HGG Advances最新文献

{"title":"The impact of genetic ancestry on survival outcomes in pediatric rhabdomyosarcoma: A report from the Children's Oncology Group.","authors":"Ekene A Onwuka, Christina L Magyar, Bailey A Martin-Giacalone, Michael E Scheurer, Deborah A Marquez-Do, Mark Zobeck, Elizabeth G Atkinson, Erin R Rudzinski, Michael A Arnold, Donald A Barkauskas, David Hall, Javed Khan, Jack F Shern, Paul Scheet, Brian Crompton, Corinne M Linardic, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Chad D Huff, Melissa A Richard, Philip J Lupo","doi":"10.1016/j.xhgg.2025.100466","DOIUrl":"10.1016/j.xhgg.2025.100466","url":null,"abstract":"<p><p>Emerging evidence suggests genetic ancestry may influence childhood cancer outcomes, but its impact on pediatric rhabdomyosarcoma (RMS) is unknown. We explored genetic ancestry's impact on survival among children with RMS. This multi-center observational cohort study is a secondary analysis of previously collected biobanking, genomic, and clinical data. The study included 920 individuals with newly diagnosed RMS under 40 years of age enrolled from 2005 to 2017 under the COG soft tissue sarcoma biobanking protocol D9902. The primary endpoints were (1) event-free survival (EFS), defined as the time from study enrollment to tumor recurrence/progression, secondary malignancy, or death from any cause; and (2) overall survival (OS), defined as the time from study enrollment to death from any cause. Genetic ancestry was estimated using Grafpop software, and Cox regression assessed the association between genetic ancestry and EFS and OS, considering RMS overall, by fusion status, and by histological subtype. Covariates included sex, age at diagnosis, tumor stage, and histology, except during stratified analyses. In embryonal RMS and PAX3/7:FOXO1 fusion-negative RMS, individuals with South Asian or Asian-Pacific Islander ancestry showed worse EFS (hazard ratio [HR] 2.06, 95% confidence interval [CI] 1.07-3.97, p = 0.03 and HR 2.01, 95% CI 1.07-3.76, p = 0.03, respectively) and OS (HR 2.30, 95% CI 1.09-4.84, p = 0.03 and HR 2.33, 95% CI 1.15-4.70, p = 0.020, respectively) compared to those with primarily European genetic ancestry. These findings suggest that genetic ancestry influences survival outcomes within RMS subtypes, and further understanding may improve precision-medicine-based efforts.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100466"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coupling deep phenotypic quantification with next-generation phenotyping for 192 individuals with germline histonopathies.","authors":"Emily E Lubin, Elizabeth M Gonzalez, Annabel K Sangree, Emily L Durham, Hannah Klinkhammer, Jing-Mei Li, Sarina M Smith, Dana E Layo-Carris, Kelly J Clark, Ashley J Melendez-Perez, Xiao Min Wang, Rajesh Angireddy, Erin E Weiss, Tahsin Stefan Barakat, Sandra Mercier, Benjamin Cogné, Saskia Koene, Yvonne Hilhorst-Hofstee, Malgorzata Rydzanicz, Rafal Ploski, María de Los Ángeles Gómez Cano, María Palomares-Bralo, Tania Barragán Arévalo, Tiong Yang Tan, Lyndon Gallacher, Suzanne P MacFarland, Rebecca C Ahrens-Nicklas, Tomoki T Nomakuchi, Elizabeth J K Bhoj","doi":"10.1016/j.xhgg.2025.100440","DOIUrl":"10.1016/j.xhgg.2025.100440","url":null,"abstract":"<p><p>Mendelian histonopathies are rare neurodevelopmental disorders (NDDs) caused by germline variants in histone-encoding genes. Here, we perform a more expansive pan-histonopathy interrogation than previously possible. We analyze data from 192 individuals affected by histonopathies. This analysis includes representation of the 185 published individuals with HIST1H1E syndrome, Bryant-Li-Bhoj syndrome, and Tessadori-Bicknell-van Haaften NDD; as well as from seven unpublished individuals, five of whom harbor variants in genes not previously associated with disease (HIST1H2AL/H2AC16, H2AFZ/H2AZ1, HIST1H3D/H3C4, and HIST3H3/H3-4). By intersecting clinician-reported phenotypic data with next-generation phenotyping of published 2D facial photographs (n = 98), we sought to address the lack of established craniofacial gestalts or characteristic phenotypic patterns for this community. While