Genetics in Medicine最新文献

{"title":"Integrative long-read sequencing, RNA-seq and machine learning framework characterizes and predicts autosomal silencing in unbalanced X-autosome translocations.","authors":"Bianca P Favilla, Ahmed Al-Rikabi, Paula Asprino, Eduardo Perrone, Danilo Moretti-Ferreira, Vera A Meloni, Pedro A F Galante, Danielle C F Bruno, Iscia Lopes-Cendes, Thomas Liehr, Fernanda Bellucco, Maria Isabel Melaragno","doi":"10.1016/j.gim.2026.102769","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102769","url":null,"abstract":"<p><strong>Purpose: </strong>X-chromosome inactivation (XCI) equalizes dosage between females (XX) and males (XY), yet its functional and clinical consequences remain challenging to interrogate in humans. Unbalanced X-autosome translocations constitute a natural model in which skewed inactivation of the derivative chromosome can spread into autosomes, contributing to phenotypic variability. Evaluating this spread and possible mediating factors is therefore essential for accurate clinical management.</p><p><strong>Methods: </strong>Using allele-resolved long-read sequencing and RNA sequencing, we investigated DNA methylation and gene expression across autosomal regions involved in unbalanced X-autosome translocations.</p><p><strong>Results: </strong>We identified gene-level variability in autosomal silencing, marked by promoter hypermethylation, gene body hypomethylation, and reduced gene expression with clinical impact in affected individuals. Using epigenetic and genomic features around silenced and active autosomal genes reported here and in the literature, we developed an interpretable machine-learning model that identified intrinsic sequence and chromatin features associated with susceptibility or resistance to silencing. This framework enables discrimination between silenced and active autosomal genes and prioritization of clinically relevant genes.</p><p><strong>Conclusion: </strong>Our findings reveal principles underlying the variable spreading of XCI into autosomal genes, supporting a model in which intrinsic DNA sequences and chromatin features modulate the extent of XIST-mediated silencing and its clinical impacts.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102769"},"PeriodicalIF":6.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenomic correlates of co-morbid psychosis in 22q deletion syndrome.","authors":"Alexander S Byrne, Sarah J Goodman, Hannah Nie, Arteen Torabi-Marashi, Jair Tenorio, Julián Nevado, Maude Schneider, Sanaa Choufani, Prajkta Kallurkar, Andrei Turinsky, James Stavropoulos, Martin M C Chui, Andrea Shugar, Cheryl Cytrynbaum, A Micheil Innes, Leona Fishman, Brian Hon-Yin Chung, Jung Min Ko, Stéphan Eliez, Pablo Lapunzina, Rosanna Weksberg","doi":"10.1016/j.gim.2026.102768","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102768","url":null,"abstract":"<p><strong>Purpose: </strong>22q11.2 deletion syndrome (22q11DS) confers one of the strongest genetic risks of psychiatric disorders, with up to 25% of 22q11DS patients developing symptoms of psychosis. The broad phenotypic spectrum, variable deletion size, and lack of a defined pathogenic mechanism make it likely that 22q11DS phenotypes are mediated by non-genetic factors, such as epigenetics.</p><p><strong>Methods: </strong>We developed a DNA methylation (DNAm) signature for 22q11DS in whole blood from 41 individuals with the common 2.54Mb 22q11.2 deletion and 42 matched controls using the Illumina MethylationEPIC v.2.0 array. We used the signature to classify a cohort with 22q11DS (n=108), stratified by deletion size, or with the reciprocal duplication syndrome (n=18), and ran a secondary genome-wide analysis on psychotic disorders in 22q11DS.</p><p><strong>Results: </strong>Our 22q11DS DNAm signature demonstrated 100% specificity (n=259/259) and 96% sensitivity (n=49/51), independent of deletion size. Individuals with 22q11.2 duplication syndrome did not carry identifiable DNAm alterations, despite phenotypic overlap with 22q11DS. Within the 22q11DS cohort, we found 16 differentially methylated regions between individuals with and without a psychosis spectrum disorder.</p><p><strong>Conclusion: </strong>DNAm continues to provide new insights into 22q11DS, including psychosis risk and, in the future, may serve as a reliable predictor of co-morbidities within this broad phenotype.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102768"},"PeriodicalIF":6.