European Journal of Human Genetics最新文献

{"title":"CMIP as a novel candidate gene for neurodevelopmental and neuropsychiatric disorders","authors":"Matthias De Wachter, Mathijs B. van der Lei, Amber Decleve, Kevin De Man, Ellen Elinck, An-Sofie Schoonjans, Evan Gouy, Louis Januel, Pauline Monin, Audrey Labalme, Amelle Shillington, Himanshu Goel, Juliet P. Taylor, Katherine Neas, David A. Koolen, Francois Lecoquierre, Alice Goldenberg, Theresa Brunet, Melanie Brugger, Minjie Luo, Magdalena Krygier, Maria Mazurkiewicz-Bełdzińska, Manon Degoutin, Claire Beneteau, Cyril Goizet, David D. Weaver, Emily G. Farrow, Angela Lee, Randi N. Gadea, Berten Ceulemans, Peter A. M. de Witte, Daniëlle Copmans, Anna C. Jansen, R. Frank Kooy","doi":"10.1038/s41431-026-02169-9","DOIUrl":"10.1038/s41431-026-02169-9","url":null,"abstract":"CMIP, a c-maf inducing protein that plays a key role in cytoskeletal remodeling, neuronal migration and synaptic formation, was first associated with specific language impairment and autism through the identification of a deletion in a single patient in 2012. Since then, only two additional individuals with CMIP deletions have been reported, both sharing features of autism and gastrointestinal features. However, a firm causal relationship between variants in CMIP and neurodevelopmental disorders has not yet been established. In this multicentre cohort study, we identified 25 individuals, from 17 unrelated families, with CMIP-related neurodevelopmental disorders, 22 of whom have not been previously reported. Of these, seven individuals carried heterozygous loss-of-function CMIP single-nucleotide variants, while the other 18 individuals had a complete or partial deletion of CMIP, some involving adjacent genes. The clinical phenotype was variable with a high prevalence of developmental delay (20/25), autism spectrum disorder features (13/25), attention-deficit/hyperactivity disorder features (11/25) and other psychiatric disorders (15/25). Epilepsy was present in nine individuals (9/25), of whom three had therapy-resistant seizures. To study the pathogenicity of CMIP variants, a cmip mutant zebrafish model carrying a premature stop codon was investigated. These mutants showed temperature-dependent altered locomotor activity suggestive of seizure-like behavior, which was confirmed by spontaneous epileptiform discharges in cmip+/– mutant zebrafish larvae. Our patient cohort and the zebrafish data establish CMIP as a gene implicated in neurodevelopmental and neuropsychiatric disorders. We recommend inclusion of CMIP in the genetic work-up of neurodevelopmental delay, with or without autism or psychiatric disorders and epilepsy.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 8","pages":"1070-1080"},"PeriodicalIF":4.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02169-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367611","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":"Scoping review and recommendations for development and delivery of education resources for reproductive genetic carrier screening.","authors":"Claudine M Kraan, Amanda Springer, Janet C Long, Jeffrey Braithwaite, Belinda Dawson-McClaren, Alison D Archibald","doi":"10.1038/s41431-026-02152-4","DOIUrl":"https://doi.org/10.1038/s41431-026-02152-4","url":null,"abstract":"<p><p>Reproductive genetic carrier screening (RGCS) is increasingly available and publicly funded in some jurisdictions. There is a pressing need for user-centric resources to support decision-making. We conducted a scoping review using the Joanna Briggs Institute framework with the aim of mapping studies published between 2014 and 2025 examining individual and reproductive couple perspectives on RGCS. Searches were conducted in Medline, Embase, PubMed and Web of Science. Studies were categorised by design and descriptive characteristics. Eighty-nine studies were included. Research documented motivations for accepting or declining RGCS and the interplay of systemic, structural and personal factors related to decision-making. Investigation of educational needs emphasized moving beyond clinical framing to reflect experiential knowledge. Multiple touchpoints were identified across the service implementation pathway, revealing opportunities for fit-for-purpose resource integration; and perspectives from those with experiential knowledge of genetic conditions added unique insights. However, population diversity was low, with limited research from rural, regional and/or remote locations, diverse family structures, people with intellectual disability or neurodiversity and cultural and linguistically diverse communities. This review maps individual and reproductive couple perspectives on RGCS and offers six expert recommendations for resource development. A key call to action is to engage priority populations in future RGCS research to avoid deepening health inequities.