European Journal of Human Genetics最新文献

{"title":"Pharmacogenomics in drug therapy: global regulatory guidelines for managing high-risk drug reactions.","authors":"Safa Omran, Siew Hua Gan, Siew Li Teoh","doi":"10.1038/s41431-025-01950-6","DOIUrl":"https://doi.org/10.1038/s41431-025-01950-6","url":null,"abstract":"<p><p>Pharmacogenomics is rapidly transforming precision medicine, yet regulatory policies governing its implementation vary widely across countries. This review aims to provide a global perspective on pharmacogenomics guidelines, with a particular focus on high-risk drug reactions such as carbamazepine therapy-induced severe cutaneous adverse reactions. Carbamazepine was selected as a representative example due to its inclusion on the World Health Organization's essential medicines list and its well-documented association with high-risk alleles, which are linked to severe cutaneous adverse reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis-conditions with significant mortality rates. Two databases, Overton and Dimensions, were searched to identify relevant national guidelines and policy documents in English. Countries were identified based on document availability and access to governmental sources. The review revealed that all examined countries recognized genetic variation in carbamazepine response within their guidelines, showing notable consistency. However, religious implications related to pharmacogenomics were largely absent. The findings also indicated a growing global momentum toward integrating pharmacogenomics into healthcare systems, although the depth and scope of regulation differ. The United States stands out for its comprehensive pharmacogenomics policy framework, which extends to clinical and industry settings. Lessons from the U.S. model can inform policy development in other regions, tailored to each country's healthcare infrastructure and cultural context. In conclusion, global harmonization of pharmacogenomics policies is essential to foster international collaboration, enable data sharing, and enhance the safe and equitable implementation of pharmacogenomics in clinical practice.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136870","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":"LNKing genotype to phenotype: the expanding clinical spectrum of SH2B3 disorders.","authors":"Enrico Attardi, Marcin W Wlodarski","doi":"10.1038/s41431-025-01942-6","DOIUrl":"https://doi.org/10.1038/s41431-025-01942-6","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130378","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":"Expanding the molecular spectrum of aggrecanopathies: exploring 24 patients with ACAN significant variants.","authors":"Melek Trigui, Nathalie Pallares-Ruiz, David Geneviève, Cyril Amouroux, Thomas Edouard, Sabine Sigaudy, Marjolaine Willems, Mouna Barat-Houari","doi":"10.1038/s41431-025-01943-5","DOIUrl":"https://doi.org/10.1038/s41431-025-01943-5","url":null,"abstract":"<p><p>Short stature is a prevalent clinical manifestation in children. While certain causes of short stature can be readily identifiable through routine biological tests, often physicians struggle to ascertain any underlying pathogenic cause, resulting in the diagnosis of idiopathic short stature (ISS). Aggrecan, encoded by ACAN, plays a crucial role in cartilage function and bone growth. The aim of our study is to establish a genotype-phenotype correlation in 24 patients carrying distinct ACAN variants. We conducted a panel-based analysis, including 82 genes associated with genetic skeletal disorders and/or short stature, in 388 French patients who consulted for short stature and/or or skeletal features. Genotype-phenotype correlation analysis was performed for all included subjects. Of all positive patients, 24 (≃20%) were found to carry pathogenic or likely pathogenic ACAN variants distributed across the gene, 20 of which had not been previously reported. We report 23 heterozygous cases and one original case with a homozygous SNV. Two patients harboured the same novel nonsense variant, yet exhibited different phenotypes. Familial studies performed in 21 families demonstrated that ACAN variants were inherited in 20 cases. The cohort demonstrated marked phenotypic heterogeneity, even among affected members within the same family. Radiological skeletal abnormalities were observed in 66% of patients. A comprehensive genomic approach is crucial to identify the true proportion of ISS with a monogenic condition. Our results expand the number of pathogenic ACAN variants with their associated phenotypic spectrum. Aggrecanopathies are heterogeneous and particularly frequent in apparently ISS, even without overt skeletal dysplasia.