European Journal of Human Genetics最新文献

{"title":"Genetic influences on antidepressant side effects: a CYP2C19 gene variation and polygenic risk study in the Estonian Biobank","authors":"Hanna Maria Kariis, Dage Särg, Kristi Krebs, Maarja Jõeloo, Kadri Kõiv, Kairit Sirts, The Estonian Biobank Research Team, Health Informatics Research Team, Maris Alver, Kelli Lehto, Lili Milani","doi":"10.1038/s41431-025-01894-x","DOIUrl":"10.1038/s41431-025-01894-x","url":null,"abstract":"Antidepressant side effects are prevalent, leading to significant treatment discontinuity among patients. A deeper understanding of the underlying mechanisms could help identify individuals at risk of side effects and improve treatment outcomes.We aim to investigate the role of genetic variation in CYP2C19 and polygenic scores (PGS) for psychiatric and side effect-related phenotypes in experiencing antidepressant side effects.We pooled Estonian Biobank data from the Mental Health online Survey (N = 86,244), the Adverse Drug Events Questionnaire (N = 49,366) and from unstructured electronic health records using natural language processing (N = 206,066) covering 25 common side effects. The results were meta-analysed with previously published results from the Australian Genetics of Depression Study. Among 13,729 antidepressant users, 52.0% reported side effects. In a subgroup of 9,563 individuals taking antidepressants metabolised by CYP2C19, poor metabolisers had 49% higher odds of reporting a side effect (OR = 1.49, 95%CI = 1.09–2.04), while ultrarapid metabolisers had 17% lower odds (OR = 0.83, 95%CI = 0.70–0.99) compared to normal metabolisers. PGSs for schizophrenia and depression showed the most associations with overall and specific side effects. PGSs for higher body mass index (BMI), anxiety, and systolic blood pressure were associated with respective side effects among any antidepressant and selective serotonin reuptake inhibitor (SSRI) users. Meta-analysis confirmed robust evidence linking a higher BMI PGS and weight gain across nine antidepressants and moderate evidence linking PGS for headache with headache from sertraline. Our findings underscore the role of genetic factors in experiencing antidepressant side effects and have potential implications for personalised medicine approaches to improve antidepressant treatment outcomes.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1376-1385"},"PeriodicalIF":4.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01894-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511728","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":"Homozygous COQ9 mutation: a new cause of potentially treatable hereditary spastic paraplegia","authors":"Fanny Fontaine, Audrey Labalme, Chloé Laurencin, Julian Theuriet, Arnaud Jacquier, Nicolas Lacoste, Nathalie Streichenberger, Gaëtan Lesca, Stéphane Allouche","doi":"10.1038/s41431-025-01895-w","DOIUrl":"10.1038/s41431-025-01895-w","url":null,"abstract":"Primary Coenzyme Q10 (CoQ10) deficiencies are a group of clinically heterogenous mitochondrial disorders that result from defects in CoQ10 biosynthesis. Their diagnosis is complicated by the absence of pathognomonic signs and poor genotype-phenotype correlations. Pathogenic variants in the COQ9 gene are a rare cause of CoQ10 deficiency: few cases have been reported, and the clinical presentation was described as a very severe multisystemic disorder with neonatal onset, ultimately leading to premature death. Through exome sequencing, we identified a novel homozygous splicing variant c.73 G > A in the COQ9 gene (NG_027696.1, NM_020312.4) in two adult siblings who presented with pure spastic paraplegia with onset in childhood. mRNA analysis from different tissues of one of the siblings revealed that this variant alters COQ9 splicing, resulting in undetectable levels of COQ9 and COQ7 proteins and reduced concentrations of CoQ10 in muscle and fibroblasts. Additionally, the accumulation of 6-demethoxycoenzyme Q10, the substrate of COQ7, was observed in both plasma and fibroblasts. Furthermore, fibroblast proliferation rate was reduced when enhancing the mitochondrial metabolism by replacing glucose with galactose in the culture medium, and was rescued by the addition of exogenous CoQ10, suggesting a therapeutic avenue for these patients. Altogether, we report here the first example of hereditary spastic paraplegia related to a mutation of the COQ9 gene that expands the spectrum of clinical manifestations and opens new therapeutic opportunities.