European Journal of Human Genetics最新文献

{"title":"\"We've done our due diligence\": Experiences of reproductive genetic carrier screening in people with experiential knowledge of a genetic condition.","authors":"Giorgina Maxwell, Erin Tutty, Belinda J Dawson-McClaren, Alison D Archibald","doi":"10.1038/s41431-026-02093-y","DOIUrl":"https://doi.org/10.1038/s41431-026-02093-y","url":null,"abstract":"<p><p>Reproductive genetic carrier screening (RGCS) provides people with information about the likelihood of having children with serious inherited genetic conditions. The perspectives of people who have experience with a genetic condition are important in understanding the acceptability of RGCS. Through the Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission), over 10,000 reproductive couples were offered screening for genetic conditions associated with ~1300 genes. Of those who took part, some had previously had a prenatal, neonatal or paediatric diagnosis of a genetic condition in their offspring or had a genetic condition themselves. Although these participants knew their carrier status for the condition in their family, they had RGCS to determine if they had an increased chance for children with any of the other conditions screened. These participants were invited to take part in semi-structured interviews to explore their perspectives. Thematic analysis from interviews with 19 people from 17 reproductive couples demonstrated positive attitudes towards making RGCS widely accessible. Participants valued being offered screening for additional conditions. A sense of doing 'due diligence' to protect future children from potential harm caused by a genetic condition was a strong motivator to undergo RGCS. There was a willingness to accept short-term anxiety that RGCS can create because of the peace of mind it can provide. Participant's discourse demonstrated complex prior experiences leading to heightened risk perception and highlighted that, although they valued and and were supportive of screening, people with experience of genetic conditions may benefit from additional support to navigate RGCS.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662566","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":"How variant discovery redefines genetic prevalence: the case of cystine stone disease.","authors":"Chen-Han Wilfred Wu, Joshua Chang, Katreya Lovrenert, Donald Bodner, Friedhelm Hildebrandt, Fredrick R Schumacher","doi":"10.1038/s41431-026-02085-y","DOIUrl":"https://doi.org/10.1038/s41431-026-02085-y","url":null,"abstract":"<p><p>Cystine stones are caused by pathogenic variants in SLC3A1 or SLC7A9. Our prior study revealed a large gap between genetic and clinical prevalence. With increasing discovery of novel variants, we aim to assess how these impact genetic prevalence estimates. Due to the disease rarity, direct patient recruitment and observation is impractical. We applied a population genetics approach to estimate genetic burden and prevalence. Pathogenic variants were identified from the 2022 Human Gene Mutation Database and intersected with population variants from the 1000 Genomes Project Phase 3. Allele frequency, carrier rate, and affected rate were calculated. Results were compared to prior data, and simulations were performed across varying initial allele frequencies. We identified 116 and 76 novel pathogenic variants in SLC3A1 and SLC7A9, respectively. Pathogenic allele frequencies increased by +0.12% (SLC3A1) and 0.16% (SLC7A9), leading to fold-changes in genetic prevalence of 1.51x and 2.78x. The combined updated prevalence is 1 in 17,612, a 1.74x increase. Simulations confirmed the fold-change magnitude. In rare diseases, even modest discovery of new variants can significantly increase genetic prevalence. As shown in cystine stone, this helps narrow-but not close-the gap with clinical prevalence. Further efforts are needed to bridge this gap and guide treatment development.