Human molecular genetics最新文献

{"title":"MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment.","authors":"Ruth I C Glasgow, Finn Lennartsson, Snjolaug Arnardottir, Dmitrii Igorevich Shiriaev, Sandrina P Correia, Marco Moedas, Lucía Peña-Pérez, Martin Paucar, Karin Naess, Helene Bruhn, Nicole Lesko, Rolf Wibom, Joanna Rorbach, Christoph Freyer, Anna Wedell, Sofia Ygberg, Erik A Eklund, Anna Wredenberg","doi":"10.1093/hmg/ddag042","DOIUrl":"10.1093/hmg/ddag042","url":null,"abstract":"<p><p>Mitochondrial diseases are clinically and genetically heterogeneous, often complicating diagnosis. Here, we describe four unrelated individuals with suspected mitochondrial disease who shared similar neuroimaging features, including bilateral symmetrical supra- and infratentorial white-matter abnormalities, together with variable movement disorders and intellectual impairment. Whole-genome sequencing identified the same homozygous MRPS22 variant (c.798_799delinsTA) in all four patients. MRPS22 encodes a component of the mitochondrial small ribosomal subunit (mtSSU). Functional studies in patient-derived fibroblasts showed impaired mitoribosome assembly and reduced de novo mitochondrial translation. Despite largely preserved steady-state levels of OXPHOS proteins, respiratory chain analysis identified a mild, isolated complex I deficiency. Proteomic profiling revealed reduced levels of mitochondrial ribosomal proteins and dysregulation of mitochondrial translation pathways. In line with the proteomic findings, RNA sequencing of fibroblasts from three patients revealed a distinct transcriptional signature compared with controls, with mitochondrial translation emerging as the most affected pathway. Mitochondrial-encoded transcripts were decreased, whereas nuclear-encoded mitochondrial genes were generally increased. Structural modelling suggested that the variant disrupts key interactions important for mitoribosome stability. While previously reported MRPS22 variants have been associated with severe, often prenatal-onset disease, the individuals described here exhibited a milder phenotype, thereby expanding the clinical spectrum of MRPS22-related disorders. Together, these findings support the pathogenicity of this variant and highlight the value of integrated genomic and functional analyses in diagnosing mitochondrial disease.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13231855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148149577","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":"Finding and computational analyses of a novel mutation in CEP78 linked to cone-rod dystrophy and hearing loss.","authors":"Mahtab Sahami, Mohammad Javad Mokhtari, Navid Nezafat, Mohammad Hossein Nowroozzadeh, Mojtaba Jafarinia","doi":"10.1093/hmg/ddag033","DOIUrl":"10.1093/hmg/ddag033","url":null,"abstract":"<p><p>Cone-Rod Dystrophy with Hearing Loss (CRDHL) is a rare genetic disorder marked by progressive vision and hearing loss. This research explores the genetic changes observed in patients with CRDHL and their subsequent influence on protein functionality. Whole-exome sequencing (WES) was utilized to investigate CRDHL. Carrier screening was performed using Tetra-primer ARMS PCR on 98 relatives, with subsequent Sanger sequencing to confirm the results. Bioinformatics analyses were conducted to explore the mutation's potential impact on protein structure and function. This study finds a novel CEP78 mutation, c.328A > T, p.Lys110* through WES. The c.328A > T mutation truncated the CEP78 protein from 689 to 110 amino acids. Among 98 relatives screened, 17 were identified as carriers. Affected individuals exhibited progressive vision and hearing loss. Bioinformatics analyses showed significant structural changes in the mutant protein, including loss of functional domains and conserved regions. Molecular modeling revealed reduced stability and increased flexibility, impairing protein functionality and highlighting its role in disease progression. This study highlights the c.328A > T mutation in CEP78 as a critical contributor to CRDHL. The findings emphasize the importance of genetic testing in early diagnosis and carrier identification. At the same time, bioinformatics analyses provide a foundation for potential therapeutic strategies to mitigate this mutation's impact.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148149655","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":"Partial TG6 loss of function causes motor deficits in male mice.","authors":"Luisa Donini, Linda Sartori, Anna Barbieri, Alice Migazzi, Sergio Robbiati, Maria Pennuto, Manuela Basso","doi":"10.1093/hmg/ddag037","DOIUrl":"10.1093/hmg/ddag037","url":null,"abstract":"<p><p>Mutations in Transglutaminase 6 (TG6) have been linked to a genetic form of spinocerebellar ataxia, namely SCA35. In recent years, several mutations associated with this disease have been identified. While some of them did not alter TG6 enzymatic activity, others induced a dominant-negative loss-of-function and altered subcellular localization. We previously observed that mutations identified in patients, which showed detrimental effects on neuronal viability in vitro, including mislocalization and activation of the unfolded protein response, were consistently characterized by a loss of TG6 enzymatic function. To investigate this effect in vivo, we re-derived Tgm6 knockout mice from the EMMA repository and performed behavioral characterization. We measured body weight and assessed motor performance using the rotarod, elevated beam/beam balance test, and ladder test, beginning at 1 month of age and continuing through 16 months of age. Here, we report that TG6 loss-of-function impairs motor coordination in male mice, suggesting a sex-specific function for this enzyme.