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360010","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":"Parent and professional experiences of a clinical trial of prenatal and postnatal stem cell therapy for severe osteogenesis imperfecta","authors":"Bikiran Behera,&nbsp;Charlotta Ingvoldstad Malmgren,&nbsp;Eva Åström,&nbsp;Lyn S. Chitty,&nbsp;Belinda Crowe,&nbsp;Anna L. David,&nbsp;Catherine DeVile,&nbsp;Oliver Semler,&nbsp;Magnus Westgren,&nbsp;Cecilia Götherström,&nbsp;Melissa Hill","doi":"10.1038/s41431-026-02164-0","DOIUrl":"10.1038/s41431-026-02164-0","url":null,"abstract":"Osteogenesis imperfecta (OI) is a rare genetic disorder characterised by bone fragility and frequent fractures. While current treatments aim to preserve bone mass, there is no cure. Boost Brittle Bones Before Birth (BOOSTB4) is an international clinical trial investigating postnatal (n = 15) and prenatal plus postnatal (n = 3) infusions of fetal mesenchymal stem cells as a potential treatment for severe OI. Each BOOSTB4 participant received four stem cell doses at four-month intervals. Here we explore the experiences of parents and of healthcare professionals involved in BOOSTB4. In this qualitative study, one or both parents of children participating in BOOSTB4 took part after the second dose (T1: 16 families, 22 participants) and at least 6 months after the final dose (T2: 12 families, 16 participants). Professionals delivering BOOSTB4 participated in one interview (n = 13). Data were analysed using codebook thematic analysis. Decisions to participate in the trial were influenced by the potential for improved prognosis and limited alternative therapies. Parents felt reassurance because they were taking action and gratitude for access to expertise in OI. Balancing hope, expectations and uncertainty around treatment efficacy was challenging. Parents also expressed disappointment and uncertainty about treatment ending. Practical challenges included travel for treatment with a child with OI or late in pregnancy. Professionals noted the difficulty in managing parental expectations and the regulatory and logistical barriers of an international trial. Findings emphasised the need for clear communication before, during and after the trial, transparent information and trial designs that accommodate the needs of individual families.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 8","pages":"1176-1184"},"PeriodicalIF":4.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02164-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359976","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":"Systematic analysis of homozygous autosomal copy number losses in exomes improves diagnostic yield and uncovers ultra-rare recessive disorders","authors":"Ankur Chaurasia,&nbsp;Anju Shukla,&nbsp;Shruti Pande,&nbsp;Greeshma Purushothama,&nbsp;Akhil Kanathay Ashokan,&nbsp;Purvi Majethia,&nbsp;Namanpreet Kaur,&nbsp;Priyanka Upadhyai,&nbsp;Neha Quadri,&nbsp;Gandham SriLakshmi Bhavani,&nbsp;Dhanya Lakshmi Narayanan,&nbsp;Shalini S. Nayak,&nbsp;Sheela Nampoothiri,&nbsp;Ataf H. Sabir,&nbsp;Alaa A. Mohammed,&nbsp;Sophie Shaw,&nbsp;Verity L. Hartill,&nbsp;Christopher M. Watson,&nbsp;Colin A. Johnson,&nbsp;Afrah Alshammari,&nbsp;Andrew E. Fry,&nbsp;James A. Poulter,&nbsp;William G. Newman,&nbsp;Paul R. Kasher,&nbsp;Siddharth Banka,&nbsp;Katta M. Girisha","doi":"10.1038/s41431-026-02158-y","DOIUrl":"10.1038/s41431-026-02158-y","url":null,"abstract":"Systematic analysis of copy number variants (CNVs) in large datasets is challenging, and there are limited studies of homozygous copy number losses in rare disease exomes. Here, we leveraged the genomic uniqueness and relative under-representation of the Indian population in the current public genomic databases and identified 42,386 possible homozygous losses (median 20 per individual) in a heterogeneous cohort of 2021 individuals with suspected Mendelian disorders, who had undergone exome sequencing using 12 different capture kits in a resource-limited setting. Employing a genomic position loss-count-based approach, we filtered 1224 rare homozygous loss calls in 718 individuals (median 1 per individual) for further analysis, thus significantly