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644449","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":"Acceptability of newborn screening for spinal muscular atrophy: views of the UK public, screened families, health professionals and the SMA community.","authors":"Felicity Boardman, Rebecca Howitt, Philip Young, Corinna Clark","doi":"10.1038/s41431-026-02096-9","DOIUrl":"https://doi.org/10.1038/s41431-026-02096-9","url":null,"abstract":"<p><p>With the advent of novel gene therapies, rare genetic diseases once lacking treatments are now being considered for newborn screening programmes (NBS). Wilson and Jungner criteria (drawn on worldwide to guide screening programme evaluation) necessitate effective interventions for a recommendation of screening. Spinal muscular atrophy (SMA) is an example of a condition for which the case for NBS has rapidly gathered pace in recent years. With the introduction of disease-modifying therapies (that are most efficacious when delivered pre-symptomatically), many countries are now piloting or implementing SMA NBS. Despite this, the acceptability of SMA NBS remains underexplored. To address this gap, surveys and interviews were conducted with four key groups: i) general public, ii) SMA families, iii) parents of screened babies iv) healthcare professionals. Survey responses from 9,511 respondents were analysed: 5,604 from the public, 250 from SMA families, 3,541 from parents and 116 from healthcare professionals. Fifty-three qualitative interviews were conducted with 56 participants: 10 public; 12 SMA parents; 9 adults with SMA; 9 parents of screened babies (including one positive result) and 16 healthcare professionals. Support for SMA NBS was found to be consistently high: 90% of public, 99% of SMA parents and adults, 98% of parents of screened babies and 97% of healthcare professionals supported its national implementation. Concerns centred on the impact of diagnoses through NBS, anxiety and treatment ineligabilty for adult-onset SMA. However, these were not considered barriers. SMA NBS is widely acceptable to relevant stakeholder groups, though rapid, comprehensive and high-quality support for families is essential following diagnosis.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644426","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":"Variants in the CxxC domain of the epigenetic regulator KDM2B support its role in developmental eye anomalies.","authors":"Fabiola Ceroni, Linda M Reis, Fiona Watkins, Dorine A Bax, Megan C Fischer, Karthikah Jeganathan, Rosalyn Jewell, Jacob S Martin, Alison Salt, Sarah E Seese, Jenny Thomson, Elena V Semina, Nicola K Ragge","doi":"10.1038/s41431-026-02090-1","DOIUrl":"https://doi.org/10.1038/s41431-026-02090-1","url":null,"abstract":"<p><p>KDM2B encodes an epigenetic regulator that binds to promoter-associated CpG islands via its CxxC zinc-finger domain, protecting them from DNA methylation. It also helps establish transcriptional programs essential for development by recruiting the non-canonical Polycomb Repressive Complex 1.1 to lineage-specific genes. Heterozygous variants in KDM2B were recently associated with a neurodevelopmental disorder. Notably, some individuals with variants in the CxxC domain also exhibited congenital heart, kidney and/or structural eye anomalies. By screening 706 families with developmental eye disorders, we identified two cases with KDM2B-CxxC variants, NM_032590.5:c.1841G>C;p.(Arg614Pro) and NM_032590.5:c.1880G>C;p.(Cys627Ser), both resulting in a characteristic KDM2B DNA episignature. Both individuals exhibited complex structural eye defects, with neurodevelopmental, cardiac and renal anomalies variably present. These cases strengthen the association between KDM2B-CxxC variants and eye, kidney and heart malformations and highlight the importance of testing this gene and its episignature in individuals with structural eye disorders, especially when accompanied by congenital cardiac and/or renal anomalies.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632601","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":"Pharmacogenetic testing in Italy: results of a nationwide survey by the Joint Working Group for the pharmacogenetics implementation in Italy.","authors":"Rossana Roncato, Samantha Perfler, Martina Gambron, Enrico Zoroddu, Monica Rosa Miozzo, Sabrina Angelini, Massimo Gennarelli, Gabriele Stocco, Valeria Conti, Amelia Filippelli, Paola Borgiani, Giuseppe Novelli, Alessio Squassina, Matteo Floris, Erika Cecchin","doi":"10.1038/s41431-026-02063-4","DOIUrl":"https://doi.org/10.1038/s41431-026-02063-4","url":null,"abstract":"<p><p>Pharmacogenetics enables personalization of drug therapy based on an individual's genetic profile. Despite clinical relevance, implementation