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"TRACEBACK has probably saved my life\": experiences of being notified about clinically significant cancer genetic information by the Australian TRACEBACK program.","authors":"Anishka Abeysinghe, Rachel Delahunty, Mary-Anne Young, Linh Nguyen, Paul A James, David Bowtell, Kathryn Alsop, Laura Forrest","doi":"10.1016/j.gim.2026.102770","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102770","url":null,"abstract":"<p><strong>Purpose: </strong>The Australian TRACEBACK program retrospectively identified women with tubo-ovarian cancer diagnosed between 2000 and 2016 who did not have genetic testing, most of whom were now deceased. Germline panel sequencing of 10 ovarian cancer-related genes was performed on tissue blocks or stored DNA. Probands or next of kin were notified of the sequencing outcome if a pathogenic variant was found. This exploratory study aimed to understand the experiences of probands and next of kin of receiving information from TRACEBACK, often unexpectedly.</p><p><strong>Method: </strong>Twenty-seven TRACEBACK participants were interviewed, and the qualitative data thematically analysed.</p><p><strong>Results: </strong>Many participants described their initial shock and distress when they were notified unexpectedly about the germline information. However, these feelings were moderated by a sense of pragmatism as they gained understanding of their cancer risk management options. The majority valued TRACEBACK for enabling them to clarify their cancer risk through cascade testing, which provided opportunities for cancer prevention measures. Participants suggested germline results should be returned to biologically related relatives to minimise the risk of information not being communicated to at-risk relatives.</p><p><strong>Conclusion: </strong>The benefits of unexpectedly receiving genetic information from TRACEBACK outweighed any potential harms, but consideration about to whom notification occurs is needed.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102770"},"PeriodicalIF":6.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Birt-Hogg-Dubé syndrome, prevalence of identified cases according to clinical indication in a cohort of 1,084 patients with genetic analysis.","authors":"Agathe Hercent, Ibrahima Ba, Jerôme Lamoril, Philippe Lafitte, Karim Diallo, Mickael Mary, Malika Chelbi, Farah Mesli, Amira Benattia, Stephan Richard, Marie-Charlotte Villy, Marine Sroussi, Olivier Ingster, Pauline Bataille, Geoffroy Hickman, Pascaline Berthet, Maud Branchaud, Bruno Crestani, Raphael Borie, Caroline Kannengiesser, Dimitri Tchernitchko","doi":"10.1016/j.gim.2026.102753","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102753","url":null,"abstract":"<p><strong>Purpose: </strong>Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by pathogenic variants (PVs) in the FLCN gene. This study aimed to characterize the clinical presentation of patients carrying a FLCN pathogenic variation and to identify the most indicative clinical features of the syndrome.</p><p><strong>Methods: </strong>We analysed clinical and molecular data from 1,084 consecutive probands with a clinical suspicion of BHD. The frequency of FLCN PVs was assessed, based on clinical presentation and family history.</p><p><strong>Results: </strong>Among the 1,084 probands analysed, 29% carried a PV in FLCN. Isolated fibrofolliculomas showed the highest diagnostic yield (55.8%, 95% CI: 44.7-66.5%), whereas isolated pulmonary cysts and renal cancer were less frequently associated with FLCN PVs (4.8%, 95% CI: 2.9-7.5% and 0.6%, 95% CI: 0.0-3.2%, respectively). Multivariable analysis identified fibrofolliculomas (OR=12.9) and pneumothorax (OR=5.8) as the strongest predictors. A family history of BHD-related symptoms increased the likelihood of detecting a FLCN PV. 244 relatives who carry the familial pathogenic variation were assessed: in the age 50-60 years group, only 60% had developed BHD-related symptoms. Finally, two patients with a mosaic FLCN PV were discovered.</p><p><strong>Conclusion: </strong>Fibrofolliculomas represent the strongest predictor of FLCN pathogenic variants. The combination of clinical features significantly improves diagnostic yield, supporting a targeted genetic screening approach.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102753"},"PeriodicalIF":6.2,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A budget impact analysis for the addition of rare disease genes to secondary findings screening during genome-wide sequencing.","authors":"Nicola Kopac, Nick Dragojlovic, Elisabet Rodriguez Llorian, Anna Lehman, Larry D Lynd","doi":"10.1016/j.gim.2026.102755","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102755","url":null,"abstract":"<p><strong>Purpose: </strong>To estimate the potential budget impact to payers of returning secondary findings (SFs) for rare diseases identified through genome-wide sequencing (GWS) in the United States (US) and Canada.