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 8","pages":"997-1005"},"PeriodicalIF":4.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511729","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":"Comprehensive analysis of CNOT3-related neurodevelopmental disorders: phenotypic and genotypic characterization","authors":"Camille Engel, Michaela Rendek, Jessica Assoumani, Emanuela Argilli, Francesca Ariani, Anne-Laude Avice-Denizet, Emilia K. Bijlsmaa, Pierre Blanc, Lucia Pia Bruno, Bert Callewaert, Valeria Capra, Michele Carullo, Bertrand Chesneau, Sandra Coppens, Cynthia Curry, Breanne Dale, Eric Dahlen, Andrée Delahaye-Duriez, Anne-Sophie Denommé-Pichon, Bénédicte Demeer, Lenka Dvořáková, Jan Fischer, David Geneviève, Thea Giacomini, Mette M. Handrup, Delphine Heron, Irina Hüning, Michelle Iacomino, Bertrand Isidor, Boris Keren, Stanislav Kmoch, David A. Koolen, Andrea Kübler, Jana Laštůvková, Carolyn Le, Jonathan Levy, Caterina Lo Rizzo, Silvia Maitz, Sandrine Marlin, Cyril Mignot, Ghayda Mirzaa, Inga Nagel, Sebastian Neuens, Lenka Nosková, Emily Pao, Anna Pecková, Julie Plaisancie, Joseph Porrmann, Flavia Privitera, André Reis, Alessandra Renieri, Marlène Rio, Alyssa Rippert, Lukáš Ryba, Marcello Scala, Jolanda H. Schieving, Elliott H. Sherr, Andrew Shuen, Richard Sidlow, Thomas Smol, Julie Soblet, Pasquale Striano, Mohnish Suri, Hannes Syryn, Frédéric Tran Mau-Them, Andre M. Travessa, Julien Van Gils, Georgia Vasileiou, Jolijn J. A. Verseput, Catheline Vilain, Catherine Vincent-Delorme, Emílie Vyhnálková, Emma L. Wakeling, Pia Zacher, Federico Zara, Paul Kuentz, Juliette Piard","doi":"10.1038/s41431-025-01884-z","DOIUrl":"10.1038/s41431-025-01884-z","url":null,"abstract":"The CCR4-NOT complex, crucial in gene expression regulation, includes CNOT3, a subunit linked to neurodevelopmental disorders when mutated. This study investigates 51 patients from 42 families with heterozygous CNOT3 variants, aiming to expand the understanding of CNOT3-related neurodevelopmental disorders and explore genotype-phenotype correlations. Patients originated from various countries, reflecting the disorder’s global significance. All patients exhibited developmental delays, particularly in the language area. Intellectual disability was found in 87% of patients and was typically mild to moderate. Behavioral issues, including autism spectrum disorders and attention deficits, were common, affecting over half of the patients. Dysmorphic features were highlighted and may help establishing the diagnosis. Epilepsy was uncommon (10%). Twenty-eight novel variants were identified, including missense, nonsense, frameshift, intronic variations and a deletion of 12 exons. Missense variants clustered at the N- and C-terminal regions of the protein, indicating critical functional roles. No clear genotype-phenotype correlation was observed, suggesting that all identified variants resulted in a loss-of-function effect. Finally, this work delineates the clinical and molecular spectrum of CNOT3-related disorders thanks to an in-depth characterization of a large cohort. Further research will be necessary to understand the functional consequences of the variants and enhance patient long-term outcomes.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 8","pages":"989-996"},"PeriodicalIF":4.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495378","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":"The utility of next generation sequencing targeted multigene panels in the Adult Neurogenetic Clinic at Tygerberg Hospital, South Africa","authors":"Cumine Van Tonder, Mardelle Schoeman, Jonathan Carr, Franclo Henning, Claude Bailly, Shahida Moosa","doi":"10.1038/s41431-025-01900-2","DOIUrl":"10.1038/s41431-025-01900-2","url":null,"abstract":"Next generation sequencing (NGS) based tests have become first-line investigative modalities in adult neurogenetic clinics. Studies in high-income countries (HICs) show that NGS is cost-effective and reliable in diagnosing adult