European Journal of Human Genetics最新文献

{"title":"Novel biallelic COL25A1 variants broaden the clinical spectrum from congenital cranial dysinnervation disorders to fetal lethal phenotypes.","authors":"Frederike L Harms, Christian Müller, Fanny Kortüm, Maja Hempel, Malik Alawi, Maha S Zaki, Rasha M Elhossini, Mohamed S Abdel-Hamid, Lama AlAbdi, Fowzan S Alkuraya, Wesam Kurdi, Tristan Celse, Marta Spodenkiewicz, Tiphany Laurens, Klaus Dieterich, Sujatha Jagadeesh, Sandesh Salvankar, Katta M Girisha, Kerstin Kutsche","doi":"10.1038/s41431-025-01839-4","DOIUrl":"https://doi.org/10.1038/s41431-025-01839-4","url":null,"abstract":"<p><p>Biallelic variants in COL25A1 have been associated with isolated congenital cranial dysinnervation disorders (CCDDs) and arthrogryposis multiplex congenital (AMC) with or without CCDD. COL25A1 encodes collagen XXV that belongs to the subfamily of membrane-associated collagens with interrupted triple helices. COL25A1 contains four non-collagenous and three collagenous domains. Three alternatively spliced COL25A1 transcript variants are known. In mice, Col25a1 is required for intramuscular motor innervation and cranial motor neuron development. We report seven subjects with novel biallelic COL25A1 pathogenic variants, including three AMC-affected individuals, one of whom died in infancy, and four unrelated fetuses. We expand the associated phenotypic spectrum as fetuses showed lethal phenotypes including reduced or no movement, contractures, and hydrops in three and growth retardation and skeletal abnormalities in one. The molecular spectrum includes two microdeletions encompassing several 5' or 3' exons, two missense, one nonsense, one frameshift, and one variant affecting splicing. In fibroblasts of the subject who was compound heterozygous for the c.367G > C and c.1198G > T variants, we identified skipping of exon 3 in COL25A1 mRNAs due to the G-to-C change. These aberrantly spliced transcripts were subject to nonsense-mediated mRNA decay. Analysis of transcriptome sequencing data from primary human fibroblasts without COL25A1 pathogenic variants revealed novel COL25A1 exon-exon junctions and 13 not previously annotated alternatively spliced in-frame exons. We hypothesized that interindividual variation in the splicing of COL25A1 exons in different tissues may underlie the variable phenotypes in the affected individuals.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742727","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":"Exploring individuals' experiences with self-reported unmet need for genetic testing.","authors":"Kennedy Borle, Larry D Lynd, Jehannine Austin","doi":"10.1038/s41431-025-01838-5","DOIUrl":"https://doi.org/10.1038/s41431-025-01838-5","url":null,"abstract":"<p><p>In practice, healthcare systems and insurers determine that there is \"need\" for genetic testing when there is potential for clinical utility. However, it is not currently known how the public understands the need for genetic testing and if this aligns with clinical utility. We recruited participants in Canada through a survey distributed through a market research company (Leger Opinion Panel). Participants who self-reported the need for genetic testing were then purposively sampled to complete a semi-structured virtual interview. We used an interpretive description approach and reflexive thematic analysis. We completed 19 interviews and found that participants' self-identified need for genetic testing was informed by their experiences with genetic information and the perceptions that genetic information is actionable (clinical utility) and has personal meaning (personal utility). Most participants would not be eligible for funded testing based on their personal and family history, however, they had unmet informational and psychological needs, indicating unmet need for genetic counseling. The public understanding of the need for genetic testing is complex and varied. Participants identified many benefits resulting from genetic testing which are not reflected in how need is operationalized in reimbursement decisions, however unmet expectations for testing contributed to medical distrust and dissatisfaction.