these analyses may suggest a histone core versus linker protein basis of delineation, they more strikingly highlight data gaps that confound the identification of phenotypic patterns at this time. Based on this, we developed an updated standardized clinical survey, which allowed us to identify the second known individual with a germline histonopathy and a cancer diagnosis. Notably, the community-wide cancer incidence is currently 1%, which falls below the recommended 5% cut off for routine surveillance. Ultimately, this work highlights the ways in which histonopathy-associated phenotypes change throughout the lifespan, necessitating longitudinal re-evaluation; that every identified individual shapes our understanding of these syndromes in a way that improves care for this community; and the value of ongoing translational work to address the outstanding question of cancer predisposition for individuals living with germline histonopathies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100440"},"PeriodicalIF":3.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homozygous variants in EIF3K associated with neurodevelopmental delay, microcephaly, and growth retardation.","authors":"Bobbi McGivern, Tess Holling, Maria J Guillen Sacoto, Hákon Gudbjartsson, Ibrahim M Abdelrazek, Malik Alawi, Yan Bai, Olaf Bodamer, Amy Crunk, Amy E Dameron, Lisa M Dyer, Lindsay B Henderson, Mira Irons, Kerstin Kutsche, Caroline McGowan, Kristin G Monaghan, Kaitlyn O'Connor, Asma Rashid, Olivia L Redlich, Adi Reich, Christopher Simotas, Sara Welner, Ingrid M Wentzensen","doi":"10.1016/j.xhgg.2025.100438","DOIUrl":"10.1016/j.xhgg.2025.100438","url":null,"abstract":"<p><p>We report two rare homozygous variants, including a recurrent missense and intronic variant, in the EIF3K gene in four unrelated individuals with global developmental delay, microcephaly, proportionate short stature, dysmorphic craniofacial features, digit flexion deformities, and the cardiac anomaly, patent ductus arteriosus. Three individuals, who were all of Puerto Rican descent, were homozygous for the NM_013234.3:c.128A>G; p.(Asp43Gly) variant in EIF3K and homozygous for a missense variant in SYNE4 (NM_001039876.2:c.355C>T; p.(Arg119Trp)). SYNE4 is associated with autosomal recessive bilateral sensorineural hearing loss, which was also reported in these probands. Analysis of our dataset confirmed these EIF3K and SYNE4 variants were in linkage disequilibrium in affected individuals, suggesting a possible common ancestor and founder event. A fourth individual from Egypt harbored the homozygous intronic variant c.355-13A>G in EIF3K, which segregated with the phenotype in the family and led to aberrant splicing of EIF3K pre-mRNAs, as shown by insertion of 12 intronic base pairs, skipping of 2 exons, and significantly reduced EIF3K protein levels in skin fibroblasts. Through genetic and functional approaches, we suggest that biallelic EIF3K variants are associated with an autosomal recessive syndromic neurodevelopmental disorder with growth retardation, microcephaly, congenital heart defect, and other anomalies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100438"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12059664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic germline variants in small cell lung cancer: A systematic review and meta-analysis.","authors":"Sami Ul Haq, Aleem Aamir, Chloe Mighton, Katrina Hueniken, Vivek Philip, Raymond H Kim, Geoffrey Liu, Peter Sabatini, Scott V Bratman, Benjamin H Lok","doi":"10.1016/j.xhgg.2025.100445","DOIUrl":"10.1016/j.xhgg.2025.100445","url":null,"abstract":"<p><p>This systematic review and meta-analysis examined the prevalence and clinical impact of germline variants in small cell lung cancer (SCLC). Primary objectives included estimating the prevalence of germline variants in SCLC patients, while secondary objectives focused on their effects on patient outcomes. A comprehensive search was conducted in Ovid MEDLINE, EMBASE, and gray-literature databases (as of July 2024). Studies reporting germline variants in SCLC patients were included. Data were extracted to calculate pooled prevalence