reducing the analysis burden. Clinical correlation and validation of these rare calls enabled 10 new diagnoses in 240 unsolved individuals. This led to a two-fold increase in diagnosis owing to homozygous deletions. Further analysis of the data and identification of additional affected individuals through collaboration led to identification of biallelic FILIP1 and FAM177A1 variants as causes of a syndromic arthrogryposis and a neuromuscular disorder respectively. Both conditions were recently reported as ultra-rare recessive disorders, thus validating our approach. We also show that biallelic loss-of-function TFCP2L1 variants cause chronic kidney disease and VPS36 variants cause a severe recessive neurodevelopmental disorder characterised by microcephaly, motor delay, agenesis of the corpus callosum, cerebellar atrophy, seizures, hypotonia, spasticity and early death. Overall, these results demonstrate a scalable approach to screen homozygous losses for improving diagnostic yield and discovering disease-genes in large exome cohorts.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 8","pages":"1059-1069"},"PeriodicalIF":4.6,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02158-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337572","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":"Australian parents' perspectives on extended genomic screening: what information to return and when?","authors":"Fiona Lynch, Christopher Gyngell, Stephanie Best, Clara Gaff, Lilian Downie, Alison Archibald, Ilias Goranitis, Julian Savulescu, Sebastian Lunke, Zornitza Stark, Danya F Vears","doi":"10.1038/s41431-026-02168-w","DOIUrl":"https://doi.org/10.1038/s41431-026-02168-w","url":null,"abstract":"<p><p>Genomic newborn screening (gNBS) has the potential to generate information that remains relevant across the lifespan, yet little is known about how families who have directly experienced gNBS, understand its long-term role and value. This study analysed the results of eight focus groups with 32 parents whose children had received findings from gNBS (through the BabyScreen+ study, a population-based Australian gNBS pilot programme), to explore how they conceptualise the use of genomic information beyond infancy (which we refer to as extended genomic sequencing, or eGS). Parents described a complex interplay of factors including treatability, severity, certainty, and personal capacity to manage information that shaped their desire to receive results. Using the Health Belief Model as a lens, we show how parental reflections mapped to constructs such as perceived benefits, barriers, severity, susceptibility, self-efficacy, and cues to action. However, parents' reasoning was dynamic rather than static, illustrating how shifts in clinical options or family circumstances influence decision making over time. Overall, our findings demonstrate that families view gNBS data as a potential lifetime resource and support the need for flexible consent pathways, ongoing counselling, and governance frameworks that anticipate both the benefits and burdens of genomic information. This work offers timely insights to inform ethical implementation of eGS in Australia and contributes to international discussions about integrating genomic sequencing into population-level screening.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338335","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":"Psychosocial outcomes of reproductive genetic carrier screening up to five years post-result.","authors":"Erin Tutty, Alison D Archibald, Belinda J Dawson-McClaren, Cameron Patrick, Martin B Delatycki, Sharon Lewis","doi":"10.1038/s41431-026-02167-x","DOIUrl":"10.1038/s41431-026-02167-x","url":null,"abstract":"<p><p>The long-term psychosocial outcomes of reproductive genetic carrier screening (RGCS) have yet to be adequately quantified. We examined long-term psychosocial outcomes of RGCS within the Australian Reproductive Genetic Carrier Screening Project ('Mackenzie's Mission'), where 9107 reproductive couples had RGCS for ~1300 genes and 175 (1.9%) received a new increased chance result. We administered a survey at approximately three to five years (mean = 3.7) post-result, capturing attitudes toward the result, state anxiety (using the STAI-6) and decision regret for all participants, plus empowerment and decisional conflict for participants with an increased chance result. Using STAI-6 data from previous surveys, we used linear mixed models to examine change in state anxiety over time. Participants with a low