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729467","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 hypomorphic FLVCR2 variant resulting in moderate transport deficiency causes hydranencephaly syndrome with brain calcifications.","authors":"Marcello Scala, Nancy C P Leong, Thanh Nha Uyen Le, Yu Zhang, Yichang Wu, Mariasavina Severino, Francesca Madia, Mohammad Sadegh Shams Nosrati, Alireza Dostmohammadi, Valeria Capra, Dario Paladini, Francesca Buffelli, Ezio Fulcheri, Serena Cappato, Ludovica Menta, Renata Bocciardi, Federico Zara, Long N Nguyen","doi":"10.1038/s41431-025-01836-7","DOIUrl":"https://doi.org/10.1038/s41431-025-01836-7","url":null,"abstract":"<p><p>FLVCR2 is a highly conserved member of the major facilitator superfamily (MFS), the largest superfamily of solute carriers that are involved in the transport of small molecules across lipid bilayers. The loss of the murine ortholog Mfsd7c, an endothelial transporter in brain blood vessels, causes brain angiogenic growth deficiency and lethality. Recessive FLVCR2 variants cause proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as Fowler syndrome. This often-lethal condition features microcephaly, skeletal deformities, and severe cerebrovascular defects. Although a number of cases have been reported, very limited evidence of the pathogenicity of FLVCR2 variants is available. In this study, we thoroughly investigated a new fetal case of Fowler syndrome. Through exome sequencing, we identified two compound heterozygous FLVCR2 variants: the maternal c.1124+3_1124+6del and the paternal p.(Arg492Trp). The effects of the c.1124+3_1124+6del variant were investigated through a minigene assay, which showed impaired splicing of the exon 5 of FLVCR2. To characterize the impact of the p.(Arg492Trp) substitution, we performed protein modeling using Rosetta and DynaMut2, that showed a highly destabilizing effect. Then, based on the very recent evidence that choline is a major FLVCR2 ligand, we performed a radiolabeled-choline or ethanolamine transport assays in HEK 293 cells and found that the p.(Arg492Trp) variant causes a 50-60% reduction of FLVCR2 transport activity, resulting in a net activity of 25-30%. Our findings suggest that FLVCR2 deficiency may be sufficient to cause PVHH even in the absence of a complete loss of transport activity, possibly involving extragenetic factors in the pathophysiology of this complex condition.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709260","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":"Novel variants in FOXI3 gene confirm its implication in Oculo-Auriculo-Vertebral spectrum.","authors":"Angèle Sequeira, Thomas Sagardoy, Laetitia Bourgeade, Didier Lacombe, Elizabeth Sarrazin, Annick Toutain, Caroline Rooryck","doi":"10.1038/s41431-025-01837-6","DOIUrl":"https://doi.org/10.1038/s41431-025-01837-6","url":null,"abstract":"<p><p>Molecular bases of the clinically heterogenous Oculo-Auriculo-Vertebral Spectrum or Craniofacial Microsomia remain largely unknown. Although genetic diagnosis is established in less than 10% of the patients, variants in the FOXI3 gene are the most recurrent genetic cause. We studied a large family with 6 affected individuals on 4 generations showing an autosomal dominant transmission of Oculo-Auriculo-Vertebral Spectrum with incomplete penetrance. The genome sequencing strategy allowed the identification of a new likely pathogenic missense variant located within the Nuclear Localization Signal of FOXI3 and affecting its subcellular localization. Moreover, we described 3 additional rare FOXI3 variants identified in 3 other patients from a cohort of 251 patients with Oculo-Auriculo-Vertebral Spectrum. These variants were classified as Variants of Unknown Significance. In conclusion, this study confirms FOXI3 implication in the Oculo-Auriculo-Vertebral Spectrum and the importance of Nuclear Localization Signal integrity. Genotype-phenotype correlations and putative modifier haplotype are discussed.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700059","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":"Exploring the potential usefulness of the GCOS-16 for expanded applications.","authors":"Yvette Kuo, Kennedy Borle, Jehannine Austin","doi":"10.1038/s41431-025-01830-z","DOIUrl":"https://doi.org/10.1038/s41431-025-01830-z","url":null,"abstract":"<p><p>The Genetic Counselling Outcome Scale-24 (GCOS-24) measures empowerment reliably in the context of genetic services, but its potential utility is constrained by some of its features. Using Rasch Measurement Theory, the GCOS-16 was developed: eight items were removed and the Likert scale collapsed from seven response options to three. The GCOS-16 has improved performance, and potential for usefulness beyond its original design i.e., identifying/triaging patients who may benefit most, and comparing genetic counseling (GC) to non-GC interventions. In this study, using the GCOS-24 data collected from a psychiatric GC clinic, we aimed to use a statistical method to determine the minimal