HGG Advances最新文献

{"title":"Exome sequencing early in outpatient evaluation in NCGENES 2: Changing the course of the diagnostic odyssey?","authors":"Tamara S Roman, Shannon M Gray, Tam P Sneddon, Ann Katherine M Foreman, Kristy Lee, Cynthia M Powell, Karen E Weck, Jonathan S Berg, Bradford C Powell","doi":"10.1016/j.xhgg.2026.100605","DOIUrl":"10.1016/j.xhgg.2026.100605","url":null,"abstract":"<p><p>The impact of clinical exome and genome sequencing (ES/GS) depends on the clinical setting. In the sequencing arm of a multifactor randomized clinical trial to evaluate broadening access, we assessed the diagnostic and inconclusive findings of ES as a \"first-tier\" test in 101 pediatric participants in whom suspicion of a genetic condition by primary care providers had prompted initial outpatient consultation in a pediatric genetics or neurology clinic. This implementation focused on the early stages of the diagnostic odyssey, capturing a clinically less-selected population with lower pre-test probability than traditional specialist cohorts. Variants were prioritized using phenotype-driven gene lists. After returning the results to participants, the clinical teams performed familial variant testing or additional phenotyping at their discretion, based on potential diagnostic benefit. We then implemented a multidisciplinary case conference in which the laboratory and clinical teams assessed additional clinical information. Initially, 57% of participants had non-negative reports: 5% had one or more variant findings considered explanatory for the presenting phenotype, with 52% having results initially classified as inconclusive. After family testing and/or phenotypic characterization, a total of 9% were considered positive/diagnostic, 10% were reclassified from inconclusive to negative, and 38% remained inconclusive. While ES, as a first-tier genetic test, can expedite some diagnoses, these results demonstrate challenges in early implementation. In this population, initial testing can leave substantial residual uncertainty, shifting the diagnostic odyssey rather than concluding it and necessitating factors such as parental testing, ongoing phenotyping, and reassessment of variants over time to resolve inconclusive results.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100605"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623772","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":"Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder.","authors":"Lauretta El Hayek, Ashlesha Gogate, Wei-Chen Chen, Kiran Kaur, Maha S Zaki, Matthias De Wachter, Kristof Van Schil, Leeran Dublin-Ryan, Mina Zamani, Meghan N Bartos, Susan M Hiatt, Cécile Courdier, Vincent Michaud, Janna Kenny, Michael Day, Lewis Pang, Mahya Ebrahimi Nasab, Seyed Ali Madani Manshadi, Atieh Eslahi, Masoomeh Ale Rasoul, Eduardo Humberto Sanchez-Mendoza, Charles DeLuca, Dana Marafi, Servi J C Stevens, Ivan Ivanovski, Tanja Frey, Katharina Steindl, Anita Rauch, Kaitlyn O'Connor, Milen Velinov, Xiaoming Shen, Etienne J M Janssen, Sahar Sedighzadeh, Dor Mohammad Kordi-Tamandani, Ali Khajeh, Reem M Elshafie, Laila Bastaki, Vinod K Misra, Zahra Firoozfar, Paula C Goldenberg, Mehran Beiraghi Toosi, Majid Mojarrad, Karl Kavanagh, Daniel C Koboldt, Henri Margot, Anna C E Hurst, Axel Weber, Carsten Bergmann, Henry Houlden, Reza Maroofian, Denisa Weis, Berten Ceulemans, Maria H Chahrour","doi":"10.1016/j.xhgg.2026.100594","DOIUrl":"10.1016/j.xhgg.2026.100594","url":null,"abstract":"<p><p>Chromatin regulation is critical for neurodevelopment, and its disruption has emerged as a key pathogenic mechanism in neurodevelopmental disease, including autism spectrum disorder (ASD), a condition known for genetic and phenotypic heterogeneity. We previously identified an ASD gene, KDM5A, encoding a histone H3 lysine 4 demethylase, and reported de novo and inherited variants in nine individuals with severe ASD and other neurodevelopmental phenotypes. Here, we expand the genetic and phenotypic spectrum of KDM5A-related neurodevelopmental disorders and investigate the functional impact of identified variants. Through international collaborations, we assembled a cohort of 24 additional individuals from 21 families with rare, protein-altering KDM5A variants. All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features. The variants include missense, nonsense, frameshift, and splice