Journal of Medical Genetics最新文献

{"title":"Commentary on <i>UBTF</i> haploinsufficiency associated with <i>UBTF</i>-related global developmental delay and distinctive facial features without neuroregression.","authors":"Tony Yammine, Sandra Mercier, Céline Poirsier, Nathalie Bednarek, Christine Clavel, Benjamin Cogné, Jan M Friedman, Sila Rogan, Marlène Rio, Laurence Lodé, Alban Ziegler","doi":"10.1136/jmg-2025-110686","DOIUrl":"10.1136/jmg-2025-110686","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"653-655"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic pathogenic <i>TULP3</i> variants presenting as neonatal cholestasis, liver fibrosis and neurological manifestations.","authors":"Jia-Qi Li, Yan Li, Ruida He, Zaisheng Lin, Jiayan Feng, Bin Yang, Qing-Wen Shan, Sixing Chen, Ye Cheng, Qinghe Xing, Muqing Cao, Jian-She Wang","doi":"10.1136/jmg-2025-110658","DOIUrl":"10.1136/jmg-2025-110658","url":null,"abstract":"<p><strong>Background: </strong>Biallelic pathogenic <i>TULP3</i> variants have been associated with a novel ciliopathy named hepatorenocardiac degenerative fibrosis, which is characterised by hepatic fibrosis in childhood or early adulthood, fibrocystic kidney disease later in life and hypertrophic cardiomyopathy in the elderly. Its genotype and phenotype spectrum are largely unknown.</p><p><strong>Methods: </strong>Patients presenting with liver diseases between 2015 and 2023 at The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, and carrying biallelic rare variants of <i>TULP3</i> were studied. Variants of uncertain significance were evaluated for pathogenicity in vitro.</p><p><strong>Results: </strong>Two unrelated children carrying biallelic rare variants in <i>TULP3</i> were identified. Patient 1 had variants c.666T>G, p. (Tyr222Ter) and c.1291G>C, p. (Gly431Arg). She initially presented with neonatal cholestasis, which rapidly progressed to liver fibrosis, with liver transplantation at 2 years of age. She also had intellectual disability and attention deficit hyperactivity disorder. Patient 2 had variants c.73C>T, p. (Gln25Ter) and c.1211T>G, p. (Met404Arg). He was found to have liver fibrosis, portal hypertension and abnormal cranial imaging at the age of 7.5 years. Both non-sense variants, c.73C>T and c.666T>G, were predicted to result in non-sense-mediated mRNA decay. Missense variant Met404Arg abolished TULP3 expression, while Gly431Arg reduced the localisation of TULP3 in cilia. Both Met404Arg and Gly431Arg impaired ciliogenesis and the trafficking of ARL13B and INPP5E into cilia.</p><p><strong>Conclusion: </strong>Severe neonatal cholestasis and/or neurological symptoms may be novel manifestations of disease in patients harbouring compound heterozygous <i>TULP3</i> variants. Missense variants in <i>TULP3</i> may impair ciliogenesis or normal cilia function by abolishing the normal expression or localisation of cilia proteins.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"631-640"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel 8-octapeptide repeat insertion in <i>PRNP</i> causing Huntington disease-like 1 in a Chinese family: a case report and literature review.","authors":"Jie Ni, Fangxue Zheng, Lihua Yu, Fangping He, Fang Ji, Yi Ling, Ping Liu, Guoping Peng, Qing Ke","doi":"10.1136/jmg-2024-110520","DOIUrl":"10.1136/jmg-2024-110520","url":null,"abstract":"<p><strong>Background: </strong>Approximately 1-3% of patients with Huntington disease (HD) present with HD-like phenotype but test negative for the HD gene, suggesting other causes.</p><p><strong>Methods: </strong>This study presents the first case of Huntington disease-like 1 (HDL-1) in a Chinese family and summarises the clinical features of previously reported HDL-1 cases and patients with octapeptide repeat insertion (OPRI) mutations.</p><p><strong>Results: </strong>The proband, a 36-year-old woman, presented with progressive involuntary movements, bradykinesia, cognitive decline and personality changes over 6 years, worsening over the past year. Similar manifestations were noted in her grandmother, father and aunt. Genetic testing revealed an 8-OPRI mutation in <i>PRNP</i>, confirming HDL-1. Neuroimaging showed increased T2-Fluid Attenuated Inversion Recovery (FLAIR) signals in the hippocampi and atrophic changes in the frontal and parietal lobes. Electroencephalography indicated a slowed background rhythm. A 1-year follow-up visit showed amelioration of choreic movements. A literature review identified five families with HDL-1, with age of onset ranging from 18 years to 54 years and disease duration from 3 months to over 20 years. Common manifestations included movement disorders, dementia, personality changes and heterogeneous symptoms such as epilepsy. Imaging showed ventricular enlargement and diffuse brain atrophy, primarily affecting the basal ganglia, frontal lobes, temporal lobes and cerebellum. Pathologically, prion protein antibody staining was positive, although spongiform changes were not prominent.</p><p><strong>Conclusion: </strong>These cases highlight the importance of considering familial prion diseases in patients with hereditary chorea and a negative HD gene test. Careful attention to treatment and follow-up can provide valuable insights for managing these patients.