European Journal of Human Genetics最新文献

{"title":"What’s new in April’s EJHG?","authors":"Alisdair McNeill","doi":"10.1038/s41431-025-01842-9","DOIUrl":"10.1038/s41431-025-01842-9","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 4","pages":"393-394"},"PeriodicalIF":3.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01842-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809975","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":"The value of large-scale programmes in human genomics.","authors":"Ruth Horn, Angeliki Kerasidou, Jennifer Merchant","doi":"10.1038/s41431-025-01844-7","DOIUrl":"https://doi.org/10.1038/s41431-025-01844-7","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810896","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: Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes.","authors":"German Demidov, Steven Laurie, Annalaura Torella, Giulio Piluso, Marcello Scala, Manuela Morleo, Vincenzo Nigro, Holm Graessner, Siddharth Banka, Katja Lohmann, Stephan Ossowski","doi":"10.1038/s41431-025-01841-w","DOIUrl":"https://doi.org/10.1038/s41431-025-01841-w","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802901","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":"Perinatal genetic diagnostic yield in a population of fetuses with the phenotype arthrogryposis multiplex congenita: a cohort study 2007-2021.","authors":"Arda Arduç, Johanna I P De Vries, Maria B Tan-Sindhunata, Quinten Waisfisz, Eva Pajkrt, Ingeborg H Linskens","doi":"10.1038/s41431-025-01848-3","DOIUrl":"https://doi.org/10.1038/s41431-025-01848-3","url":null,"abstract":"<p><p>Arthrogryposis multiplex congenita (AMC) presents challenges for prenatal detection due to its heterogeneous etiology, onset, and phenotypical manifestations. This study aims to describe the genetic diagnostic yield in a population of fetuses with detailed phenotypic description over a 15-year period (2007-2021) at the Fetal Medicine Unit of Amsterdam UMC, the Netherlands. The fetal and neonatal phenotypes were classified into three clinical AMC Groups, with the exception that Groups 1 and 2 were combined in the prenatal classification. Group 1 involves limb involvement primarily, Group 2 includes musculoskeletal involvement plus other system anomalies, and Group 3 involves musculoskeletal involvement with central nervous system disability, lethality, fetal akinesia deformation sequence, and/or intellectual disability. The cohort consisted of 64 consecutive cases, 13 in Groups 1 + 2 and 51 in Group 3. Perinatal genetic testing occurred in all cases: prenatally in 56 of the 64 (88%), postnatally in 36 of the 64 (56%), and combined testing in 28 of the 64 cases (44%). The overall genetic diagnostic yield was 28% (18/64), and it increased over the 5-year period from 14% to 50%. Whole exome sequencing had the highest yield (41.7%). The yield per phenotype was 30.8% (4/13) for AMC Group 1 + 2 and 27.4% (14/51) for AMC Group 3. Detailed fetal phenotyping and perinatal genetic testing in all cases showed improved diagnostic yield over time, likely due to the introduction of Next-generation sequencing-based tests. The availability of stored DNA will be beneficial for future investigations since further improvements in genetic testing possibilities are expected.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802904","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":"Reanalysis of unsolved prenatal exome sequencing for structural defects: diagnostic yield and contribution of postnatal/postmortem features.","authors":"Christel Thauvin-Robinet, Aurore Garde, Maud Favier, Julian Delanne, Caroline Racine, Thierry Rousseau, Sophie Nambot, Ange-Line Bruel, Sébastien Moutton, Chloé Quelin, Cindy Colson, Anne-Claire Brehin, Anne-Marie Guerrot, Caroline Rooryck, Audrey Putoux, Patricia Blanchet, Sylvie Odent, Elise Schaefer, Odile Boute, Alice Goldenberg, Agnes Guichet, Carine Abel, Godelieve Morel, Melanie Fradin, Bertrand Isidor, Marie Vincent, Christine Francannet, Gabriella Vera, Florence Petit, Mathilde Nizon, Constance Wells, Mederic Jeanne, Caroline Deiller, Alban Ziegler, Manon Godin, Pascale Saugier-Veber, Kevin Cassinari, Pierre Blanc, Emmanuel Simon, Christine Binquet, Yannis Duffourd, Hana Safraou, Anne-Sophie Denomme-Pichon, Antonio Vitobello, Christophe Philippe, Laurence Faivre, Frédéric Tran-Mau-Them, Nicolas Bourgon","doi":"10.1038/s41431-025-01823-y","DOIUrl":"https://doi.org/10.1038/s41431-025-01823-y","url":null,"abstract":"<p><p>In 30-40% of fetuses with structural defects, the causal variant remains undiagnosed after karyotype, chromosomal microarray, and exome sequencing. This study presents the results