and hazard ratios (HRs). Study quality was assessed using the Translating ROBBINs tool, and heterogeneity was evaluated using the I² statistic. Of 6,117 screened studies, 124 met inclusion criteria, with 8% (10/124) reporting pathogenic/likely pathogenic (P/LP) findings. Meta-analysis using a random-effects model estimated the prevalence of P/LP germline variants in SCLC patients at 11% (95% CI: 5%-25%). Gene-level prevalence was estimated for ATM (pooled prevalence = 1%; 95% CI: 0%-5%), BRCA1 (1%; 95% CI: 1%-3%), BRCA2 (1%; 95% CI: 1%-3%), and TP53 (1%; 95% CI: 0%-3%). Patients with P/LP variants in DNA damage repair genes showed a non-significant prognostic survival benefit (pooled HR: 0.8; 95% CI: 0.51-1.29, I² = 8%). We have conducted a comprehensive systematic review of germline variants and their impact on clinical outcomes of SCLC patients. Our meta-analysis identified an estimated prevalence of P/LP variants in SCLC patients, suggesting a rationale for screening in the clinic.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100445"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The phenotypic spectrum of individuals with SLC16A2 variants in MCT8 deficiency.","authors":"Kirsty McWalter, Houda Zghal Elloumi, Richard Sidlow, Ben Willis, Andrew J Bauer","doi":"10.1016/j.xhgg.2025.100455","DOIUrl":"10.1016/j.xhgg.2025.100455","url":null,"abstract":"<p><p>Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked condition caused by pathogenic variants in the SLC16A2 gene, resulting in dysfunctional thyroid hormone transport throughout the body. Human Phenotype Ontology (HPO) terms provide a standardized clinical vocabulary of symptomology in human disease. Here, we contribute a cohort of individuals with fully categorized SLC16A2 variants and associated HPO terms to the phenotypic spectrum of MCT8 deficiency. We queried de-identified genetic data for SLC16A2 variants mostly determined through exome sequencing. Clinical abstraction of medical records was performed to generate HPO terms. In a cohort of 122 individuals with SLC16A2 variants, we identified 68 cases with likely pathogenic/pathogenic (L/PATH) variants and 54 individuals with variants of uncertain significance (VUSs). A total of 611 different HPO terms were retrieved for 108 individuals with characterized SLC16A2 variants. Common HPO terms included global developmental delay (79/108, 73.1%), generalized hypotonia (40/108, 37.0%), and delayed speech and language development (29/108, 26.9%). Some HPO terms associated with a severe MCT8 deficiency phenotype, such as failure to thrive, feeding difficulties, and delayed myelination, were more common in individuals with L/PATH variants than in those with VUSs. HPO terms related to thyroid function and/or hormone levels were not commonly reported, with hypothyroidism the most frequently reported term, seen in six individuals. This study highlights the utility of comprehensive genetic testing and standardized clinical vocabulary in diagnosing rare genetic conditions. In MCT8 deficiency, this approach can help characterize genotype-phenotype correlations, expedite concurrent thyroid hormone testing, and improve affected individual and caregiver support.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100455"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic risk score prediction accuracy convergence.","authors":"Léo Henches, Jihye Kim, Zhiyu Yang, Simone Rubinacci, Gabriel Pires, Clara Albiñana, Christophe Boetto, Hanna Julienne, Arthur Frouin, Antoine Auvergne, Yuka Suzuki, Sarah Djebali, Olivier Delaneau, Andrea Ganna, Bjarni Vilhjálmsson, Florian Privé, Hugues Aschard","doi":"10.1016/j.xhgg.2025.100457","DOIUrl":"10.1016/j.xhgg.2025.100457","url":null,"abstract":"<p><p>Polygenic risk scores (PRSs) models trained from genome-wide association study (GWAS) results are set to play a pivotal role in biomedical research addressing multifactorial human diseases. The prospect of using these risk scores in clinical care and public health is generating both enthusiasm and controversy, with varying opinions among experts about their strengths and limitations. The performance of