neurogenetic disorders (NGDs). African populations harbour vast genomic diversity, but there is limited knowledge on the molecular basis of NGDs affecting these populations due to lack of access to the necessary technology. The primary objective of this retrospective study was to describe the clinical utility of NGS panels in an African low-middle income country (LMIC). It included data of 74 adult participants seen at the multidisciplinary neurogenetic clinic at Tygerberg Hospital, South Africa, over a 4 – year period. Forty-three symptomatic index cases underwent NGS panel testing, while 31 relatives received targeted familial variant testing based on specific indications relevant to each case. Twenty-two different disease group-specific NGS panels were requested, spanning the NGD phenotypic spectrum. The diagnostic yield (DY) in index cases was 39.5% (17/43). Four relatives were clinically affected, and all tested positive for the familial-specific variant. This study demonstrated the DY achieved with NGS testing in an LMIC adult neurogenetic cohort, was comparable to DYs previously reported in HICs. These results argue for the use of NGS panels as first-tier testing in resource constrained LMICs, to limit lengthy diagnostic odysseys and unnecessary investigations. A definitive molecular diagnosis enables evidence-based management, surveillance, genetic counselling, and familial variant screening for relatives. Lastly, it assists with enrolment into clinical trials focussed on the development of precision medicine.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 9","pages":"1144-1152"},"PeriodicalIF":4.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01900-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495379","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":"Houge-Janssens syndrome","authors":"Gunnar Douzgos Houge, Sofia Douzgou Houge, Tzung-Chien Hsieh, Iris Verbinnen, Veerle Janssens","doi":"10.1038/s41431-025-01901-1","DOIUrl":"10.1038/s41431-025-01901-1","url":null,"abstract":"Houge-Janssens syndrome (HJS) is caused by protein phosphatase type 2A (PP2A) dysfunction. The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems. PP2A oppose the activity of serine/threonine protein kinases, including growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic de novo missense variants in several PP2A subunits, some of which are associated with macrocephaly if congenital, or cancer if somatic. The current review gives an overview of both the clinical spectrum and known or potential pathogenic mechanisms in Houge-Janssens syndrome. For the latter, a basic insight in PP2A-mediated serine/threonine dephosphorylation is needed, although many fundamental questions regarding PP2A substrate specificity and activity determinants remain currently insufficiently resolved to provide a fully satisfactory molecular explanation of the effect of some mutations. So far, dominant pathogenic variants in at least two B subunits (PPP2R5D in HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause Houge-Janssens syndrome. The main aim is to explain why and how the different Houge-Janssens syndrome subtypes biochemically and clinically overlap, providing a framework for understanding new variants and new subtypes that will be found in the future. Hypothetically, small molecules that alleviate substrate blockade by affected B subunits or correct misfolding of affected A subunit, could represent treatment options, but these remain to be found.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1228-1239"},"PeriodicalIF":4.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483722","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":"Editorial Déjà Vu: This time, it’s actually ‘what’s new in EJHG in May 2025?’","authors":"Seda S. Zonuzi","doi":"10.1038/s41431-025-01890-1","DOIUrl":"10.1038/s41431-025-01890-1","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 6","pages":"693-694"},"PeriodicalIF":3.