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13235716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163072","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":"tubb5 knockout in zebrafish causes neurodevelopmental defects via notch pathways.","authors":"Huihui Liu, Jinze Li, Linglu Xiao, Meiqi Hou, Zhike Zi, Xianqin Zhang","doi":"10.1093/hmg/ddag041","DOIUrl":"10.1093/hmg/ddag041","url":null,"abstract":"<p><p>Mutations in TUBB5 cause complex cortical dysplasia with other brain malformations. However, the pathogenic mechanisms underlying TUBB5 mutations remain incompletely understood. We generated tubb5 knockout zebrafish using CRISPR/Cas9 genome editing technology. Homozygous mutants were lethality within two weeks post-fertilization along with developmental delay, craniofacial malformations, uncoordinated movement and increased seizure susceptibility. tubb5 knockout larvae also showed reduced locomotor activity and impair photomotor responses. Furthermore, tubb5 knockout larvae exhibited significantly attenuated locomotor activity under alternating light/dark conditions compared to wild-type controls. Pharmacological intervention with carbamazepine and sodium valproate ameliorated both locomotor dysfunction and PTZ-induced seizure susceptibility in mutant larvae. Transcriptome analysis revealed that tubb5 knockout larvae showed upregulated expression of notch1a and her5, which inhibit neural progenitor differentiation. Whole-mount in situ hybridization demonstrated decreased neurogenin1 and huc positive neurons, while sox2 positive neurons were increased in tubb5 mutants, indicating disrupted neural progenitor differentiation. DAPT treatment rescued both developmental and locomotor deficits tubb5 knockout zebrafish. This study demonstrates that tubb5 regulates neural progenitor differentiation via the Notch signaling pathway and identifies DAPT as a potential therapeutic agent for disorders associated with human TUBB5 mutations.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163113","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 causal association between sleep traits and osteoarthritis traits: evidence from bidirectional mendelian randomization.","authors":"Shibo Chen, Lorraine Southam, Ana Luiza Arruda, Eleftheria Zeggini","doi":"10.1093/hmg/ddag043","DOIUrl":"10.1093/hmg/ddag043","url":null,"abstract":"<p><p>Sleep disorder is associated with risk of osteoarthritis, yet their causal association has not been fully understood. This study aims to evaluate the causal association between sleep traits and osteoarthritis, by performing two sample Mendelian randomization (MR) leveraging the currently largest genome-wide association study (GWAS) summary statistics for sleep traits and osteoarthritis traits. We demonstrate that insomnia has a risk-increasing causal effect on osteoarthritis at any site, hip osteoarthritis, and hip and/or knee osteoarthritis, corresponding to approximately 60%, 100%, and 50% higher odds of disease, respectively, with the strongest effect observed for hip osteoarthritis. Conversely, genetic predisposition to osteoarthritis at any site was associated with a modest 4% increase in the odds of insomnia. These findings reveal a bidirectional causal relationship between insomnia and osteoarthritis-related traits, underscoring the critical interplay between sleep health and joint disease, and suggesting opportunities for preventive and therapeutic strategies that align with the body's intrinsic timing systems.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13225258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143229","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":"Identification of multi-omic pleiotropy factors for peripheral artery disease.","authors":"Jiaqi Hu, Cassius I Ochoa Chaar, Hongyu Zhao, Andrew T DeWan","doi":"10.1093/hmg/ddag035","DOIUrl":"10.1093/hmg/ddag035","url":null,"abstract":"<p><strong>Background: </strong>Peripheral artery disease (PAD) is prevalent and frequently co-occurs with type 2 diabetes (T2D) and coronary artery disease (CAD). Although shared genetic factors-pleiotropy-may contribute to these comorbidities, few studies have examined pleiotropy at the transcriptomic and proteomic levels.</p><p><strong>Methods: </strong>We generated summary statistics for transcriptome-wide (TWAS) and proteome-wide (PWAS) association analyses across PAD, T2D, and CAD. Joint tests for pleiotropy at the variant, transcript, and protein levels were performed using PLACO, and the contributions of these pleiotropic factors to genetic correlations were quantified. Furthermore, we developed pleiotropy models integrating variants, transcripts, and proteins.