clinically important difference (MCID) of the GCOS-16, and to examine whether the GCOS-16, or any individual items or subdomains could be used to identify patients who would most benefit from GC. The GCOS-24 data (24-items, 7-point Likert scale) from 307 charts were transformed into the GCOS-16 scoring (16 items, 3-point Likert scale). The GCOS-16 scores increased from pre- to post-GC (p < 0.001, d = 0.935), and the MCID was determined to be an increase of 2.5 points. There were significant differences between pre- to post-GC for all items and subdomains except for item #6. Patients receiving in-person GC were more likely to meet the MCID than those receiving service by telephone or telehealth (p < 0.001). Our data demonstrate that the GCOS-16 is sensitive to change in empowerment without ceiling effects - this could be used to triage patients for GC, and to compare GC to non-GC interventions.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691432","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":"Determinants of diagnostic yield in a multi-ethnic Asian inherited retinal disease cohort.","authors":"Jane Andrea Lieviant, Choi Mun Chan, Yasmin Bylstra, Kanika Jain, Jing Xian Teo, Wan Wan Lim, Sylvia Kam, Tang Wei Chao, Nellie Chai Bin Siew, Sonia Davila, Eranga Nishanthie Vithana, Ranjana Sanjay Mathur, Tien-En Tan, Patrick Tan, Saumya S Jamuar, Beau James Fenner, Weng Khong Lim","doi":"10.1038/s41431-025-01833-w","DOIUrl":"10.1038/s41431-025-01833-w","url":null,"abstract":"<p><p>As the discovery of new genes causing inherited retinal disease (IRD) has plateaued, we look to other factors which could be used to maximize diagnostic yield. We analyzed whole-exome sequencing (WES) data from 506 IRD probands, focusing on the interplay between diagnostic yield, age of symptom onset or diagnosis, family history, and initial clinical diagnosis. The cohort's overall diagnostic yield was 49.2%. Diagnostic yield was negatively correlated with the age of symptom onset and positively correlated with the number of affected family members. Diseases with distinctive clinical presentations such as Bietti crystalline dystrophy (BCD) or Leber congenital amaurosis (LCA) were more reliably diagnosed than more common and heterogeneous diseases like retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). Recurrent genes and variants in this Chinese-majority cohort resemble those found in Chinese cohort studies but differ from populations of European descent, with implications for the design and prioritization of gene therapies. These insights may help optimize the diagnostic utility of genetic testing for IRDs, enhance the delivery of genetic counseling for patients, and guide the development of more inclusive targeted therapies.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669370","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":"XRCC4-related microcephalic primordial dwarfism: description of a clinical series of 7 cases, phenotype expansion and new diagnostic approaches.","authors":"Silvestre Cuinat, Nicolas Chatron, Florence Petit, Perrine Brunelle, Etienne Dincuff, Marion Aubert Mucca, Eric Bieth, Ariane Schmetz, Harald Rieder, Bernd Wollnik, Silke Kaulfuß, Gökhan Yigit, Colina McKeown, Tim Savage, Meghan R Mulligan, Louise S Bicknell, Nicole Corsten-Janssen, Patrick Edery, Gaetan Lesca, Jean-Pierre de Villartay, Audrey Putoux","doi":"10.1038/s41431-025-01821-0","DOIUrl":"https://doi.org/10.1038/s41431-025-01821-0","url":null,"abstract":"<p><p>The non-homologous end joining (NHEJ) pathway is essential to repair DNA double-strand breaks. XRCC4 acts as a stabilizer of the DNA ligase LIG4 in the NHEJ process. In humans, XRCC4 pathogenic variants are responsible for a microcephalic primordial dwarfism syndrome (MPD). Currently, 17 patients have been reported with XRCC4-related MPD and we report 7 new patients from 6 different families, including one fetus. The patients present with short stature, severe microcephaly, neurodevelopmental disorder and additional features, such as transient increase in nuchal translucency, congenital glaucoma, thumb anomalies, hepatic steatosis, seizures, essential tremor and oligodontia which have not been previously described. Hyper- and hypopigmented skin macules, dermatofibrosarcoma, mandibular osteoid osteoma and pancytopenia are also new features, reminiscent of cancer susceptibility syndromes. Functional studies were performed on two patients carrying the known pathogenic p.