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01890-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339684","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":"Clinical application of whole exome sequencing (WES) in the genetic diagnosis of 768 Chinese patients with bilateral hearing loss.","authors":"Hongfei Kang, Jingjing Li, Huikun Duan, Lisha Su, Yanjie Xia, Zili Li, Xiangdong Kong","doi":"10.1038/s41431-025-01896-9","DOIUrl":"10.1038/s41431-025-01896-9","url":null,"abstract":"<p><p>Hearing loss is a prevalent sensory disability with strong genetic heterogeneity, affecting approximately 60% of patients due to genetic factors. To investigate the possible genetic causes of hearing loss in 768 unrelated Chinese patients and analyze the genetic diagnosis rates among patients with different clinical phenotypic characteristics, 768 patients were enrolled, and whole-exome sequencing (WES) was performed for genetic testing. Sanger sequencing, MLPA, or qPCR were used to verify the parental origin of identified variants. We identified possible genetic etiologies in 501 of the 768 patients (65.2%), including 456 with non-syndromic and 45 with syndromic hearing loss. A total of 214 variants from 30 genes were identified: 174 previously reported and 40 novel pathogenic/likely pathogenic variants, the 18 hotspot variants accounted for 71.9% of all identified variants. Notably, 15 patients carried de novo variants. The genetic diagnosis rate was significantly higher in patients with severe-profound hearing loss (95.8%, 474/495) compared to those with mild-moderate hearing loss (9.9%, 27/273), P < 0.001. Our findings expand the spectrum of genetic variants associated with hearing loss and demonstrate high genetic diagnosis rates in patients with severe-profound hearing loss and congenital onset. WES combined with parental origin verification is an effective and economical method for identifying the genetic etiology of hearing loss and can be considered a priority in clinical practice for guiding early intervention and preventing further hearing loss.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336436","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":"Structural variation in nebulin and its impact on phenotype and inheritance: establishing a dominant distal phenotype caused by large deletions","authors":"Lydia Sagath,&nbsp;Kirsi Kiiski,&nbsp;Kireshnee Naidu,&nbsp;Krutik Patel,&nbsp;Per Harald Jonson,&nbsp;Milla Laarne,&nbsp;Djurdja Djordjevic,&nbsp;Grace Yoon,&nbsp;Anna LaGroon,&nbsp;Curtis Rogers,&nbsp;Maureen Kelly Galindo,&nbsp;Katalin Scherer,&nbsp;Erdmute Kunstmann,&nbsp;Erkan Koparir,&nbsp;Desirée Ho,&nbsp;Mark Davis,&nbsp;Purwa Joshi,&nbsp;Alexander Zygmunt,&nbsp;Rotem Orbach,&nbsp;Sandra Donkervoort,&nbsp;Carsten G. Bönnemann,&nbsp;Marco Savarese,&nbsp;Andoni Echaniz-Laguna,&nbsp;Valérie Biancalana,&nbsp;Casie A. Genetti,&nbsp;Susan T. Iannaccone,&nbsp;Alan H. Beggs,&nbsp;Carina Wallgren-Pettersson,&nbsp;Franclo Henning,&nbsp;Katarina Pelin,&nbsp;Vilma-Lotta Lehtokari","doi":"10.1038/s41431-025-01891-0","DOIUrl":"10.1038/s41431-025-01891-0","url":null,"abstract":"Structural variants (SVs) of the nebulin gene (NEB), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathies. Here we provide an overview of 35 families with muscle disorders caused by such SVs in NEB. Using custom Comparative Genomic Hybridization arrays, exome sequencing, short-read genome sequencing, custom Droplet Digital PCR, or Sanger sequencing, we identified pathogenic SVs in 35 families with NEB-related myopathies. In 23 families, recessive intragenic deletions and duplications or pathogenic gains of the triplicate region segregating with the disease in compound heterozygous form, together with a small variant in trans, were identified. In two families the SV was, however, homozygous. Eight of these families have not been described previously. In 12 families with a distal myopathy phenotype (of which 10 are previously unpublished), eight unique, large deletions encompassing 52–97 exons in either heterozygous (n = 10) or mosaic (n = 2) state were identified. In the families where inheritance was recessive, no correlation could be made between the types of variants and the severity of the disease. In contrast, all patients with large dominant deletions in NEB had milder, predominantly distal muscle weakness. For the first time, we establish a clear and statistically significant association between large NEB deletions and a form of distal myopathy. In addition, we provide the hitherto largest overview of the spectrum of SVs in NEB.