existing polygenic scores is still limited but is expected to improve with increasing GWAS sample sizes and the development of new, more powerful methods. Theoretically, the variance explained by PRS can be as high as the total additive genetic variance, but it is unclear how much of that variance has already been captured by PRS. Here, we conducted a retrospective analysis to assess progress in PRS prediction accuracy since the publication of the first large-scale GWASs, using data from six common human diseases with sufficient GWAS information. We show that although PRS accuracy has grown rapidly over the years, the pace of improvement from recent GWAS has decreased substantially, suggesting that merely increasing GWAS sample sizes may lead to only modest improvements in risk discrimination. We next investigated the factors influencing the maximum achievable prediction using whole-genome sequencing data from 125,000 UK Biobank participants and state-of-the-art modeling of polygenic outcomes. Our analyses suggest that increasing the variant coverage of PRS, using either more imputed variants or sequencing data, is a key component for future improvements in prediction accuracy.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100457"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The chromosomal challenge of human embryos: Mechanisms and fundamentals.","authors":"Anna Ivanova, Elena Korchivaia, Maria Semenova, Igor Lebedev, Ilya Mazunin, Ilya Volodyaev","doi":"10.1016/j.xhgg.2025.100437","DOIUrl":"10.1016/j.xhgg.2025.100437","url":null,"abstract":"<p><p>Chromosomal abnormalities in human pre-implantation embryos, originating from either meiotic or mitotic errors, present a significant challenge in reproductive biology. Complete aneuploidy is primarily linked to errors during the resumption of meiosis in oocyte maturation, which increase with maternal age, while mosaic aneuploidies result from mitotic errors after fertilization. The biological causes of these abnormalities are increasingly becoming a topic of interest for research groups and clinical specialists. This review explores the intricate processes of meiotic and early mitotic divisions in embryos, shedding light on the mechanisms that lead to changes in chromosome number in daughter cells. Key factors in meiotic division include difficulties in spindle assembly without centrosomes, kinetochore (KT) orientation disturbances, and inefficient cell-cycle checkpoints. The weakening of cohesion molecules that bind chromosomes, exacerbated by maternal aging, further complicates chromosomal segregation. Mitotic errors in early development are influenced by defects in sperm centrosomes, KT misalignment, and the gradual depletion of maternal regulatory factors. Coupled with the inactive or partially active embryonic genome, this depletion increases the likelihood of chromosomal aberrations. While various theoretical mechanisms for these abnormalities exist, current data remain insufficient to determine their exact contributions. Continued research is essential to unravel these complex processes and improve outcomes in assisted reproductive technologies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100437"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two-sample bi-directional causality between two traits with some invalid IVs in both directions using GWAS summary statistics.","authors":"Siyi Chen","doi":"10.1016/j.xhgg.2025.100449","DOIUrl":"10.1016/j.xhgg.2025.100449","url":null,"abstract":"<p><p>Mendelian randomization (MR) is a widely used method for assessing causal relationships between risk factors and outcomes using genetic variants as instrumental variables (IVs). While traditional MR assumes uni-directional causality, bi-directional MR aims to identify the true causal direction. In uni-directional MR, invalid IVs due to pleiotropy can violate assumptions and introduce biases. In bi-directional MR, traditional MR can be performed separately for each direction, but the presence of invalid IVs poses even greater challenges. We introduce a new bi-directional MR method incorporating stepwise selection (Bidir-SW) designed