of pharmacogenetics remains limited. In Italy, integration is fragmented, with heterogeneous practices and a lack of national coordination. A comprehensive assessment of the current landscape is essential. A nationwide survey was conducted between January and October 2025 to map laboratories providing pharmacogenetic testing. A structured questionnaire collected data on institutional characteristics, testing workflows, pharmacogene panels, analytical methodologies, interpretation procedures, and reimbursement. Forty-nine laboratories participated (response rate: 65%). Most were part of public institutions (82%), primarily general or research hospitals. Testing was predominantly performed in medical genetics units (39%) and focused on oncology, specifically DPYD (94%) and UGT1A1 (84%) for fluoropyrimidine and irinotecan therapies. Adherence to national (SIF/AIOM) and international (CPIC/DPWG) guidelines was generally high; compliance with AMP Tier 1 analytical standards varied substantially. Pharmacological counseling was provided by only 29% of laboratories, mainly by clinical pharmacology units. Considerable heterogeneity emerged in testing platforms, bioinformatics tools, and the use of CE-IVD-certified kits. Marked geographical disparities were evident, with pharmacogenetic activity concentrated in Northern Italy. This survey provides the first national overview of pharmacogenetics implementation in Italy, revealing variability in laboratory practices, interpretation standards, and clinical integration. While oncology-related testing is widely adopted and guideline adherence is increasing, the lack of a coordinated national framework restricts consistency and equitable access. Establishing a coordinated network of pharmacogenetic laboratories with harmonized standards for testing, reporting, and education is crucial for evidence-based pharmacogenetic care.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608460","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":"Position statement from the Italian Society of Human Genetics (SIGU) on the implementation of germline pharmacogenetic testing.","authors":"Matteo Floris, Antonino Moschella, Mario Capasso, Myriam Alcalay, Maria R Iascone, Paola Grammatico, Monica Rosa Miozzo","doi":"10.1038/s41431-026-02033-w","DOIUrl":"https://doi.org/10.1038/s41431-026-02033-w","url":null,"abstract":"<p><p>The Italian Society of Human Genetics (SIGU) Working Group on Pharmacogenomics has released recommendations for the implementation, interpretation and reporting of germline pharmacogenetic testing in clinical practice within the Italian National Health Service (SSN). These guidelines outline the key principles for the responsible use, reporting, and interpretation of pharmacogenetic data, emphasizing clinical validity, clinical utility, cost-effectiveness, and ethical considerations. With the aim of promoting a systematic standardized, and evidence-based implementation of germline pharmacogenetic testing in Italy, SIGU strongly recommends addressing the following points: (1) Pharmacogenetic testing should be performed based on validated scientific evidence, primarily following Association for Molecular Pathology (AMP) and Dutch Pharmacogenetics Working Group (DPWG) guidelines, and restricted to gene-drug pairs with ClinPGx clinical annotation level 1 A. (2) Patients must be appropriately informed and provide specific consent, particularly when pharmacogenetic data are derived as secondary findings from diagnostic next generation sequencing (NGS) analyses. (3) Testing should prioritize clinically actionable variants that influence therapeutic efficacy or prevent severe adverse drug reactions. (4) The interpretation and reporting of results must be carried out by a qualified geneticist in collaboration with clinical pharmacologists to ensure appropriate therapeutic recommendations. (5) The implementation of pharmacogenetic testing should be supported by robust quality assurance procedures in laboratories, in line with international standards. (6) The inclusion of pharmacogenetic tests in the Italian LEA (Essential Levels of Assistance) should be updated in accordance with international evidence and EMA-AIFA recommendations. (7) Further pharmaco-economic and psychosocial research is needed to evaluate the impact of pre-emptive versus reactive testing strategies on patient outcomes and healthcare sustainability.