European Journal of Human Genetics最新文献

{"title":"Timothy syndrome and CACNA1C-Related Disorder: first international language and management guidelines consensus statement.","authors":"Jack F G Underwood, Katherine W Timothy, Holly Tyroll, Rebecca J Levy, Ivy E Dick, Geoffrey S Pitt, Elizabeth M Tunbridge, Anwar Baban, Gemma Wilkinson, Nicola A L Hall, Georgia Sarquella Brugada, Rosemary Bauer, Dominic Abrams, Jeremy Hall","doi":"10.1038/s41431-026-02178-8","DOIUrl":"10.1038/s41431-026-02178-8","url":null,"abstract":"<p><p>Timothy syndrome is a multisystemic genetic disorder, classically characterised by prolonged QT interval and subsequent cardiac arrhythmias, neurodevelopmental disorders including developmental delay and autism and syndactyly or hip dysplasia. It is caused by variants in the CACNA1C gene, which encodes the widely expressed Ca_v1.2 voltage-gated calcium channel. Since its characterisation in 2004, the number of variants in CACNA1C associated with Timothy syndrome has expanded. With advances in sequencing and the inclusion of CACNA1C in genomic screening, further variants have been identified presenting with incomplete features of Timothy syndrome or further aligned phenotypes, which are inconsistent with the original description. In the absence of a formal nomenclature, these presentations have been reported in a proliferation of ill-defined terms, e.g. Atypical Timothy Syndrome. At the same time, advances in knowledge and therapeutics have improved morbidity and life expectancy for these individuals when appropriately identified and managed. Here, we present guidelines for the diagnosis of individuals presenting with variants in CACNA1C, developed by an international panel of experts through Delphi consensus with the involvement of the CACNA1C community. We formalise the language around syndromic presentations linked to CACNA1C variants, reassert and demarcate the classical Timothy syndrome phenotype and provide a structured co-produced definition for CACNA1C-Related Disorder. Finally, we present minimum expected standards of clinical care for individuals with CACNA1C-Related Disorder or Timothy syndrome, with implications for long-term management and improved outcomes for affected individuals.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419866","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":"Drawing lines: how the public defines “Serious” genetic conditions for reproductive testing","authors":"Shizuko Takahashi,&nbsp;Rie Iizuka,&nbsp;Serene Ong,&nbsp;Tianxiang Lan,&nbsp;Tsutomu Sawai","doi":"10.1038/s41431-026-02170-2","DOIUrl":"10.1038/s41431-026-02170-2","url":null,"abstract":"Prior normative and empirical research has identified a gap between how patients and the public conceptualize “serious” conditions eligible for preimplantation genetic testing for monogenic disorders (PGT-M) and how seriousness is defined. Japan represents a highly restrictive regulatory context shaped by its historical experience with eugenics. Although PGT-M has been available since 1998, its use has been tightly limited, with the first birth occurring six years later and approximately 36 conditions approved to date. This study examines how Japanese adults of reproductive age understand “seriousness” in genetic disease and how they view PGT-M in relation to concerns about eugenic selection (inochi no senbetsu, “sorting of lives”). We conducted a cross-sectional online survey of 458 adults aged 18–42 years. Measures included perceived seriousness across clinical parameters (penetrance, survival, daily life impact), willingness to use PGT-M, perceived barriers to access, and attitudes toward eugenic selection. Awareness of PGT-M was low (12%), yet 44% of participants would consider its use. Participants defined seriousness more broadly than current Japanese policy permits: most rated highly penetrant or childhood-lethal conditions as serious, and over half also included conditions associated with mild to moderate functional limitations. Participants distinguished disease prevention from enhancement. Economic burden was the most frequently cited barrier (70%). Many participants who expressed ethical discomfort with eugenic selection nonetheless reported willingness to consider PGT-M. These findings reveal a substantial gap between policy, public reasoning, and reproductive preferences, with implications for European debates on seriousness and proportionality in reproductive genetic testing.