of a reanalysis of unsolved prenatal ES (pES) cases and investigates how postnatal/postmortem phenotyping contributes to identifying relevant variants. pES data was prospectively reanalyzed for unsolved cases enrolled in the AnDDI-Prénatome cohort study. Postnatal/postmortem data were included with prenatal features using Human Phenotype Ontology terms up to 3 years after pES. The reanalysis involved updating bioinformatic processing and querying raw data using a GREP query. We reanalyzed 58/94 (62%) unsolved pES cases, including 8 variants of unknown significance. Data for clinical examination at birth was available for all live newborns, and postmortem examination was available in 12 terminated fetuses. Additional features were identified at birth in 27/58 cases (44%): 9 terminated fetuses, 2 stillbirths, and 16 live newborns. One diagnosis (SNAPC4) was obtained through a periodic query following recent associations with human disease, and without additional clinical data. Three additional VUS were identified through reanalysis with the addition of new clinical features, illustrating the limited contribution of updated postnatal/postmortem phenotyping in identifying relevant variants after negative pES. In conclusion, the benefit of prospective reanalysis of unsolved pES is limited, even over time. Postnatal genome sequencing may be a more appropriate option than reanalysis with postnatal/postmortem phenotyping to establish a causal diagnosis.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788348","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: Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis.","authors":"Nan Jiang, Liyuan Zhang, Zeyan Zheng, Hanze Du, Shi Chen, Hui Pan","doi":"10.1038/s41431-025-01825-w","DOIUrl":"10.1038/s41431-025-01825-w","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779464","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: RNA-sequencing unveils FLT4 splice site variants in variable congenital heart disease.","authors":"Maxim Verlee, Erika D'haenens, Laurenz De Cock, Laura Muiño Mosquera, Katya De Groote, Kristof Vandekerckhove, Joseph Panzer, Ellen Roets, Björn Menten, Sofie Symoens, Paul Coucke, Tim Van Damme, Sarah Vergult, Bert Callewaert","doi":"10.1038/s41431-025-01831-y","DOIUrl":"10.1038/s41431-025-01831-y","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763472","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":"Reassessment of FBN1 variants of uncertain significance using updated ClinGen guidance for PP1/BS4 and PP4 criteria.","authors":"Ju Hyeon Shin, Young-Gon Kim, Shin Yi Jang, June Huh, Duk-Kyung Kim, Jong-Won Kim, Ja-Hyun Jang, Taek Kyu Park, Mi-Ae Jang","doi":"10.1038/s41431-025-01826-9","DOIUrl":"https://doi.org/10.1038/s41431-025-01826-9","url":null,"abstract":"<p><p>Marfan syndrome (MFS) is a genetic disorder caused by an FBN1 variant and is diagnosed based on the revised Ghent criteria, which incorporate clinical manifestations and genetic testing. Up-to-date FBN1 variant interpretation is crucial for proper diagnosis and management of MFS; however, some FBN1 variants of uncertain significance (VUSs) remain inconclusive despite applying Clinical Genome Resource (ClinGen) FBN1-specific guideline. Recently, the ClinGen guidance for PP1/BS4 co-segregation and PP4 phenotype specificity criteria (new PP1/PP4 criteria) were released. Here, we performed reassessment of FBN1 VUSs using these new PP1/PP4 criteria. FBN1 VUSs collected from December 2015 to April 2024 were reassessed according to the ClinGen FBN1-specific guideline and new PP1/PP4 criteria. Medical records and previous studies were reviewed to evaluate the phenotype-specificity of evidence based on the revised Ghent criteria. Collectively, 927 patients with suspected MFS underwent FBN1 sequencing and 72 VUSs were detected. When applying the FBN1-specific guideline only, of 72 VUSs, 29 (40.3%) were reclassified as pathogenic variants (PVs) or likely PVs (LPVs). When additionally applying the new PP1/PP4 criteria, 16 (37.2%) of the remaining 43 VUSs were reclassified as LPVs. After reassessing FBN1 VUSs according to the new PP1/PP4 criteria, the rate of reclassification from VUS to PV/LPV significantly increased from 40.3% to 62.5%. The new PP1/PP4 criteria provide sufficient evidence for evaluating the pathogenicity of FBN1 variants detected in MFS patients fulfilling the revised Ghent criteria and will be helpful in clinical analysis.