atta Mensah, Wiebke Hülsemann, Kristian Händler, Malte Spielmann","doi":"10.1038/s41431-026-02224-5","DOIUrl":"https://doi.org/10.1038/s41431-026-02224-5","url":null,"abstract":"<p><p>Orofaciodigital syndrome type VI (OFD VI) is a recessive ciliopathy characterized by excessive polydactyly, molar tooth sign, cleft lip, and developmental delay, caused by pathogenic variants in CPLANE1. Here, we present a patient with OFD VI that remained genetically unexplained after routine genetic testing, including short-read whole genome sequencing (WGS). Using long-read sequencing, we found two biallelic splice-site variants in CPLANE1, c.8633-4_8633-3del, and an Alu element insertion close to an exon-intron boundary. Transcript analysis showed that each variant independently resulted in exon skipping, and quantitative expression studies revealed reduced total CPLANE1 mRNA levels in patient-derived fibroblasts. Based on these findings, we were able to re-classify the c.8633-4_8633-3del variant from a variant of uncertain significance (VUS) to likely pathogenic. The identification of an Alu element insertion missed by short-read WGS highlights the added diagnostic value of long-read sequencing in uncovering cryptic, transposable element-associated pathogenic variants.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955196","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":"Professional bodies: how best to promote and support individuals working in human genetics and genomics.","authors":"William G Newman","doi":"10.1038/s41431-026-02032-x","DOIUrl":"https://doi.org/10.1038/s41431-026-02032-x","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944461","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":"The role of pathology laboratories in integrating genetic testing into Australian primary care: an implementation science perspective.","authors":"Maryam Vizheh, Samran Sheriff, Klay Lamprell, Romika Patel, Jeffrey Braithwaite, Janet C Long","doi":"10.1038/s41431-026-02213-8","DOIUrl":"https://doi.org/10.1038/s41431-026-02213-8","url":null,"abstract":"<p><p>As genomic testing moves into mainstream healthcare, non-genetic healthcare professionals, including general practitioners (GPs), play a critical role as gatekeepers to genetic services. Laboratories are essential in supporting this transition by providing not only high-quality genetic tests but also point-of-care tools, educational materials and clinical guidance to support their use. This study aimed to explore how these tools and supports are conceptualized, developed, implemented and evaluated and how laboratories integrate them into their relationships with GPs, an essential process for paving the way toward better use of genomics in primary care. A qualitative study design was employed using semi-structured, in-depth interviews with representatives from genetic laboratories across Australia. The Consolidated Framework for Implementation Research (CFIR) guided deductive content analysis of data. Findings spanned the four CFIR domains (Intervention Characteristics, Outer Setting, Inner Setting and Implementation Process) across 34 constructs. Participants reported that laboratories viewed point-of-care tools and resources as essential responses to persistent genomic knowledge gaps among GPs. Development of evidence-based, practice-driven and adaptable resources was supported and rewarded within laboratory organisations. A strong culture of clinical responsibility and implementation readiness, combined with robust networks and communications, enabled timely support for GPs. Gaps identified included lack of implementation planning, misalignments between laboratory-developed resources and GPs' real-world needs and inadequate mechanisms for obtaining GPs' feedback, which made evaluation problematic. By applying an implementation science framework, these findings provide insights for future efforts to build and sustain the provision of point-of-care tools and support, ultimately improving the integration of genomics in primary care.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944507","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":"Correction: Hemizygous loss-of-function variants of EIF1AX are associated with a syndromic neurodevelopmental disorder.","authors":"Kazuyuki Komatsu, Atsushi Sugie, Yohei Nitta, Jiro Osaka, Ummul Halilunnisa Mansoor Hussain, Mitsuru Kubota, Nobuyuki Shimozawa, Melissa T Carter, Petra J G Zwijnenburg, Quinten Waisfisz, Felix Boschann, Denise Horn, Mitsuko Nakashima, Hirotomo Saitsu","doi":"10.1038/s41431-026-02219-2","DOIUrl":"https://doi.org/10.1038/s41431-026-02219-2","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944456","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":"Concealed cardiomyopathy in sudden childhood death: translation from molecular autopsy to family assessment.","authors":"Andrea Greco, Jose Cruzalegui, Estefanía Martínez-Barrios, Agustín Luján-Carrillo, Marisa Ortega, Núria Molina, Sergi Cesar, Fernanda Merchán, Fredy Chipa, Nuria Diez-Escuté, Patricia Cerralbo, Irene Zschaeck, Juan Carlos Canós, Simone Grassi, Antonio Oliva, Rocío Toro, Eneko Barberia, Silvia Planas, Georgia Sarquella-Brugada, Oscar Campuzano","doi":"10.1038/s41431-026-02229-0","DOIUrl":"https://doi.org/10.1038/s41431-026-02229-0","url":null,"abstract":"<p><p>One of the ongoing challenges in childhood remains the unexplained sudden death. Autopsies identify a subset of cases that harbor rare variants in genes associated with cardiomyopathy in structurally normal hearts, suggesting a concealed cardiomyopathy. Our goal is to interpret all available data in each case to provide answers to unexplained deaths, while also implementing preventative measures for at-risk family members. Our retrospective study included 68 childhood cases of sudden death, classified as inconclusive at autopsy. Molecular autopsy analyzed all genes currently associated with inherited arrhythmogenic syndromes. Variants were reinterpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Seventeen