</p><p><strong>Methods: </strong>A population-based model was used to estimate the number of patients that would be identified in a given jurisdiction in Canada or the US for the 11 diseases on the ACMG-SFv3.2 list classified as \"inborn errors of metabolism\" or \"miscellaneous phenotypes\", as well as the budget impact of treating those patients over 5 years. Uncertainty was assessed using one-way sensitivity and scenario analyses.</p><p><strong>Results: </strong>Based on current trends in GWS utilization, 489 affected patients would be identified in the US and 35 in Canada in the first year of implementation, translating into potential budget impacts of US$66.8 million and US$2.5 million, respectively, in the two countries. By year 5, the estimated annual budget impact would grow to US$828.8 million in the US and US$18.6 million in Canada. Notably, amyloidosis therapies account for 94% of the total projected budget impact.</p><p><strong>Conclusion: </strong>The addition of new rare diseases treatable with targeted drug therapies to the ACMG SF list may result in a significant number of cases diagnosed each year, and the budget impact of these findings should be considered when considering expanding access to GWS.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102755"},"PeriodicalIF":6.2,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individuals heterozygous for LTBP2 loss-of-function variants have an increased risk of adult-onset primary open-angle glaucoma.","authors":"Mauricio Garcia, Yuyang Luo, Jyoti Lama, Terri L Young, Elizabeth Rossin, Louis R Pasquale, Pirro G Hysi, Anthony P Khawaja, David A Mackey, Jamie E Craig, Emmanuelle Souzeau, Inas F Aboobakar, Ayellet V Segrè, Janey L Wiggs","doi":"10.1016/j.gim.2026.102750","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102750","url":null,"abstract":"<p><strong>Purpose: </strong>Glaucoma, a leading cause of irreversible blindness, can affect individuals across the lifespan, with childhood glaucoma typically exhibiting Mendelian inheritance and adult-onset disease inherited as complex traits. While large-scale genome-wide association studies suggest several childhood glaucoma genes may also contribute to adult-onset disease, the impact of heterozygosity for deleterious variants in recessive childhood glaucoma genes on the risk of adult-onset primary open-angle glaucoma has not been assessed.</p><p><strong>Methods: </strong>Using exome sequence data for >450,000 participants in the UK Biobank, we investigated the association of heterozygosity for loss-of-function variants with adult-onset glaucoma for three genes (LTBP2 (HGNC:6715), CYP1B1 (23228), and CPAMD8 (HGNC:28543) known to cause autosomal recessive childhood glaucoma.</p><p><strong>Results: </strong>Gene burden testing demonstrated a significant increase in adult-onset glaucoma risk for individuals with heterozygous loss-of-function (LoF) LTBP2 variants (OR of 4.14, 95% CI 2.73 - 6.28, p = 4.0 × 10^-13). This association was replicated by gene burden testing in the All of Us cohort. Glaucoma participants with LTBP2 LoF variants were diagnosed 8 years earlier than participants without LoF LTBP2 variants. The LoF variants with heterozygous effects are localized in key protein domains, and single-nucleus expression of LTBP2 supports a pathogenic role for extracellular matrix dysfunction in the trabecular meshwork and Schlemm's canal. No significant associations were detected for CYP1B1 or CPAMD8.</p><p><strong>Conclusion: </strong>These findings suggest that LTBP2, a gene known to contribute to autosomal recessive childhood glaucoma, also confers an increased risk of developing adult-onset disease in a heterozygous LoF state.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102750"},"PeriodicalIF":6.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delineating the Phenotypic Spectrum of SLC26A2-related Skeletal Dysplasias in a Cohort of 115 Patients: Evidence for a Novel Complex Allele Modifying Disease Severity.","authors":"Daria Gorodilova, Tatiana Markova, Vladimir Kenis, Evgenii Melchenko, Alexandra Filatova, Natalia Ogorodova, Gusein Rustamov, Elena Dadali, Tatiana Nagornova, Natalya Skoblova, Olga Khailova, Alexandra Akinshina, Artem Borovikov, Vyacheslav Tabakov, Eugene Tatarskiy, Andrey Marakhonov, Yurii Skoblov, Olga Shchagina, Sergey Kutsev, Mikhail Skoblov","doi":"10.1016/j.gim.2026.102746","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102746","url":null,"abstract":"<p><strong>Purpose: </strong>SLC26A2-related skeletal dysplasias range from recessive multiple epiphyseal dysplasia (rMED) to lethal atelosteogenesis type 2, but factors underlying clinical variability are not fully defined. This study aimed to delineate genotype-phenotype correlations and identify disease modifiers in the largest cohort reported to date.