site, distributed across nearly all functional domains of the protein. Structural modeling revealed localized conformational disruptions, particularly at conserved residues in enzymatic or chromatin-interacting domains. For a subset of variants, we demonstrated reduced KDM5A protein levels in cell lines derived from affected individuals. Transcriptomic profiling revealed variant-specific gene expression changes, most pronounced in variants affecting the PLU1 chromatin-binding motif and the Jumonji C domain of the enzymatic core. American College of Medical Genetics and Genomics-guided reclassification supported pathogenicity for the majority of variants, including multiple upgrades from uncertain significance to pathogenic or likely pathogenic. Together, these findings implicate diverse KDM5A alleles in a rare but recurrent form of ASD and establish KDM5A as a key regulator of neurodevelopment and chromatin-mediated ASD pathogenesis.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100594"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13090590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147522043","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":"Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.","authors":"Matthieu Mantecon, Cerina Chhuon, Kevin Roger, Ida Chiara Guerrera, Christine Bole, Patrick Nitschke, Claire-Marie Dufeu-Bérat, Margaret Ashcroft, Robert W Taylor, Nathalie Boddaert, Agnès Rötig","doi":"10.1016/j.xhgg.2026.100615","DOIUrl":"10.1016/j.xhgg.2026.100615","url":null,"abstract":"<p><p>Mitochondrial disorders show remarkable clinical and genetic heterogeneity and result from variants in either mitochondrion- or nucleus-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly pathway that imports small cysteine-containing substrates. We report a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Western blot analysis showed decreased levels of CHCHD4 and diminished assembly of complexes I and IV in his fibroblasts. To demonstrate that CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring levels of complex I and IV proteins and the associated assembly defects. Proteomic studies pointed to electron transport and complex I biogenesis as the main dysregulated pathways and showed a severe loss of several complex I and IV proteins and/or assembly factors rescued by overexpression of wild-type CHCHD4. CHCHD4 has numerous targets and interacting factors and is involved in the export of iron-sulfur clusters synthesized inside mitochondria. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a cause of dysregulated mitochondrial protein import resulting in a severe neurological condition.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100615"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692638","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":"Heterozygous CECR2 variants support a distinct neurodevelopmental syndrome with features overlapping cat eye syndrome.","authors":"Anushree Acharya, Irma Järvelä, Andrea Hernandez, Yasmin Rajendran, Thashi Bharadwaj, Dana H Goodloe, Susan M Hiatt, Jennifer Morrison, Patricia G Wheeler, Jesse M Hunter, Rachel Supinger, Scott E Hickey, Andrea K Petersen, Kari Magnussen, Marcello Scala, Pasquale Striano, Federico Zara, Juha Leppälä, Suzanne M Leal, Isabelle Schrauwen","doi":"10.1016/j.xhgg.2026.100613","DOIUrl":"10.1016/j.xhgg.2026.100613","url":null,"abstract":"<p><p>The CECR2 histone acetyl-lysine reader facilitates chromatin remodeling and plays a significant role in neurodevelopment. It resides within the cat eye syndrome (CES) critical region at 22q11.1q11.21. An increased copy number of this region, often as tetrasomy or a supernumerary chromosome, results in CES. The complex chromosomal arrangements and phenotypic variability have hampered the identification of the true cause(s) of CES. Patients and their clinical data were collected from multiple diagnostic and research laboratories. Exome or genome sequencing was performed in affected individuals and, when available, their relatives. Here, we describe six patients with a heterozygous single-nucleotide or small insertion/deletion variant in CECR2 and their clinical features. Variants were either loss-of-function [c.1734dupC:p.(Thr580Hisfs∗98), c.1819C>T:p.(Arg607∗), and c.2281C>T:p.(Arg761∗)] or missense in an intrinsically disordered and potentially critical region at the C terminus of the protein [c.4153C>G:p.