to address these challenges. Our approach leverages public genome-wide association study (GWAS) datasets for two traits and uses model selection criteria to identify invalid IVs iteratively by stepwise selection. This method accounts for potential bi-directional causality in the presence of common invalid IVs for both directions, even if only GWAS summary statistics are provided. Through simulation studies, we demonstrate that our method outperforms traditional MR techniques, such as MR-Egger and inverse-variance weighted (IVW), with uncorrelated SNPs. We also provide simulations to compare our approach with existing transcriptome-wide association study (TWAS) to show its effectiveness. Finally, we apply the proposed method to genetic traits such as CRP levels and BMI to explore possible bi-directional relationships among these traits. We also used the proposed method to discover causal protein biomarkers. Our findings suggest that the Bidir-SW approach is a powerful tool for bi-directional MR or TWAS, which can provide a valuable framework for future genetic epidemiology studies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100449"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking barriers in rare disease research: The RARE-X Open Science Data Challenge as a model for collaborative innovation and community partnership.","authors":"Karmen Trzupek, Ravi Bhargava, Cynthia Kuan, Fanny Sie, Vanessa Vogel-Farley, Katelyn Hobbs, Verena Chung, Maria Diaz, Charlene Son-Rigby, Joseph Geraci, Jacob Albrecht","doi":"10.1016/j.xhgg.2025.100462","DOIUrl":"10.1016/j.xhgg.2025.100462","url":null,"abstract":"<p><p>Trzupek et al. describe a rare disease Open Science Data Challenge, using data collected systematically on RARE-X across 27 neurodevelopmental disorders. Clinical diagnoses, symptoms, genetic data, and PROs were included. Researchers and statisticians generated solutions that identified previously underappreciated symptoms and used machine learning to test predictive models for diagnosis.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100462"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MED13L pathogenic missense variants impair protein stability and interaction, underlying diverse clinical outcomes.","authors":"Thomas Smol, Frédéric Frenois, Morgane Billotte, Roseline Caumes, Leonie A Menke, Amara Nassar-Sheikh Rashid, Caroline Thuillier, Didier Monté, Florence Petit, Alexis Verger, Jamal Ghoumid","doi":"10.1016/j.xhgg.2025.100467","DOIUrl":"10.1016/j.xhgg.2025.100467","url":null,"abstract":"<p><p>Heterozygous pathogenic variants in the Mediator complex subunit 13-like gene located in the locus 12q21.21 (MED13L) are associated with intellectual disability, developmental delay, and distinctive facial features. While nonsense and frameshift variants typically cause haploinsufficiency, resulting in a well-characterized clinical presentation, missense variants have been associated with a broader range of phenotypes, including epilepsy and severe motor delay. In this study, we investigated five pathogenic missense variants in MED13L-c.2597C>T p.Pro866Leu, c.2605C>T p.Pro869Ser, c.3392G>A p.Cys1131Tyr, c.5695G>A p.Gly1899Arg, and c.6485C>T p.Thr2162Met-associated with different clinical severities. We identified significant reductions in protein stability across these variants, with some exhibiting aberrant cytoplasmic localization, suggesting disruptions in structural integrity and function. In particular, exon 15 variants (p.Pro866Leu and p.Pro869Ser) correlated with severe phenotypes, including epilepsy and severe motor impairment, whereas p.Gly1899Arg and p.Thr2162Met were associated with milder manifestations. 3D protein modeling suggested that these missense variants may disrupt MED13L's interaction with the CDK8 kinase module, leading to functional deficits. Our findings highlight different pathogenic mechanisms, ranging from protein instability to altered molecular interactions, that contribute to the clinical variability observed in MED13L-related disorders.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100467"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}