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130461","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":"Toward minimal SNP sets for record-matching with CODIS STR profiles.","authors":"Tamara Gjorgjieva, Noah A Rosenberg","doi":"10.1038/s41431-025-01941-7","DOIUrl":"https://doi.org/10.1038/s41431-025-01941-7","url":null,"abstract":"<p><p>Genetic record-matching is a technique by which profiles with one set of genetic markers can be queried against databases of profiles with a different set of markers to determine if profiles containing different marker sets trace to the same individual. In forensic genetics, the potential for using genetic record-matching to test single-nucleotide polymorphism (SNP) profiles for genetic matches to short-tandem repeat (STR) profiles could enable development of backward-compatible SNP marker systems to ultimately replace existing forensic STR systems. This study aims to identify minimal SNP sets for achieving record-matching accuracies comparable to those previously observed with tens or hundreds of thousands of SNPs. Using phased SNP-STR reference data in a worldwide panel of individuals, we evaluate record-matching accuracy with SNP sets chosen by each of a variety of SNP selection strategies. When selecting SNPs randomly, ~9000 SNPs are required for achieving record-matching accuracy comparable to that seen with the full SNP set in the \"needle-in-haystack\" matching scenario, namely 99% of SNP and STR profiles correctly paired with no false-positive identifications in the median accuracy for test sets of size 626 profile pairs. Selecting SNPs based on various thresholds for their minimal minor allele frequency and physical distance to the STR, however, panels of 1800 SNPs, and as few as 900 SNPs, suffice. These results advance toward a potential minimal size for backward-compatible forensic SNP systems that proceed by genetic record-matching.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124224","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":"Further phenotypical delineation of DLG3-related neurodevelopmental disorders.","authors":"Marlène Malbos, Thierry Gautier, Amelle Shillington, Estelle Colin, Xavier Le Guillou, Oana Caluseriu, Bertrand Isidor, Benjamin Cogné, Cyril Mignot, Boris Keren, Sacha Weber, Clémence Jacquin, Tracy Dudding, Daniel Calame, Juliette Piard, Jonathan Levy, Xenia Latypova, Alain Verloes, Tanguy Niclass, Aurélia Jacquette, Lori White, Marie-Pierre Moizard, Hélène Dollfus, Sébastien Moutton, Julian Delanne, Caroline Racine, Quentin Thomas, Anne-Sophie Denommé-Pichon, Frédéric Tran Mau-Them, Ange-Line Bruel, Hana Safraou, Christophe Philippe, Yannis Duffourd, Christel Thauvin-Robinet, Jérôme Govin, Antonio Vitobello, Laurence Faivre","doi":"10.1038/s41431-025-01937-3","DOIUrl":"https://doi.org/10.1038/s41431-025-01937-3","url":null,"abstract":"<p><p>SAP102, a member of the membrane-associated guanylate kinase proteins family, is a scaffolding protein encoded by the DLG3 gene whose hemizygous variants with loss-of-function effect are associated with X-linked Intellectual developmental disorder 90. We gathered international data from 17 new individuals with 16 different DLG3 variants (10 with pathogenic loss-of-function and 6 variants of uncertain significance), and reviewed genotypic and phenotypic data from 37 previously published families with 34 different variants. Using family segregation, frequency in publication databases, protein structure modelling and in silico prediction scores, we reclassified six missense variants (five from the literature and one common to our cohort and the literature) as likely benign. Among the individuals newly reported with likely pathogenic or pathogenic DLG3 variants, intellectual disability was more frequently associated with morphological features than in the literature, leading to a proposed extension of the associated X-linked intellectual developmental disorder 90 to a more syndromic neurodevelopmental disorder. In conclusion, we provide here an international clinical series of novel individuals with DLG3 variants in order to better define the clinical and molecular spectrum associated with this condition, and a review of the literature.