(Trp43Arg) variant in homozygous state, using a fast, cost-effective and non-invasive approach on PBMCs: (1) Survival analyses after ionizing radiation confirm important radiosensitivity. (2) Flow cytometry showed the lack of TCR-Va7+ T-lymphocytes, suggesting recombination defect of V(D)J coding segments. (3) This was confirmed by multiplexed RT-PCR (PROMIDISα biomarker), analyzing the diversity of V(D)J coding segments in a subset of the TCRα repertoire. We therefore extend the phenotype of XRCC4-related MPD and suggest a combination of three functional assays, based on radiosensitivity and V(D)J recombination defect, to improve the interpretation of XRCC4 variants in fast, cost-effective and non-invasive manner. These findings will improve the diagnosis, genetic counselling, follow-up and management of these patients.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669375","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":"Heterozygous CELF4 variants in the N-term region crucial for the RNA-binding activity lead to neurodevelopmental disorder and obesity.","authors":"Ange-Line Bruel, Anneke T Vulto-vanSilfhout, Frédéric Bilan, Gwenaël Le Guyader, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Sophie Rondeau, Marlène Rio, Kristen N Lee, Adelyn Beil, Mohnish Suri, François Guerin, Valentin Ruault, Alice Goldenberg, François Lecoquierre, Nicole Bertsch, Rhonda Anderson, Xiao-Ru Yang, Micheil Inness, Emi Rikeros-Orozco, Maria Palomares-Bralo, Jennifer Cassady Hayek, Jennifer Cech, Ankita Jhuraney, Runjun D Kumar, Saadet Mercimek-Andrews, Anastasia Ambrose, Erin N Wakeling, Ingrid M Wentzensen, Erin Torti, Catherine Gooch, Laurence Faivre, Christophe Philippe, Yannis Duffourd, Antonio Vitobello, Christel Thauvin-Robinet","doi":"10.1038/s41431-025-01809-w","DOIUrl":"https://doi.org/10.1038/s41431-025-01809-w","url":null,"abstract":"<p><p>RNA-binding proteins play a key role in post-transcriptional events, such as mRNA splicing, transport, stability, translation and decay. Dysregulation of RNA life can have dramatic consequences. CELF RNA-binding proteins appear to be essential during embryo development. In this study, we identified 15 patients with heterozygous missense or loss-of-function variants in the CELF4 gene by exome or genome sequencing. All variants affecting the N-terminus of the protein are essential and sufficient for the RNA-binding and splicing activity or RRM domains. Most patients presented with neurodevelopmental disorders including global developmental delay/intellectual disability (11/14), seizures (9/15) and overweight/obesity (10/14) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype. This study highlights the essential role of CELF4 in development and its involvement as a novel etiology of neurodevelopmental disorders with obesity.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663117","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":"Pathogenic germline variants in patients with early-onset colorectal cancer according to phenotype.","authors":"Antoine Dardenne, Marion Dhooge, Noémie Basset, Albain Chansavang, Julie Metras, Solenne Farelly, Jeanne Netter, Florence Coulet, Patrick R Benusiglio","doi":"10.1038/s41431-025-01808-x","DOIUrl":"https://doi.org/10.1038/s41431-025-01808-x","url":null,"abstract":"<p><p>We assessed retrospectively the prevalence of pathogenic germline variants (PGV) in 268 French adult patients diagnosed with colorectal cancer (CRC) before age 41, stratified by phenotype. APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH3, MSH6, MUTYH, NTHL1, POLE, POLD1, PTEN, PMS2, SMAD4, STK11 and TP53 were analyzed. Overall, 21.6% of cases carried a PGV. A high prevalence was observed in Mismatch Repair-deficient (MMRd) CRC (60.1%, MMR genes) and polyposis-associated CRC (48%, APC, MUTYH and MSH3-biallelic, POLE). Only 2.3% of patients with MMR proficient and without polyposis carried a PGV. The genes involved in this third group were POLE and MSH2, and three out of four cases had either two synchronous CRC or a CRC family history. Phenotypic features should be taken into account for testing decision. Evaluating the cost-effectiveness of testing all CRC cases < 41 years, as well as how it aligns with the constraints of various healthcare systems, is warranted.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647796","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":"Reevaluating 'seriousness' in genetic conditions: balancing clinical criteria and lived experiences.","authors":"Shizuko Takahashi, Rie Iizuka, Tsutomu Sawai","doi":"10.1038/s41431-025-01829-6","DOIUrl":"https://doi.org/10.1038/s41431-025-01829-6","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633975","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}