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1538-1546"},"PeriodicalIF":4.6,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02170-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411064","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":"Tyrosine kinase inhibitors in Kosaki/Penttinen syndromes: new reports, follow-up of treated individuals and literature review","authors":"Céline Jost,&nbsp;Alessandro Mussa,&nbsp;Jean-Emmanuel Kurtz,&nbsp;Ashmika Gokhul,&nbsp;Ann Nordgren,&nbsp;Silvia Kalantari,&nbsp;Diana Carli,&nbsp;Andrea Gazzin,&nbsp;Claudio Isella,&nbsp;Enzo Medico,&nbsp;Anna Cassisa,&nbsp;Daniela Cantarella,&nbsp;Thirona Naicker,&nbsp;Antoinette Chateau,&nbsp;Jean-Baptiste Demoulin,&nbsp;Nikolas Herold,&nbsp;Yordi-Michaël Bouhatous,&nbsp;Liubinka Mirakovska,&nbsp;Agnès Maurer,&nbsp;Théo Gaumet,&nbsp;Tara Wenger,&nbsp;Helena Iznardo,&nbsp;Eulalia Baselga,&nbsp;José Manuel Mascaro,&nbsp;Cécilie Bredrup,&nbsp;Olav Aga Kildal,&nbsp;Titas Gladkauskas,&nbsp;Cecilie F. Rustad,&nbsp;Ingrid Voktor Svinvik,&nbsp;Dinel Pond,&nbsp;Elise Schaefer,&nbsp;Maxime Luu,&nbsp;Marc Bardou,&nbsp;Laurence Faivre","doi":"10.1038/s41431-026-02153-3","DOIUrl":"10.1038/s41431-026-02153-3","url":null,"abstract":"Heterozygous activating variants in platelet-derived growth factor receptor beta (PDGFRβ) are associated with ultra-rare and clinically heterogeneous conditions, including KOGS (Kosaki Overgrowth Syndrome), PS (Penttinen Syndrome) and related conditons. Tyrosine kinase inhibitors (TKIs), which are widely used in hematological and oncological diseases, are now being explored as potential treatments for these conditions. While four published cases have reported encouraging results, there is still insufficient data available to draw definitive conclusions on the benefit–risk ratio. The international consortium Knowing and Treating KOGS/PS was launched to assess the real-life outcomes of such treatments. The consortium presents four new cases and updates four previously published cases of KOGS/PS treated with TKIs from seven countries. A recent publication was also included in the analysis. Individuals received treatment for between three and a half months and eight years (imatinib N = 8/8, dasatinib N = 3/8, sunitinib N = 1/8), with a mean duration of 44.4 months (SD = 29.8). The age at treatment initiation ranged from 6 to 57 years (six patients treated in childhood and two in adulthood). All individuals showed improvement within weeks/months, with minimal side effects. However, efficacy decreased over time in some cases, prompting a switch to a different TKI. These preliminary findings highlight the potential of TKIs for managing KOGS/PS patients. Standardized follow-up protocols and an electronic Case Report Form (eCRF) have been implemented to enhance monitoring and data collection, enabling systematic comparisons between treated and untreated individuals despite the disorders’ rarity.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1454-1464"},"PeriodicalIF":4.6,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02153-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411130","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":"Summer highlights from EJHG","authors":"Seda S. Zonuzi","doi":"10.1038/s41431-026-02172-0","DOIUrl":"10.1038/s41431-026-02172-0","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 7","pages":"893-894"},"PeriodicalIF":4.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02172-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389295","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":"Confirmation of frameshift variants in the last exon of FGFR1 as a cause of multiple epiphyseal dysplasia","authors":"Marion Aubert Mucca,&nbsp;Roberto Mendoza-Londono,&nbsp;Valérie Cormier-Daire,&nbsp;Thomas Edouard,&nbsp;Lucie Dupuis,&nbsp;Andrew W. Howard,&nbsp;Olivier Patat,&nbsp;Hanna Faghfoury,&nbsp;Josh Silver,&nbsp;Renaud Touraine,&nbsp;Philippe M. Campeau,&nbsp;Alban Ziegler","doi":"10.1038/s41431-026-02176-w","DOIUrl":"10.1038/s41431-026-02176-w","url":null,"abstract":"Multiple epiphyseal dysplasia (MED) is a genetically diverse skeletal disorder characterized by abnormal and delayed epiphyseal ossification, early-onset osteoarthritis, joint pain and mild short stature. MED is primarily caused by pathogenic variants in genes involved in cartilage and bone development, including COMP, MATN, COL9A1-3, CANT1 and SLC26A2. FGFR1 was suggested as a cause of MED in a study published in 2020, which reported a frameshift variant in the last exon of this gene. We assembled an international cohort