autopsy-inconclusive childhood cases (70.59% males) carried at least one rare variant in any of the cardiomyopathy-susceptibility genes. A definite deleterious variant was identified in seven cases (10.3%), whereas ten (14.7%) carried only variants of uncertain significance. Slight non-diagnostic myocardial alterations were identified in five cases (7.35%), and three of them carried a deleterious variant. Clinical and genetic analyses of all families identified a carrier of deleterious variants with a diagnosis of cardiomyopathy in six of them (8.82%). Our data support the inclusion of a comprehensive analysis of all genes associated with inherited cardiomyopathies in childhood cases of unexpected death. A personalized multidisciplinary interpretation of post-mortem and genetic data, including family assessment, helps to clarify the role of rare variants and determine the most plausible cause of the unexpected death in one-tenth of the childhood individuals.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944524","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":"Three-dimensional facial gestalt analysis for three neurodevelopmental disorders: Koolen-de Vries, Jansen-de Vries and KBG syndrome.","authors":"Jolijn J A Verseput, Nina Claessens, Michiel Vanneste, Guido de Jong, Hilde Peeters, Benedikt Hallgrímsson, Leonie M de Vries, Sanne L de Vries, Thomas Maal, Peter Claes, Bert B A de Vries","doi":"10.1038/s41431-026-02221-8","DOIUrl":"https://doi.org/10.1038/s41431-026-02221-8","url":null,"abstract":"<p><p>Diagnosing children with developmental disorders is often challenging due to the large number of rare syndromes and their variable clinical presentations. While next-generation sequencing has improved diagnostic yield, results are frequently inconclusive, highlighting the continued importance of detailed phenotypic assessment. Three-dimensional (3D) facial imaging has shown advantages over traditional two-dimensional (2D) photographs in syndrome identification, offering new opportunities for more accurate diagnosis. In this study, we explored the benefits of 3D shape analysis for three syndromes seen at the Radboudumc expertise clinic for neurodevelopmental disorders: Koolen-de Vries syndrome (KdVS, N = 16), Jansen-de Vries syndrome (JdVS, N = 9) and KBG syndrome (N = 16). Each patient's facial shape was aligned with a 3D growth curve derived from healthy controls, which allowed us to objectively evaluate how their features compared to their age- and sex-matched average. This analysis aligned with previously recognized features for all three syndromes and led to the identification of a novel phenotypical feature for JdVS, supraorbital grooves. The consistency of the facial features for each of these three syndromes was calculated using a cosine distance analysis and compared with that of 19 other dysmorphically well-characterized syndromes, for the overall face as well as for eight facial segments. In line with current understanding facial phenotypic consistency was highest for KdVS, whereas features of JdVS and KBG syndrome were more diverse in this cohort. These small cohort derived results indicate the potential of 3D imaging for neurodevelopmental disorders, enhance current phenotypical knowledge and provide a foundation for future 3D shape analysis of these three syndromes.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918196","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":"Appreciating diversity: a review of the Iranian genomic landscape.","authors":"Somayeh Alinaghi, Farzane Zare Ashrafi, Zohreh Elahi, Masoumeh Ghasemi, Hossein Najmabadi, Michael Nothnagel","doi":"10.1038/s41431-026-02220-9","DOIUrl":"https://doi.org/10.1038/s41431-026-02220-9","url":null,"abstract":"<p><p>Understanding population structure is crucial for designing and interpreting human genetic studies. This is of particular importance for Iran as a large, ethnically diverse country whose population has often been treated as a genetically homogenous entity. Here, we synthesize published literature on the genetic structure of the Iranian population. We further complement this by recapitulating the geographic, historic, and ethnic background, by comparisons with neighboring countries, and by reviewing autozygosity in Iran. This synthesis confirms large genetic diversity, likely building upon an autochthonous component that was reshaped by multiple migrations. The substantial autosomal substructure falls apart into groups of largely shared genetic ancestry (Central Iranian Cluster) and those with substantial admixture in the past. Structure with respect to uniparental markers is less pronounced. We also find consistency for generally high but varying levels of autozygosity, influenced by ethnicity, residence, and socioeconomic factors. Finally, we recapitulate some examples for geographical differences in disease prevalence and (founder) mutation carrier frequency. Our synthesis emphasizes the need to account for this diversity in human genetic studies in the Iranian population. We provide conclusions for the design of such studies and state expectations on the transferability of genetic findings and genomic predictions, such as polygenic scores, within Iran as well as to neighboring countries. Iran's diversity and geographic location provide renewed motivation for conducting population genetic and ancient DNA studies as well as providing genomic reference resources in this part of the world.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911168","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":"Editorial on the hereditary cancer special issue","authors":"Maurizio Genuardi,&nbsp;Laura Valle","doi":"10.1038/s41431-026-02212-9","DOIUrl":"10.1038/s41431-026-02212-9","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 9","pages":"1191-1193"},"PeriodicalIF":4.6,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02212-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148904445","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}