chance result (n = 2512) had low state anxiety, minimal decision regret and felt reassured by their result. For participants with an increased chance result (n = 86), increased state anxiety after result disclosure gradually decreased, almost returning to baseline by 3-5 years post-result. This group also had high empowerment, minimal decision regret, low decisional conflict regarding reproductive choices and positive attitudes about the utility of their increased chance result. Predictors of clinically meaningful state anxiety at 3-5 years post-result were: having an increased chance result, higher trait anxiety and having a child with a medical condition/disability. Findings highlight that large-panel RGCS is valuable for reproductive planning. Elevated state anxiety after increased chance result disclosure aligns with other reproductive genetic screening and decreases over time. It is important that RGCS programmes provide appropriate, longitudinal psychosocial support to promote the reproductive empowerment of all who participate.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338368","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 parents decide whether to have genomic newborn screening: experiences from BabyScreen.","authors":"Anaita Kanga-Parabia, Erin Tutty, Nathasha Kugenthiran, Jade Caruana, Lilian Downie, Clara Gaff, Nitzan Lang, Sebastian Lunke, Katrina Scarff, Zornitza Stark, Stephanie Best, Alison D Archibald","doi":"10.1038/s41431-026-02159-x","DOIUrl":"https://doi.org/10.1038/s41431-026-02159-x","url":null,"abstract":"<p><p>Education and consent processes for genomic newborn screening (gNBS) must be informed by evidence about parental decision-making. BabyScreen+ piloted gNBS for 1000 newborns in Victoria, Australia. Prospective parents consented online with genetic counselling available on request. We aimed to explore how BabyScreen+ participants (n = 1139) made decisions about gNBS using a convergent parallel mixed methods design. Demographic (n = 1080), survey (n = 1010), and interview (n = 24) data were analysed using descriptive statistics, logistic regression, and deductive content analysis mapped to the Health Belief Model (domains indicated in italics). Most participants perceived low susceptibility of having a child with a genetic condition and found it difficult to conceptualise severity. Participants were motivated to consider gNBS due to benefits such as information about their child's health, reassurance, and research contributions. Some perceived barriers included inequitable access to gNBS information, difficulty navigating high chance results, and potential data misuse. Most participants (987/1139, 87%) proceeded with gNBS because they believed barriers were outweighed by benefits or were manageable due to high self-efficacy. Remaining participants (152/1139, 13%) did not proceed with gNBS because benefits were unclear, or due to low self-efficacy. Experiences were modified by sociodemographic factors and the BabyScreen+ model of care. This research provides timely evidence about parental gNBS decision-making. It supports acceptability and feasibility of the BabyScreen+ model of care. Moving forward, education and consent processes must be equitable, tailored to individual context, and designed to foster self-efficacy. Such considerations will support decision-making and reduce psychological impacts for parents considering gNBS in the future.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338359","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":"Decoding splicing variants in high-throughput sequencing: a functional validation approach integrating deep learning tools","authors":"Clément Hersent,&nbsp;Lise Larrieu,&nbsp;Patricia Fergelot,&nbsp;Julie Miro,&nbsp;Mehdi Benkirane,&nbsp;Chloé Angelini,&nbsp;Francis Ramond,&nbsp;Cecilia Marelli,&nbsp;Isabelle Sabatier,&nbsp;Gaëtan Lesca,&nbsp;Christel Vaché,&nbsp;Mireille Cossée,&nbsp;Anne Bergougnoux,&nbsp;Klaus Dieterich,&nbsp;Christine Tranchant,&nbsp;Isabelle Marey,&nbsp;Anna Castrioto,&nbsp;Christel Thauvin-Robinet,&nbsp;Lydia Abou Haidar,&nbsp;François Rivier,&nbsp;Sylvie Tuffery-Giraud,&nbsp;Michel Koenig","doi":"10.1038/s41431-026-02162-2","DOIUrl":"10.1038/s41431-026-02162-2","url":null,"abstract":"High-throughput genome and exome sequencing have uncovered numerous intronic variants in disease genes, yet predicting their impact on pre-mRNA splicing is still challenging. While deep learning tools have improved variant prioritization, their ability to detect atypical regulatory