of 13 individuals with MED carrying C-terminal frameshift variants in FGFR1 (NM_023110.3: c.2424_2425del, c.2436_2440del, and c.2460dup). In all three families, the frameshift variants are predicted to result in the same 164-amino acid C-terminal elongation tail. The cohort includes two families (three affected individuals in one, nine in the other) and one previously reported individual. All affected individuals presented with MED without vertebral involvement. Age of symptom onset ranged from 3 to 13 years, with complete penetrance. Genu valgum was very frequent, and most affected patients required its surgical correction. Hypogonadotropic hypogonadism was present in approximately half of the cases. Adult height was mildly reduced, with an median of 164.0 cm in males (−1.7 SDS) and 153.1 cm in females (−1.6 SDS). Structural modeling for the novel C-terminal stretch as a result of the variants could acquire secondary structures, including an α-helix and a β-sheet domain, and could bring a potential antimorphic effect. Our findings confirm FGFR1 C-terminal frameshift variants as a cause of MED and provide further clinical characterization of this disorder.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1449-1453"},"PeriodicalIF":4.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404129","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":"A changed landscape: five-year retrospective on the paradigm shift in genetic testing practices for ALS in Canada","authors":"Maya Binet,&nbsp;Gordon Jewett,&nbsp;Ari Breiner,&nbsp;Marvin Chum,&nbsp;Angela Genge,&nbsp;Kerri Schellenberg,&nbsp;Christen Shoesmith,&nbsp;Gerald Pfeffer,&nbsp;Kristiana Salmon","doi":"10.1038/s41431-026-02171-1","DOIUrl":"10.1038/s41431-026-02171-1","url":null,"abstract":"Offering genetic testing is increasingly recommended for all individuals with amyotrophic lateral sclerosis (ALS), particularly following the development of gene-targeted therapies, such as tofersen for SOD1-ALS. Historically, testing was routinely offered to those with familial ALS (fALS), but inconsistently to those with sporadic ALS (sALS). We evaluated changes in genetic testing and counseling practices among Canadian ALS physicians over a five-year period spanning pivotal clinical trial results and regulatory approval of tofersen. Members of the Canadian ALS Research Network were surveyed in 2020, 2022, and 2025 about genetic testing practices for symptomatic and asymptomatic individuals, gene panel composition, access to genetic counseling, and perceived drivers of change. Clinics offering genetic testing for sALS increased from 33% of clinics in 2020 and 57% in 2022 to 100% of respondents in 2025. Genetic testing for patients with a family history (fALS) was near-universal across all timepoints. Broader use of multi-gene panel testing increased over time, coinciding with sponsored testing availability. 61% of respondents reported that Health Canada approval of tofersen directly influenced their practice. Predictive testing offerings increased from 37% in 2020 to 61% in 2025. Genetic testing practices in Canada shifted substantially during late-stage clinical development and following regulatory approval of a gene-targeted therapy (tofersen). Proactive planning during the clinical trial phase facilitated rapid, nationwide adoption. This study captures a key turning point in ALS care, illustrating how therapeutic breakthroughs can redefine national clinical standards.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1529-1537"},"PeriodicalIF":4.6,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02171-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396445","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":"Parental and public views on genomic newborn screening: a systematic review.","authors":"Rachael Sweetland, Fiona Ulph","doi":"10.1038/s41431-026-02173-z","DOIUrl":"https://doi.org/10.1038/s41431-026-02173-z","url":null,"abstract":"<p><p>The potential integration of whole genome sequencing (WGS) into the UK newborn screening programme (NBS) represents a major advancement in population health genomics. Multiple studies have assessed professionals' opinions on the healthcare system's readiness for this change. Parental and public views are under-represented and limited regional and national assessments have been undertaken. This study systematically reviews qualitative literature exploring public and parental views of genomic newborn screening (gNBS) to identify potential barriers and enablers of its