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763475","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":"DDX3X-related neurodevelopmental disorder in males - presenting a new cohort of 19 males and a literature review.","authors":"Milou G P Kennis, Dmitrijs Rots, Arjan Bouman, Charlotte W Ockeloen, Caroline Boelen, Carlo L M Marcelis, Bert B A de Vries, Mariet W Elting, Quinten Waisfisz, Mohnish Suri, Esperanza Font-Montgomery, Dawn S Peck, Deirdre E Donnelly, R Curtis Rogers, Ruth Richardson, Roseline Caumes, Boris Chaumette, Cécile Louveau, Suzanne C E H Sallevelt, Saskia M Maas, Jeroen J Smits, Mieke M van Haelst, Rebecca J Levy, Helen Stewart, Bart L Loeys, Rolph Pfundt, Tjitske Kleefstra, Lot Snijders Blok","doi":"10.1038/s41431-025-01832-x","DOIUrl":"https://doi.org/10.1038/s41431-025-01832-x","url":null,"abstract":"<p><p>DDX3X-related neurodevelopmental disorder is one of the most common monogenic causes of intellectual disability in females, with currently >1000 females diagnosed worldwide. In contrast, reports on affected males with DDX3X variants are scarce. The limited knowledge on this X-linked disorder in males hinders the interpretation of hemizygous DDX3X variants in clinical practice. In this study, we present a new cohort of 19 affected males (from 17 unrelated families) with (possibly) disease-causing DDX3X variants, for whom we collected clinical and molecular data. Additionally, we reviewed the existing literature on 13 males with DDX3X variants. The phenotype in males is diverse, including intellectual disability, speech/language delays, behavioural challenges and structural brain abnormalities. The vast majority of males have missense variants, including two recurrent variants (p.(Arg351Gln) and p.(Arg488Cys)). No truncating variants have been reported, consistent with the presumed embryonic lethality of complete loss-of-function of DDX3X in males. In our novel cohort, 6/17 variants are de novo in the affected male and 3/17 variants are de novo in the mother. This study provides significant insights in the genetic and phenotypic spectrum of males with DDX3X variants, by presenting the data of a combined cohort (n = 32) of novel and published individuals. Our data show that variants in DDX3X can cause an X-linked neurodevelopmental disorder in males, with unaffected or mildly affected carrier females. These findings will aid the interpretation of hemizygous missense variants in DDX3X and can guide clinical management and counselling, in particular with regard to recurrence risks in the respective families.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751830","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":"Challenges in interpreting Mendelian randomization studies with a disease as the exposure: Using COVID-19 liability studies as an exemplar.","authors":"Siyu Chen, Ying Liang, Jacky Man Yuen Mo, Queenie Ho Yi Li, Baoting He, Shan Luo, Stephen Burgess, Shiu Lun Au Yeung","doi":"10.1038/s41431-025-01840-x","DOIUrl":"10.1038/s41431-025-01840-x","url":null,"abstract":"<p><p>Mendelian randomization (MR) studies using diseases as exposures are increasingly prevalent although any observed associations do not necessarily imply effect of diseases. To illustrate this challenge, we conducted a systematic review of MR studies focusing on COVID-19 consequence. We hypothesized if outcome genome-wide association studies (GWAS) were conducted before COVID-19 pandemic in late 2019, any observed associations in these studies were unlikely to be driven by COVID-19. We systematically searched PubMed, EMBASE, and MEDLINE for all MR studies published between 1 January 2019 and 20 May 2023. Inclusion criteria included MR studies which used COVID-19 as the exposure and designed to assess COVID-19's impact on health outcomes. We extracted relevant information, such as result interpretation and relevance assumption assessment. This review was registered at PROSPERO (CRD42023421079). Amongst 57 included studies, 45 studies used outcome GWAS published prior to 2019 whilst the remaining studies likely used outcome GWAS containing data collected before 2019. Relevance assumption was assessed mainly by p values. A total of 35 studies showed an association of COVID-19 liability with health outcomes. Regardless of the results, 45 studies attributed these as evidence (or lack of evidence) of COVID-19 consequence. In MR studies using disease liability as exposure, relevance assumption should consider the prevalence of the disease in the outcome GWAS in the context of 2 sample Mendelian randomization study rather than p values/F-statistic alone. Even when these are verified, these studies likely suffered from pleiotropy, making corresponding interpretation as effect of disease challenging.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751829","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}