</p><p><strong>Methods: </strong>A total of 115 individuals with biallelic SLC26A2 variants underwent comprehensive clinical and radiographic phenotyping using a novel 30-criterion severity scoring scale. Molecular analyses included Sanger and next-generation sequencing (including panel and GS), targeted RNA-seq, and functional sulfate uptake assays in patient- and parent-derived fibroblasts.</p><p><strong>Results: </strong>Four recurrent variants: p.(Cys653Ser), p.(Arg279Trp), c.-26+2T>C, p.(Val341del) accounted for 84% of all alleles. Compared with gnomAD v4.1.1, p.(Cys653Ser) was significantly enriched and p.(Arg279Trp) under-represented in a local dataset, indicating ancestry-specific allele frequencies. Functional assays confirmed pathogenicity of ten variants, including five novel ones. A novel complex allele, p.[Cys653Ser;Arg671His], was identified as a cis-acting modifier allele shifting rMED toward severe DTD, supported by functional and structural analyses. The severity scale objectively stratified patients into distinct groups: rMED (score <25), intermediate rMED/DTD (25-28), and DTD (≥29). p.(Cys653Ser) homozygotes exhibited the mildest phenotype, while the complex allele was associated with a DTD as severe as that of p.(Arg178Ter), consistent with a severe, near-null effect of this allele.</p><p><strong>Conclusion: </strong>Phenotypic variability extends beyond simple biallelic combinations, with complex alleles acting as modifiers. Our severity scale enables standardized clinical stratification, refining the understanding of SLC26A2-related skeletal dysplasias.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102746"},"PeriodicalIF":6.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features.","authors":"Júlia Huguet Herrero, Pauline Arnaud, Angelique Bibimbou, Deborah E Seifert, Zakaria Mougin, Louise Benarroch, Caroline Michot, Yline Capri, Lyse Ruaud, Sophie Dupuis-Girod, Alexandre Guilhem, Constance Beyler, Fanny Bajolle, Olivier Milleron, Guillaume Jondeau, Nadine Hanna, Dieter P Reinhardt, Dong-Chuan Guo, Dianna Milewicz, Catherine Boileau, Mélodie Aubart, Timothy J Mead, Carine LE Goff","doi":"10.1016/j.gim.2026.102741","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102741","url":null,"abstract":"<p><strong>Purpose: </strong>Marfan syndrome, Loeys-Dietz syndrome, and heritable thoracic aortic aneurysms and dissections (hTAAD) are autosomal dominant connective-tissue disorders with overlapping features and considerable genetic variability. Many cases arise from pathogenic variants affecting extracellular matrix (ECM) components or TGFβ signaling, yet a substantial proportion of hTAAD cases remain genetically unexplained. This study aimed to identify new genetic contributors to aortic disease and to clarify their molecular and clinical impact.</p><p><strong>Methods: </strong>Exome and genome sequencing of a French cohort with syndromic or isolated hTAAD revealed rare damaging variants in ADAMTS6 in four unrelated individuals.</p><p><strong>Results: </strong>Functional analyses showed that these variants impaired ADAMTS6 secretion and catalytic activity, disrupting the processing of fibrillin-1 and fibrillin-2, leading to abnormal ECM accumulation and disorganized microfibrils. The recurrent p.(Leu814Arg) variant additionally altered Hippo and TGFβ signaling and affected cell adhesion. Patient-derived fibroblasts and Adamts6-deficient mice exhibited parallel pathological defects, supporting ADAMTS6 loss-of-function as disease-causing Clinically, presentations ranged from early-onset multisystem disease with cardiovascular, skeletal, craniofacial, and neurodevelopmental abnormalities to isolated adult-onset aortic aneurysm.</p><p><strong>Conclusion: </strong>these findings establish ADAMTS6 deficiency as a newly recognized connective-tissue disorder with heart defects, aortic aneurysm, and neurodevelopmental features, highlighting ADAMTS6's key role in ECM integrity.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102741"},"PeriodicalIF":6.2,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mainstreaming general genetics referrals: measuring the impact on wait times in a general genetics practice.","authors":"Rachelle Dinchong, Stefani Evans, Melanie Guy, Helen Coo, Andrea Guerin","doi":"10.1016/j.gim.2026.102740","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102740","url":null,"abstract":"<p><strong>Purpose: </strong>Examine the impact of mainstreaming on wait times for test results among general genetics referrals over a one-year period.