uptake. Using thematic synthesis of seventeen studies from five countries, key themes emerged around preconceptions about individual's benefits and costs of engaging and assumptions about the design of gNBS services. Participants generally recognised the benefits of early diagnosis and medical intervention but expressed concerns about psychological impacts, data privacy, and the scope of screened conditions. Views were shaped by limited public understanding of genomics, with misconceptions potentially influencing consent decisions. This research highlights a preference for flexible, tiered screening options and the importance of inclusive, multimodal communication strategies delivered pre- and perinatally by trusted healthcare professionals. Equitable access and robust privacy protections were identified as critical for public trust. These findings underscore the importance of co-designing gNBS implementation with stakeholders to ensure informed, voluntary participation and maximise public health benefits. This systematic review informs policymakers and healthcare providers about public attitudes, which are essential for shaping ethically responsible and socially acceptable genomic screening programmes.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387507","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: follow-up, cancer risk and mortality in Peutz-Jeghers syndrome: data from the PRED-IdF network.","authors":"Maxime Rémond, Youenn Drouet, Antoine Dardenne, Guillaume Perrod, Jeanne Netter, Yann Parc, Christophe Cellier, Romain Coriat, Solenne Farelly, Fanny Maksimovic, Diane Molière, Julie Metras, Patrick Benusiglio, Olivier Caron, Catherine Genestie, Christine Lasset, Chrystelle Colas, Bruno Buecher, Emmanuelle Fourme, Anne-Sophie Bats, Florence Coulet, Albain Chansavang, Nadim Hamzaoui, Marion Dhooge","doi":"10.1038/s41431-026-02156-0","DOIUrl":"10.1038/s41431-026-02156-0","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381796","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":"Characterisation of the SMN1/2 locus using a highly specific variant caller on whole-genome sequence data from 500,000 individuals.","authors":"Timothy S Hall, Robin N Beaumont, James Fasham, Emma L Baple, Leigh Jackson, Michael N Weedon, Caroline F Wright","doi":"10.1038/s41431-026-02175-x","DOIUrl":"https://doi.org/10.1038/s41431-026-02175-x","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a rare autosomal recessive condition caused by biallelic loss of the SMN1 gene that results in severe lower motor neuron degeneration in childhood. Targeted pre-symptomatic treatments have been shown to dramatically improve outcomes, supporting the inclusion of SMA in newborn screening programmes. However, ~95% of infantile-onset cases are caused by homozygous deletions of exon 7-8 of the SMN1 gene, which is challenging to detect using short-read next-generation DNA sequencing technology due to the high sequence similarity between SMN1 and its nearby paralog SMN2. Here, we evaluate the performance of an SMN-specific variant caller in ~490,000 adults with whole-genome sequence data in UK Biobank. We also perform a phenome-wide association study (PheWAS) of 4782 diseases and traits for SMN1 deletion carriers. We show that the SMNCopyNumberCaller performs extremely well, identifying 8856 (1.8%) heterozygous carriers and just two (0.0004%) individuals with homozygous SMN1 deletions, of whom one had been diagnosed with SMN1-SMA. From the PheWAS, we found novel associations between SMN1/2 copy number and the level of several circulating proteins encoded or regulated by genes near the SMN locus, further validating the accuracy of the caller. Our results suggest that using a specialist variant caller can accurately determine SMN1/2 copy number from short-read DNA sequencing technology, achieving a very high specificity (~100%) for homozygous SMN1 deletions. The number of false positive results for SMN1-SMA is therefore likely to be extremely low when using short-read whole-genome sequencing at a population level.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375014","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":"When truncation is not loss of function: neo-tail architecture as a determinant of pathogenicity in NMD-escaping frameshift variants.","authors":"Himanshu Goel","doi":"10.1038/s41431-026-02174-y","DOIUrl":"https://doi.org/10.1038/s41431-026-02174-y","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367613","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}