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 9","pages":"1153-1162"},"PeriodicalIF":4.6,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01891-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293561","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":"Detection and characterization of rare variants in NOTCH2NLC causing false negative molecular diagnosis through long-read sequencing","authors":"Xiaosheng Zheng,&nbsp;Nan Jin,&nbsp;Peng Liu,&nbsp;Dehao Yang,&nbsp;Lebo Wang,&nbsp;Yixin Kang,&nbsp;Jiaxiang Li,&nbsp;Zhidong Cen,&nbsp;Wei Luo","doi":"10.1038/s41431-025-01892-z","DOIUrl":"10.1038/s41431-025-01892-z","url":null,"abstract":"Neuronal intranuclear inclusion disease (NIID) is typically diagnosed through molecular techniques or skin biopsy, with GGC repeat expansions in NOTCH2NLC being a key molecular marker. This study investigated an NIID patient who had received skin biopsy confirmation but showed no detectable GGC repeat expansions in NOTCH2NLC through standard genetic testing. Using whole genome long-read sequencing (LRS), we identified GGC expansions in NOTCH2NLC along with three previously undetected upstream variants that had caused the initial false-negative molecular diagnosis. We further analyzed 501 essential tremor patients and 361 whole genome LRS datasets to characterize the region surrounding the GGC repeat expansion, revealing that these variants are rare. Our findings demonstrate that rare NOTCH2NLC variants can lead to false-negative molecular diagnoses in NIID patients, emphasizing the value of comprehensive genotyping through LRS. These results provide important guidance for developing diagnostic strategies for similar cases in the future.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 9","pages":"1207-1211"},"PeriodicalIF":4.6,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293560","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":"Genome sequencing in a cohort of 32 fetuses with genetic skeletal disorders.","authors":"Hillevi Lindelöf, Anna Hammarsjö, Ulrika Voss, Serena Gaetana Piticchio, Peter Conner, Nikos Papadogiannakis, Dominyka Batkovskyte, Laura Orellana, Malin Kvarnung, Helena Malmgren, Kristina Lagerstedt Robinson, Ann Nordgren, Anna Lindstrand, Gen Nishimura, Giedre Grigelioniene","doi":"10.1038/s41431-025-01886-x","DOIUrl":"https://doi.org/10.1038/s41431-025-01886-x","url":null,"abstract":"<p><p>Approximately 200 genetic skeletal disorders can present prenatally, detectable through ultrasound abnormalities during pregnancy. Severe forms are typically identified during the first or second trimester, whereas milder phenotypes are recognized later, in the third trimester. Diagnosing skeletal dysplasia prenatally is challenging due to the large number of disorders and the overlapping clinical findings that can be detected by ultrasound. This study, conducted at Karolinska University Hospital between 2015 and 2022, examines the genetic and radiographic findings in 32 fetuses (14 female and 18 male, from unrelated families) with skeletal abnormalities detected on prenatal ultrasound and confirmed by radiographs at birth or after pregnancy termination. Fetal DNA samples from all 32 fetuses underwent singleton genome sequencing using an in silico skeletal dysplasia gene panel. As a second step, for six fetuses with molecularly unsolved diagnoses, trio genome sequencing analysis involving the fetus and both parents was performed. The diagnostic yield of genome sequencing was 72%, with pathogenic or likely pathogenic variants identified in 23 of the 32 fetuses. Additionally, four variants of uncertain significance, strongly suspected to be causative based on clinical and radiographic features, as well as structural protein analyses, were identified in four fetuses with autosomal recessive conditions. The diagnoses of five fetuses remain molecularly unsolved. In conclusion, by combining detailed phenotypic data with singleton genome sequencing we were able to reach a genetic diagnosis in 72% of 32 fetal genetic skeletal disorder cases investigated at the Karolinska University Hospital.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274540","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}