</p><p><strong>Methods: </strong>We reviewed the charts of patients referred to a general genetics practice at an academic tertiary-care center over the one-year periods before and after the implementation of mainstreaming. The pre- and post-implementation referrals were each divided into two groups: mainstream-eligible and mainstream-ineligible patients. Quantile regression models were fit to estimate the difference in the median number of days between the dates of referral and test results disclosure for the overall pre and post groups; the mainstream-eligible, pre and post groups; and the mainstream-ineligible, pre and post groups.</p><p><strong>Results: </strong>There was a significant decrease overall in the median number of days between referral and results disclosure following the implementation of mainstreaming (estimated difference in medians = 69 days, 95% CI: 37, 101). A similar pattern was observed for both the mainstream-eligible (estimated difference = 69 days, 95% CI: 23, 115) and mainstream-ineligible groups (estimated difference = 74 days, 95% CI: 36, 112).</p><p><strong>Conclusion: </strong>Mainstreaming offers a novel solution to significantly reduce wait times to genetic test results disclosure for general genetics referrals.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102740"},"PeriodicalIF":6.2,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of novel CDK19 variants and Drosophila-based in vivo functional evidence supporting pathogenicity in neurodevelopmental disorders.","authors":"Hyun Yong Koh, Ranjan K Sahu, Sung Dae Kim, Tomomi Tanaka, Karampal S Grewal, Jenny Zhe Liao, Yoon-Kyung Shim, Ria Garg, Ilona Krey, Viktoria Bothe, Krzysztof Szczałuba, Emma Fosbinder, Olivier Patat, Matthew A Lines, Lisette Leeuwen, Lauren Frazier, Mark Hannibal, Cassandra Starks, Esther M Verheyen, Yuri A Zarate, Hyung-Lok Chung","doi":"10.1016/j.gim.2026.102735","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102735","url":null,"abstract":"<p><strong>Purpose: </strong>CDK19 (HGNC:19338) is a Mediator-associated kinase that regulates transcription during neurodevelopment. Although CDK19 variants have been linked to neurodevelopmental disorders, the full phenotypic spectrum and underlying pathogenic mechanisms remain incompletely defined. We aimed to further characterize clinical-genetic correlations and elucidate disease mechanisms through integrative functional and transcriptomic approaches.</p><p><strong>Methods: </strong>Through an international collaboration, 28 individuals with CDK19 variants (12 newly identified and 16 previously reported) were evaluated using systematic clinical phenotyping. To assess the functional consequences of variants identified in affected individuals, Drosophila models expressing CDK19 alleles were generated and examined for viability, lifespan, motor behavior, and seizure susceptibility. Protein stability, subcellular localization, tissue morphology, and transcriptomic alterations were assessed by western blot, immunofluorescence, and RNA sequencing of larval brains.</p><p><strong>Results: </strong>All individuals demonstrated global developmental delay, with speech delay as a consistently prominent feature; 67% had epilepsy, most commonly infantile epileptic spasms syndrome. Hypotonia (50%), craniofacial dysmorphisms, and abnormal brain MRI findings were also frequent. Several pathogenic alleles exhibited reduced protein stability, aberrant nuclear localization, and tissue toxicity, with associated structural abnormalities including elongated mitochondria, thickened myofibrils, and shortened sarcomeres. Behavioral assays revealed motor incoordination and allele-specific seizure susceptibility. RNA-seq identified consistent downregulation of synaptic and neuromuscular genes, including GluRIIA, VGAT, nAChRβ1, and Syn, implicating disrupted neurotransmission and impaired neuromuscular junction integrity. These findings, obtained in an overexpression-based allele-comparison system, are interpreted as supportive functional evidence of variant pathogenicity.</p><p><strong>Conclusion: </strong>These findings corroborate and further refine the clinical spectrum of CDK19-related NDDs, and provide in vivo functional evidence that pathogenic CDK19 variants are associated with disruption of transcriptional programs relevant to synaptic and neuromuscular function, supporting CDK19 dysfunction as part of the emerging spectrum of Mediator complexopathies.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102735"},"PeriodicalIF":6.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}