mechanisms remains unknown. We combined predictions from multiple complementary splicing prediction tools with functional RNA studies to evaluate the splicing consequences of intronic variants identified in patients with neurodegenerative diseases. Nine intronic variants with uncertain impact on splicing were selected, including six deep-intronic variants, two non-canonical splice-site variants, and one canonical splice-site variant associated with an atypical phenotype. Three variants were predicted to disrupt a donor splice site, five to create a cryptic donor splice site, and one was located close to a putative acceptor site. Transcript analysis in blood revealed splicing abnormalities in eight of the nine cases. All algorithms failed at least once: deep learning tools missed specific donor site losses or cryptic splice-site activation events, while motif-based approaches failed to predict some donor site activation or generated false-positive predictions. The only variant not directly located in a splice site was predicted to activate a deep intronic splicing enhancer. Motif-based tools suggested the creation of an SRSF2 protein–dependent enhancer. Functional studies based on minigene assays support a role for SRSF2 in promoting pseudoexon inclusion. These findings highlight the complementarity of splicing prediction tools and the need to integrate them into diagnostic pipelines, with transcript-level confirmation remaining critical for accurate pathogenicity assessment.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 8","pages":"1165-1175"},"PeriodicalIF":4.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338371","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":"Perspectives on phenotype in genetic testing for early-onset atrial fibrillation.","authors":"Leonoor F J M Wijdeveld, Bianca J J M Brundel, Ahmad S Amin, Sean J Jurgens","doi":"10.1038/s41431-026-02163-1","DOIUrl":"https://doi.org/10.1038/s41431-026-02163-1","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338389","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":"Hemizygous loss-of-function variants of EIF1AX are associated with a syndromic neurodevelopmental disorder","authors":"Kazuyuki Komatsu,&nbsp;Atsushi Sugie,&nbsp;Yohei Nitta,&nbsp;Jiro Osaka,&nbsp;Ummul Halilunnisa Mansoor Hussain,&nbsp;Mitsuru Kubota,&nbsp;Nobuyuki Shimozawa,&nbsp;Melissa T. Carter,&nbsp;Petra J. G. Zwijnenburg,&nbsp;Quinten Waisfisz,&nbsp;Felix Boschann,&nbsp;Denise Horn,&nbsp;Mitsuko Nakashima,&nbsp;Hirotomo Saitsu","doi":"10.1038/s41431-026-02151-5","DOIUrl":"10.1038/s41431-026-02151-5","url":null,"abstract":"Pathogenic variants of genes encoding initiation factors can cause neurological diseases, including neurodevelopmental disorders and brain abnormalities. The eukaryotic translation initiation factor 1 A, X-linked (EIF1AX) is a gene located at Xp22.12 that plays an important role in the regulation of translation initiation. Here, we identified de novo hemizygous EIF1AX variants in male individuals with neurodevelopmental disorders and explored their possible involvement in these neurological disorders. We performed trio-based exome or whole genome sequencing in four families. The pathogenicity of EIF1AX variants was evaluated using a molecular dynamic simulation and transgenic Drosophila models. We identified four de novo hemizygous EIF1AX variants in four male individuals with variable neurodevelopmental delay, dysmorphic features, behavioral problems, ophthalmological abnormalities, and structural abnormalities in the brain. One variant was predicted to cause a splicing alteration, and minigene analysis confirmed exon skipping leading to the generation of a premature termination codon. In transgenic Drosophila harboring wild-type (WT) EIF1AX or the three other EIF1AX missense variants, overexpression of WT and the p.(Asn17Asp) variant caused structural abnormalities in the compound eye, whereas the p.(Lys64Glu) and p.(Asp90Gly) variants significantly reduced these eye abnormalities. In addition, WT overexpression resulted in significant axonal toxicity in the Drosophila optic nerve, causing a significant reduction in the number of axons, whereas all mutants showed only a mild reduction in axonal number. Our findings indicated that all variants resulted in different degrees of EIF1AX loss-of-function. Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 8","pages":"1047-1058"},"PeriodicalIF":4.6,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307562","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}