</p><p><strong>Results: </strong>In the PAD-T2D analysis, we identified 5 SNPs, 2 predicted transcripts, and 2 predicted proteins that together contributed 2.8% to the genome-wide genetic covariance. In the PAD-CAD analysis, 33 SNPs, 2 predicted transcripts, and 2 predicted proteins accounted for 9.15% of the genetic covariance. Overall, eight pleiotropy models were established, providing a multi-layered framework for categorizing our findings.</p><p><strong>Conclusion: </strong>Employing a multi-omic framework, this study elucidates the shared genetic architecture of PAD with T2D and CAD. Our findings enhance the understanding of genetic risk factors underlying PAD and its comorbidities, with potential implications for future therapeutic strategies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 9","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143201","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":"Combined periodontitis GWAS identifies LINC01541 as a regulator of innate immunity in the oral mucosa.","authors":"Gesa M Richter, Oluwabukunmi M Akinloye, Tim Kühnlenz, January Rd Weiner, Birte Holtfreter, Alicia de Coo, Silvia Diz-De Almeida, Bruno G Loos, Søren Jepsen, Henrik Dommisch, Corinna Bruckmann, Ines Kapferer-Seebacher, Georg Homuth, Thomas Kocher, Henry Völzke, Klaus Berger, Matthias Laudes, Wolfgang Lieb, Nathalie van der Velde, Natasja M van Schoor, Lisette de Groot, Juan Blanco, Angel Carracedo, Raquel Cruz, Astrid Dempfle, Alexander Teumer, Sandra Freitag-Wolf, Arne S Schaefer","doi":"10.1093/hmg/ddag039","DOIUrl":"https://doi.org/10.1093/hmg/ddag039","url":null,"abstract":"<p><p>Periodontitis is a complex inflammatory disease in which chronic immune activation drives destruction of periodontal soft tissues and alveolar bone. Although early-onset forms show high heritability, much genetic risk remains unresolved. To identify shared genetic signals across early- and later-onset periodontitis, we combined two European genome-wide association study datasets (3183 cases, 10 326 controls) and applied Fisher's combined probability test (FCOMB) and effect-size-based genome-wide association meta-analysis (GWAMA) across > 7 million variants to capture shared signals with either heterogeneous or more concordant effect sizes. We confirmed known associations at SIGLEC5 and DEFA1A3 and identified several additional suggestive loci. Among these, FCOMB highlighted the strongest signal at the long non-coding RNA LINC01541 (rs11876034, P = 1.7 × 10-6). We evaluated the biological relevance of LINC01541 by repressing it in gingival fibroblasts using CRISPR interference. Knockdown led to significant downregulation of inflammatory mediators, including CSF2 and CSF3, regulators of neutrophil recruitment, members of the interleukin (IL) family (IL1B, IL36B, IL36RN), and chemokines (CXCL5, CXCL8, CCL20). Six of the top ten differentially expressed genes belonged to an epithelial keratinization expression cluster. Gene-set enrichment analyses following linc01541 knockdown demonstrated repression of cytokine signaling, with IL-10 signaling most affected (padj = 5.3 × 10-14; AUC = 0.81), alongside activation of cell-cycle pathways (padj = 3.3 × 10-24; AUC = 0.73). We demonstrated the utility of aggregating heterogeneous samples to detect modest but biologically meaningful genetic effects. The convergence of the genetic association at LINC01541 with functional evidence suggests that this lncRNA modulates an upstream mucosal inflammatory axis relevant to periodontal pathogenesis.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 9","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143216","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":"Alternative splicing of Scn9a exon 5: mechanistic insights and therapeutic potential in pain disorders.","authors":"Qingyue Fu, Peng Gao, Xinli Wang, Yafei Guo, Haoyan Zhang, Mengqian Xu, Bolin Zhao, Rui Chen, Jialin Bai, Li Wang","doi":"10.1093/hmg/ddag045","DOIUrl":"https://doi.org/10.1093/hmg/ddag045","url":null,"abstract":"<p><p>Alternative splicing is a fundamental mechanism of gene regulation that generates transcriptomic and proteomic diversity, and its dysregulation is widely implicated in human diseases. The voltage-gated sodium channel (VGSC) NaV1.7, encoded by SCN9A, plays an essential role in nociceptive signaling, and alterations in its activity are closely associated with inherited pain disorders. In particular, alternative splicing of mutually exclusive exons, 5N and 5A, occurs in human, represents a key regulator of pain sensation in both growth and pathological processes. In this study, we examined the splicing regulatory landscape of exon 5N/5A in the mouse Scn9a gene and identified two potent splicing silencers, including ESS18, which is predominately regulated by the RNA-binding protein HuR. We further discovered a previously unreported Scn9a-Δ5 isoform whose exon 5 skipping induces nonsense-mediated decay, thereby reducing NaV1.7 expression. Based on these findings, we designed a series of MOE/PS-modified antisense oligonucleotides (ASOs) targeting exon 5N/5A and adjacent regions. Among these, ASO 5N(24-43) robustly promoted exon 5 skipping in vitro. Intracerebroventricular administration of this ASO in adult mice significantly enhanced tolerance to thermal and mechanical stimuli, correlating with extensive exon 5 skipping across multiple central nervous system regions. Our results reveal key cis-regulatory elements controlling Scn9a exon 5 splicing and demonstrate the therapeutic potential of exon-skipping ASOs for modulating NaV1.7 expression in pain management.