(Gln1385Glu), c.4254C>G:p.(Phe1418Leu), and c.4283A>G:p.(Gln1428Arg)]. The main clinical features were delayed growth, relatively small head circumference, developmental delay, and speech issues/delay. Other clinical findings were variable and included intellectual disability; feeding problems; facial dysmorphism; cleft lip/palate; brain, ear, heart, or other organ abnormalities; behavioral abnormalities; and epilepsy. There was significant overlap with common CES features, including ear, heart, and brain abnormalities, intellectual disability, and growth restriction. In conclusion, we characterize a CECR2-associated neurodevelopmental disorder. The consistent molecular and clinical overlap with CES supports CECR2's role in the CES phenotype. These findings implicate diverse variant types in related neurodevelopmental disorders, underscoring CECR2's dosage sensitivity and essential function in epigenetic regulation during development.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100613"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147655079","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":"Investigations on transferability of polygenic risk scores depending on demography and dominance coefficients.","authors":"Leonie Fohler, Edita Latifi, Andreas Mayr, Carlo Maj, Christian Staerk, Hannah Klinkhammer, Peter M Krawitz","doi":"10.1016/j.xhgg.2026.100595","DOIUrl":"10.1016/j.xhgg.2026.100595","url":null,"abstract":"<p><p>The genetic liability to a complex phenotype can be assessed using polygenic risk scores (PRSs) and is calculated as the sum of genotypes weighted by effect-size estimates derived from summary statistics of genome-wide association study (GWAS) data. Due to different allele frequencies (AFs) and linkage disequilibrium (LD) patterns across populations, PRSs developed in one population drop drastically in predictive performance when transferred to another. One of the major factors contributing to AF and LD heterogeneity is genetic drift, which acts strongly during population bottlenecks and is influenced by the dominance of certain alleles. In particular, because causal variants on empirical data are typically not known, the presence of population-specific LD patterns will strongly affect the transferability of PRS models. In this work, we therefore conducted demographic simulations to investigate the influence of the dominance coefficient on the transferability of PRSs among European, African, and Asian populations. By modifying the length and size of the bottleneck leading to the split of Eurasian and African populations, we gain a deeper understanding of the underlying dynamics. Finally, we illustrate that in our simulations, PRS models that are adapted to the underlying dominance coefficient can substantially increase the prediction performance in out-of-target populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100595"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147533343","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":"Diagnostic utility of clinical genome reanalysis in rare pediatric disorders using long-read sequencing.","authors":"Elizabeth A Werren, Purva Vats, Gabriel E Rech, Michael Peracchio, Cameron King, Elizabeth J Charnysh, Ryan D Gorham, Peter A Audano, Peter N Robinson, Melissa A Kelly, Adam P Matson, Mark D Adams, Louisa Kalsner","doi":"10.1016/j.xhgg.2026.100620","DOIUrl":"10.1016/j.xhgg.2026.100620","url":null,"abstract":"<p><p>Over half of presumed genetic disease cases remain undiagnosed following short-read exome sequencing (SR-ES) or genome sequencing (SR-GS). Long-read GS (LR-GS) shows promise for uncovering etiologies missed by SR genetic testing, particularly structural variants (SVs). However, SV interpretation remains challenging due to limitations in call reliability, population allele frequency estimates, and functional impact prediction. To advance clinical LR-GS implementation, we analyzed the genomes of 19 children with suspected rare genetic conditions and prior negative or inconclusive clinical SR-GS/SR-ES as well as their parents using PacBio HiFi LR-GS. One additional family with limited DNA underwent Illumina SR-GS only, and 11 probands received SR-GS to complement small-variant detection. LR-GS data were processed using phased-assembly and read-based variant-calling pipelines validated in SV-positive control