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124195","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":"Older research participants are motivated to receive genetic results for the benefit of younger relatives.","authors":"Amanda M Willis, Florence Chiew, Philomena Horsley, Sommon Klumsathian, Ezekiel Ling, Chris Jacobs, Paul Lacaze, Jane Tiller, Mary-Anne Young","doi":"10.1038/s41431-025-01940-8","DOIUrl":"https://doi.org/10.1038/s41431-025-01940-8","url":null,"abstract":"<p><p>The benefit of returning medically actionable genetic research findings is widely recognised. However, there is uncertainty regarding the return of results to older people (>70 years), given the reduced actionability in this age group. The goal of this study was to assess whether older people were motivated to receive genetic results, primarily for the benefit of younger relatives. Semi-structured interviews were conducted with individuals aged ≥70 enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) study. Participants received medically actionable genetic results in Hereditary Breast and Ovarian Cancer, Lynch syndrome or Familial Hypercholesterolaemia genes. Data were analysed using reflexive thematic analysis. Sixteen individuals were interviewed (mean age 82 years). While participants recognised the limited actionability of the genetic results for themselves, the perceived benefits for younger family members motivated them to receive genetic findings and share with relatives. Participants reported positive experiences of receiving genetic results, underpinned by their existing relationship with the ASPREE trial, and reported that their age promoted their adaptation to results. These findings illustrate positive impact from returning genetic research results to older research participants and suggest that older people desire genetic information to benefit their younger family members.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124207","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":"PIGC-related encephalopathy: Lessons learned from 18 new probands.","authors":"Allan Bayat, Maria Carla Borroto, Smrithi Salian, Maha S Zaki, Hind Benkerroum, Hasnaa M Elbendary, Thi Tuyet Mai Nguyen, Abdelrahim A Sadek, Diana Carli, Alfredo Brusco, Giovanni Battista Ferrero, Marco Tartaglia, Eleanor Hay, Ilona Krey, Rami A Jamra, Tobias Bartolomaeus, Alexej Knaus, Joseph G Gleeson, Henry Houlden, Natalia Dominik, Adam Jackson, Sofia Douzgou Houge, Siddharth Banka, Javad Mohammadi-Asl, Mohammadreza Hajjari, Reza Azizimalamiri, Pardis Nourbakhsh, Mostafa Neissi, Annarita Scardamaglia, Dianfan Li, Taroh Kinoshita, Reza Maroofian, Yoshiko Murakami, Philippe M Campeau","doi":"10.1038/s41431-025-01923-9","DOIUrl":"https://doi.org/10.1038/s41431-025-01923-9","url":null,"abstract":"<p><p>PIGC encodes a protein essential for the biosynthesis of glycophosphatidylinositol-anchored proteins (GPI-APs). So far, three families with biallelic PIGC variants have been reported to exhibit developmental delay/intellectual disability and seizures. Our aim was to further elucidate the clinical and biomolecular characteristics of PIGC pathogenic or likely pathogenic variants. We established a cohort of 18 previously unreported probands. Clinical data were collected, and causative variants were identified though genome/exome sequencing. Variants were modelled in silico using AlphaFold2. Flow cytometry was performed to analyze the cell-surface expression of GPI-APs. The probands displayed a severe neurodevelopmental disorder characterized by developmental and cognitive impairment, early-onset and treatment-resistant seizures, and premature death affecting 10 out of 18 individuals (median age of 40 months, ranging from 40 days to 7 years). Additional features included brain imaging abnormalities (14/15), hypotonia (15/18), and skeletal anomalies (5/17). One patient exhibited mildly elevated alkaline phosphatase levels. All harbored biallelic PIGC variants, with 14 out of 18 of those being homozygous variants. Analysis of samples derived from probands and cellular models showed reduced cell surface levels of GPI-APs. This study confirms the association of PIGC biallelic variants with refractory seizures, severe developmental and cognitive impairments, and highlights their association with childhood-onset mortality. Additionally, it shows that dysfunctional PIGC results in defective biosynthesis of GPI-AP.