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608457","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: The development and usability of 'The Genetics Navigator': a digital solution for adult and paediatric clinical genetics services.","authors":"Saumeh Saeedi, Daena Hirjikaka, Marc Clausen, Stephanie Luca, Emma Reble, Rita Kodida, Daniel Assamad, Lauren Chad, Gregory Costain, Hanna Faghfoury, Josh Silver, Serena Shastri-Estrada, Maureen Smith, Robin Z Hayeems, Yvonne Bombard","doi":"10.1038/s41431-026-02094-x","DOIUrl":"https://doi.org/10.1038/s41431-026-02094-x","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608436","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":"Advances in genomic medicine: from diagnosis to patient perspectives","authors":"Seda S. Zonuzi","doi":"10.1038/s41431-026-02088-9","DOIUrl":"10.1038/s41431-026-02088-9","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 4","pages":"445-446"},"PeriodicalIF":4.6,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02088-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585342","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":"Correction: Comprehensive analysis of CNOT3-related neurodevelopmental disorders: phenotypic and genotypic characterization.","authors":"Camille Engel, Michaela Rendek, Jessica Assoumani, Emanuela Argilli, Francesca Ariani, Anne-Laude Avice-Denizet, Emilia K Bijlsma, Pierre Blanc, Lucia Pia Bruno, Bert Callewaert, Valeria Capra, Michele Carullo, Bertrand Chesneau, Sandra Coppens, Cynthia Curry, Breanne Dale, Eric Dahlen, Andrée Delahaye-Duriez, Anne-Sophie Denommé-Pichon, Bénédicte Demeer, Lenka Dvořáková, Jan Fischer, David Geneviève, Thea Giacomini, Mette M Handrup, Delphine Heron, Irina Hüning, Michelle Iacomino, Bertrand Isidor, Boris Keren, Stanislav Kmoch, David A Koolen, Andrea Kübler, Jana Laštůvková, Carolyn Le, Jonathan Levy, Caterina Lo Rizzo, Silvia Maitz, Sandrine Marlin, Cyril Mignot, Ghayda Mirzaa, Inga Nagel, Sebastian Neuens, Lenka Nosková, Emily Pao, Anna Pecková, Julie Plaisancie, Joseph Porrmann, Flavia Privitera, André Reis, Alessandra Renieri, Marlène Rio, Alyssa Rippert, Lukáš Ryba, Marcello Scala, Jolanda H Schieving, Elliott H Sherr, Andrew Shuen, Richard Sidlow, Thomas Smol, Julie Soblet, Pasquale Striano, Mohnish Suri, Hannes Syryn, Frédéric Tran Mau-Them, Andre M Travessa, Julien Van Gils, Georgia Vasileiou, Jolijn J A Verseput, Catheline Vilain, Catherine Vincent-Delorme, Emílie Vyhnálková, Emma L Wakeling, Pia Zacher, Federico Zara, Paul Kuentz, Juliette Piard","doi":"10.1038/s41431-026-02087-w","DOIUrl":"https://doi.org/10.1038/s41431-026-02087-w","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608431","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":"Bridging population and cell: modelling complex diseases with human induced pluripotent stem cells.","authors":"Eva S van Zanten, Elizabeth A Loehrer, Joyce B J van Meurs, Roberto Narcisi, Joost H Gribnau, Raymond A Poot, Hieab H H Adams","doi":"10.1038/s41431-026-02071-4","DOIUrl":"https://doi.org/10.1038/s41431-026-02071-4","url":null,"abstract":"<p><p>Induced pluripotent stem cells (iPSCs) have emerged as a powerful tool in biomedical research, enabling the study of cellular function and early disease mechanisms within patient-specific genetic contexts. Traditionally, iPSCs have been used to model monogenic diseases, where highly penetrant variants produce robust cellular phenotypes detectable in few cell lines. Recent advances in scalability and standardisation now enable systematic comparisons across many donors. This development is particularly relevant for complex diseases, which are driven by numerous genetic variants with small individual effects and therefore require population-scale designs to resolve genotype-phenotype relationships. However, several limitations of iPSC technology continue to challenge the reliability and reproducibility of such studies, constraining their translational relevance. Here, we review the challenges and opportunities of using iPSCs to model complex diseases, structured around three key themes: detecting subtle effects, modelling environmental context, and expanding genetic diversity.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147591008","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}