subjects, while SR-GS data were processed with the Illumina DRAGEN pipeline. Variants were prioritized using phenotype-driven approaches. Diagnostic variants (likely pathogenic or pathogenic) were identified in 2/20 (10%) families, while an additional 5/20 (25%) harbored findings of uncertain diagnostic significance, including variants of uncertain significance (VUSs) and variants in genes of uncertain significance (GUSs). All reported variants were detected independently of LR-GS by research SR-GS or by reanalysis of prior clinical SR data. Several LR-GS SV candidates were excluded after population allele frequency filtering, underscoring its importance in clinical SV interpretation. Overall, the observed 10% increase in diagnostic yield was achievable through SR analysis alone, as LR-GS was not required to identify diagnostic variants in this cohort. Functional studies are needed to clarify the clinical relevance of uncertain findings.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100620"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783519","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":"Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant-effect predictors.","authors":"Aziz Zafar, Chao Hou, Naufa Amirani, Yufeng Shen","doi":"10.1016/j.xhgg.2026.100618","DOIUrl":"10.1016/j.xhgg.2026.100618","url":null,"abstract":"<p><p>Predictive models for missense-variant pathogenicity offer little functional interpretation for intrinsically disordered regions (IDRs), since they mostly leverage conservation and co-evolution across homologous sequences. In our study, we use molecular dynamics (MD) simulations to model biophysics of IDRs for improved interpretation of variant effects. We develop MDmis, a method that uses biophysical features extracted from MD simulations of IDRs to predict pathogenicity. We find that pathogenic variants in IDRs longer than 800 residues manifest differently, being strongly associated with a propensity for transient order and depleted solvent access, compared to those in IDRs ≤ 800 residues in length. Using MD simulations of proteins with single missense variants, we identify evidence for local structural changes, such as an increase in solvent-accessible surface area, and global structural changes, such as increase in overall compaction, in IDRs > 800 amino acids (aa). Lastly, MDmis, when combined with conservation information, can aid predictive accuracy, especially for pathogenic variants in IDRs > 800 aa. Overall, extracting information from MD simulations can help elucidate biophysical behaviors affected by pathogenic variants in IDRs and understand the drivers of predictive performance in different models.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100618"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13266028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783456","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":"Functional genomic analysis reveals HAVCR1 as the key regulator of 5q33.3 locus linked to hyperlipidemia.","authors":"Wei-Ting Chen, Chia-Ni Hsiung, Yuh-Shan Jou, Hui-Chun Wang, Chen-Yang Shen, Wen-Cheng Chou","doi":"10.1016/j.xhgg.2026.100630","DOIUrl":"10.1016/j.xhgg.2026.100630","url":null,"abstract":"<p><p>Hyperlipidemia is a major risk factor for atherosclerosis and other serious cardiovascular diseases, yet it often presents without obvious symptoms in the absence of comorbidities, complicating early detection and management. Given the high heritability of lipid traits, genome-wide association studies (GWASs) have identified numerous loci associated with serum lipids; however, pinpointing the causal variants remains a challenge. Here, we investigated the 5q33.3 locus and identified HAVCR1 as a likely effector gene influencing lipid metabolism. By integrating functional genomics and experimental validation, we identified two non-linked variants, rs6882076 and rs17573010, that modulate HAVCR1 via allele-specific binding by IRF2 and GATA4, respectively. rs6882076 was refined from prior GWAS findings, while rs17573010 emerged from ancestry-specific analysis. These findings highlight the complexity of genetic regulation across populations and establish a mechanistic link between lipid metabolism and inflammation, offering insights into the genetic basis of hyperlipidemia and its potential translational relevance.