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080003","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":"Clinical exome sequencing efficacy and phenotypic expansions involving non-isolated congenital anomalies of kidney and urinary tract (CAKUT+).","authors":"E Andres Rivera-Munoz, Xiaonan E Zhao, Jill A Rosenfeld, Pamela N Luna, Chad A Shaw, Jennifer E Posey, Daryl A Scott","doi":"10.1038/s41431-025-01929-3","DOIUrl":"10.1038/s41431-025-01929-3","url":null,"abstract":"<p><p>Congenital Anomalies of Kidney and Urinary Tract (CAKUT) can occur in isolation or in conjunction with one or more non-CAKUT associated congenital anomalies or neurodevelopmental disorders (CAKUT+). A molecular cause is not identified in most individuals with CAKUT+. This is due, in part, to uncertainty regarding the efficacy of genetic testing and an incomplete understanding of the genes that cause CAKUT+. Here, we use data from 515 individuals with CAKUT+ (n = 500) or isolated CAKUT (n = 15) to determine the efficacy of clinical exome sequencing (cES) and to identify new phenotype expansions that involve CAKUT. We determined that cES established a molecular diagnosis in 27.4% (141/515) of individuals in this cohort. No statistically significant difference in efficacy was seen with regards to age, sex, CAKUT phenotype, or associated organ system abnormality. Only 3.5% (5/144) to 14.6% (21/144) of the individual diagnoses made in our cohort could have been identified using one of four clinically available CAKUT gene panels. We then used a machine-learning approach to confirm that PHIP is a CAKUT gene and to implicate ADNP and SETD5 genes associated with an increased risk of CAKUT. These findings lead us to conclude that cES should be considered in individuals with CAKUT+ for whom a molecular diagnosis has not been identified, that cES has the potential to identify many diagnoses in individuals with CAKUT+ that would be missed using a CAKUT gene panel, and that individuals with ADNP-, PHIP-, and SETD5-related disorders may present with CAKUT phenotypes.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006041","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":"What’s new in EJHG this autumn","authors":"Seda S. Zonuzi","doi":"10.1038/s41431-025-01928-4","DOIUrl":"10.1038/s41431-025-01928-4","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 9","pages":"1091-1092"},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01928-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923859","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":"Genomic sequencing technologies for rare disease in mainstream healthcare: the current state of implementation.","authors":"Michael P Mackley, Pankaj B Agrawal, Sara S Ali, Alison D Archibald, Belinda Dawson-McClaren, Holly Ellard, Lucinda Freeman, Yuanyuan Gu, Kushani Jayasinghe, Shan Jiang, Edwin P Kirk, Celine Lewis, Alison McEwen, Amy Nisselle, Catherine Quinlan, Bronwyn Terrill, Erin Tutty, Alisdair McNeill","doi":"10.1038/s41431-025-01925-7","DOIUrl":"https://doi.org/10.1038/s41431-025-01925-7","url":null,"abstract":"<p><p>Genomic sequencing technologies, which include both exome and genome sequencing, as well as panels or targeted analyses using genome-wide approaches, are being implemented across healthcare. Implementation, however, varies greatly by application and jurisdiction, with a diversity of approaches being employed around the world. This review aims to summarise the current state of implementation of genomic testing in mainstream healthcare for the detection of rare disease throughout the lifespan. Through a discussion of evidence gathered to date, highlighting exemplar studies, the following applications of genomic testing will be covered: (1) routine diagnostic genomic testing in the clinic; (2) rapid diagnostic genomic testing in the intensive care unit; (3) genomic newborn screening; and, (4) reproductive genetic carrier screening. Mainstream implementation necessarily extends beyond the clinical genetics service, where genomic testing has historically been offered. Given that the involvement of non-genetics clinicians in the delivery of these technologies has important implications for models of care and education, related areas of growing evidence are also discussed: (5) genetic counsellors working outside clinical genetics services; and, (6) workforce development considerations for mainstream genomics. The diversity of approaches and examples illustrates that integration of genomic technologies into mainstream healthcare is complex and requires significant health system transformation. Efforts to evaluate services, guided by implementation science, will be essential to ensure lessons are shared across jurisdictions and benefit is delivered to patients and the system at-large.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947801","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}