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 9","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143052","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":"Ultra-rare variants in LAMA2 are risk factors for frontotemporal dementia and motor neuron disease.","authors":"Hiu Chuen Lok, Carol Dobson-Stone, Marianne Hallupp, Sophie Matis, Ramon Landin-Romero, Boris Guennewig, Hamish Mundell, Anthony S Don, Jennifer Fifita, Emily P McCann, Sandrine Chan Moi Fat, Ian P Blair, Karen A Mather, Anbupalam Thalamuthu, Wei Wen, Perminder S Sachdev, William S Brooks, Olivier Piguet, Glenda M Halliday, Woojin S Kim, John B Kwok","doi":"10.1093/hmg/ddag034","DOIUrl":"10.1093/hmg/ddag034","url":null,"abstract":"<p><p>There is overlap between frontotemporal dementia (FTD) and motor neuron disease (MND) in terms of genetics, neuroimaging and clinical phenotypes. We aimed to identify in three patient cohorts, ultra-rare variants (frequency ≤ 0.00002) in genes whose mutations are associated with white matter dysfunction, and to examine impact of these variants on protein function in vitro, and neuroimaging and lipid profiles in vivo. Next generation sequencing (NGS) of N = 289 patients with clinical FTD recruited through two dementia research clinics identified ultra-rare variants in established leukodystrophy genes, including ARSA. Further, novel and ultra-rare loss-of-function and missense variants in LAMA2 increased risk of disease in three independent cohorts, including N = 598 MND and N = 14 logopenic variant primary progressive aphasia (lvPPA) patients (maximum odds ratio (OR) of 3.05, P = 0.0357 for FTD cohort, OR of 9.57, P = 0.0233 for lvPPA cohort, and 1.78, P = 0.0250 for MND cohort). An in vitro transfection assay demonstrated a loss-of-secretion phenotype in the subset of LAMA2 ultra-rare missense variants where the full-length proteins were translated but not secreted into growth media. LAMA2 ultra-rare variant carriers have a distinctive serum lipidomics profile compared with sporadic cases and cognitively normal controls. Finally, LAMA2 ultra-rare variants were associated with white matter changes in brain regions relevant to disease process. Our results broaden the phenotypes associated with LAMA2 from muscular dystrophies to include FTD, lvPPA and MND; and our data provide convergent evidence for the role of ultra-rare variants in LAMA2 as risk factors.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147981846","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":"Natural history of NGLY1 deficiency: motor function & clinical features.","authors":"Grace Morrison, Selina Dwight, Hal Landy, William F Mueller, Pam Ventola, Regina Deck, Becky Schweighardt, Matt Wilsey, Kevin J Lee, Bernhard Suter","doi":"10.1093/hmg/ddag013","DOIUrl":"10.1093/hmg/ddag013","url":null,"abstract":"<p><p>N-glycanase 1 (NGLY1) Deficiency is an ultra-rare neurodevelopmental disorder caused by biallelic loss-of-function mutations in the NGLY1 gene, leading to severe impairments in neurocognitive and motor function abilities in the affected patient population. Its core clinical features include global developmental delay, hyperkinetic movement disorders, elevation of liver transaminases, (hypo)alacrima, and progressive sensorimotor neuropathy. Due to the range of phenotypes and severity within the confirmed patient population, ongoing characterization of the disease is critical. A prospective natural history study (NHS) was conducted to further elucidate disease phenotypes and examine any changes in neurocognitive or motor function over a one-year period. Fifteen participants, representing roughly 10% of the total identified patient population, were enrolled to complete three onsite visits. Participants in this study exhibited phenotypes previously reported, including core disease phenotypes, hypotonia, scoliosis, musculoskeletal abnormalities, abnormal electroencephalogram (EEG) results, and visual and genitourinary abnormalities. Results from validated neurocognitive and motor function assessments revealed profound global developmental delays in all participants, including communication, gross and fine motor function, and cognitive domains. Age-equivalent scores identified a widening developmental gap between participants and neurotypical peers over time, indicating delayed milestone achievement and/or regression. Although fluctuations were observed, measurements for individual participants were mostly stable over the course of the NHS. Liver transaminase and biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA) levels were elevated in all participants. Results build on previous studies and inform the selection of potential endpoints for emerging interventional clinical trials, including laboratory values, neurocognitive and motor function assessments, and caregiver reported outcomes.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13160418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874241","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}