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100630"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148017681","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":"Functional and computational interrogation of juvenile idiopathic arthritis risk loci in CD4+ T cells.","authors":"Kaiyu Jiang, Emma K Haley, Gilad Barshad, Adam He, Anita Rogic, Edward Rice, Marc Sudman, Susan D Thompson, David A Murphy, Yao Fu, Lori Ponder, Maurice Davenport Munoz, Prashant Kolachala, Sampath Prahalad, Patrick M Gaffney, Charles G Danko, James N Jarvis","doi":"10.1016/j.xhgg.2026.100619","DOIUrl":"10.1016/j.xhgg.2026.100619","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) have identified multiple genetic regions that confer risk for juvenile idiopathic arthritis (JIA). However, identifying the single-nucleotide polymorphisms (SNPs) that drive disease risk has been impeded by the fact that the SNPs used to identify risk loci are in linkage disequilibrium (LD) with hundreds of other SNPs. Since the causal SNPs remain unknown, it is difficult to identify target genes and thus use genetic information to elucidate disease biology and inform patient care. We next used existing genotyping data from 3,939 children with JIA and 14,412 healthy controls to identify SNPs on JIA-risk haplotypes that present within open chromatin in multiple immune cell types and are more common in children with JIA than the controls (p < 0.05) in the genotyping datasets. We identified SNPs within cis-regulatory regions (cis-regulatory elements [CREs]) using precision run-on sequencing data and identified likely target genes using MicroC in both resting and activated CD4+ T cells. We identified 138 SNPs within the PROseq-identified CREs and n = 41 genes with which these CREs physically interacted. Data from Genotype-Tissue Expression (GTEx) and the Database of Immune Cell Expression Quantitative Trait Loci (DICE) corroborated these analyses by showing allelic effects for SNPs within the CREs in the ERAP2/LNPEP and locus. We further corroborated IRF1 allelic effects using a luciferase reporter assay. Our findings significantly reduce the genomic search space for risk-driving variants and target genes and support the roles of IRF1, ERAP2, and LNPEP in driving risk for JIA.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100619"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783543","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":"Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice.","authors":"Kassidy E Grover, Zoe R Cappel, Avery M Volz, Evelin M Cotella, Kelly Smallwood, Christine A Berryhill, Kimaya R Raje, Austen A Fisher, Mary Claire T Casper, Diana Nardini, Tilat A Rizvi, Rosa M Salazar, Ashley Wooten, Michael T Williams, Charles V Vorhees, Lindsey E Romick, Kenneth D Greis, Yueh-Chiang Hu, Linde A Miles, Steven P Angus, Nancy Ratner, Carlos E Prada, K Nicole Weaver, Ronald R Waclaw, J Elliott Robinson","doi":"10.1016/j.xhgg.2026.100621","DOIUrl":"10.1016/j.xhgg.2026.100621","url":null,"abstract":"<p><p>Germline pathogenic variants that activate the Ras/mitogen-activated protein kinase (MAPK) pathway cause neurodevelopmental disorders called Rasopathies. Because many affected proteins directly regulate Ras, causative mutations may alter other Ras-dependent pathways in addition to MAPK signaling. To better understand which Rasopathy sequelae result from hyperactivation of downstream MAPKs, we engineered mice with a gain-of-function mutation in the terminal MAPK gene Mapk1, which encodes ERK2 and is associated with the recently described genetic syndrome MAPK1-related Rasopathy (MRR). Mapk1 mutant mice successfully modeled key aspects of the human MRR phenotype, including small stature, facial dysmorphism, and impaired cognitive function. Importantly, they recapitulated phenotypes identified in Rasopathy models with upstream Ras activation, such as neurofibromatosis type 1 (NF1): oligodendrocyte lineage defects, reactive astrogliosis, memory deficits, and hypersensitivity to sensory stimuli. These findings emphasize the importance of downstream MAPK signaling in the pathophysiology of neurocognitive symptoms observed in Rasopathy syndromes.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100621"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13234240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783465","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}