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"647-652"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New variants and genotype-phenotype correlation in <i>KIF5A</i> mutation: the contribution of a large Italian cohort.","authors":"Rosangela Ferese, Antonio Suppa, Rosa Campopiano, Simona Scala, Federica Sammarone, Luana Di Pilla, Alba Di Pardo, Maria Antonietta Chiaravalloti, Anna Maria Griguoli, Milena Cannella, Carmelo D'Alessio, Marianna Storto, Mirco Fanelli, Alessandro Zampogna, Martina Patera, Maurizio Inghilleri, Marco Ceccanti, Chiara Cambieri, Fabio Buttari, Cristina Peconi, Emiliano Giardina, Stefania Zampatti, Diego Centonze, Stefano Gambardella","doi":"10.1136/jmg-2025-110801","DOIUrl":"10.1136/jmg-2025-110801","url":null,"abstract":"<p><strong>Background: </strong>Variants in the Kinesin-family member 5A (<i>KIF5A)</i> gene are associated with a range of motor diseases, and a strong correlation between the protein domains (motor, stalk and tail) and the clinical phenotype has been proposed. However, several studies have reported exceptions contributing to a complex genotype-phenotype correlation in recent years. Further studies are needed to improve our knowledge about the prevalence of <i>KIF5A</i> variants and their genotype-phenotype correlation.</p><p><strong>Methods: </strong>390 patients (220 hereditary spastic paraplegia, 80 Charcot-Marie-Tooth disease type 2 and 90 amyotrophic lateral sclerosis) have been selected for next-generation sequencing Clinical Exome.</p><p><strong>Results: </strong>Five patients have been found to carry causative variants in the <i>KIF5A</i> gene. Of these, three are familiar cases, and two are sporadic. Segregation analysis was performed on the familiar probands. The five patients with pathogenic variants represent 4% of the studied population, and the clinical and genetic analysis of these five families allowed us to examine different scenarios.Some of these data support the hypothesis of a complex correlation between domains and disease.</p><p><strong>Conclusion: </strong>These data confirm the complex genotype-phenotype correlation, both in terms of clinical heterogeneity associated with a specific domain and variability within the members of the same family, but also suggest a strong genotype-phenotype correlation, both intrafamiliar and interfamiliar, produced by a few variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"641-646"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive genetic landscapes and clinical heterogeneity in nanophthalmos: new insights from a large Chinese cohort.","authors":"Qingdan Xu, Yiwen Zhou, Jiajian Wang, Xiangmei Kong, Junyi Chen, Yi Dai, Shaohong Qian, Xiaobo Yu, Xinghuai Sun, Yuhong Chen","doi":"10.1136/jmg-2025-110905","DOIUrl":"https://doi.org/10.1136/jmg-2025-110905","url":null,"abstract":"<p><strong>Background: </strong>Nanophthalmos is a rare ocular condition characterised by a significantly short axial length (AL) and high hyperopia, often associated with various complications. This study aims to provide a comprehensive analysis of the clinical and genetic features of nanophthalmos in a large Chinese cohort.</p><p><strong>Methods: </strong>A total of 105 patients from unrelated families diagnosed with nanophthalmos were included. Genetic testing was performed using whole exome sequencing to identify variants in genes associated with the condition. Clinical features, including demographic data, the presence of accompanying clinical findings and various ocular parameters, were compared across different genetic groups.</p><p><strong>Results: </strong>Whole exome sequencing revealed variants in four key genes: <i>PRSS56</i>, <i>MFRP</i>, <i>MYRF</i> and <i>TMEM98</i>, with a detection rate of 71.43%. Autosomal recessive genes (<i>PRSS56</i> and <i>MFRP</i>) were associated with shorter AL, higher hyperopia, shallower vitreous chamber depth and steeper corneal curvatures (larger K1 and K2). In contrast, autosomal dominant genes (<i>MYRF</i> and <i>TMEM98</i>) were linked to earlier onset of glaucoma and a higher incidence of multiple ciliary body cysts. In the patients carrying variants in <i>PRSS56</i> and <i>MFRP</i>, biallelic variants were associated with more severe phenotypes, including more extreme ocular parameters and increased risks of specific complications, compared with monoallelic variants.</p><p><strong>Conclusion: </strong>This study represents the largest cohort of nanophthalmos patients reported to date, expanding the genetic and clinical understanding of the condition. It identifies novel variants and provides valuable insights into genotype-phenotype correlations, highlighting the impact of genetic variation on the disease severity and associated complications of nanophthalmos.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous <i>TBX2</i> frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus.","authors":"Wan Hua, Yanfei Wang, Xiang Li, Wenyu Xiong, Lanchen Wang, Meilin Chen, Fengxiao Bu, Libo Liu, Fangyi Chen, Mingjun Zhong, Yu Lu, Zhiyong Liu, Jing Cheng, Huijun Yuan","doi":"10.1136/jmg-2025-110997","DOIUrl":"https://doi.org/10.1136/jmg-2025-110997","url":null,"abstract":"<p><strong>Background: </strong>A substantial fraction of hereditary hearing loss (HL) remains unexplained by known HL genes. Tbx2 is a developmental transcription factor critical for inner ear hair cell differentiation in mice, while its pathogenic role in genetic HL in humans has yet to be documented. Here, we identified heterozygous <i>TBX2</i> frameshift variants that cause human HL, establishing a previously unrecognised genetic link.</p><p><strong>Methods: </strong>Linkage analysis combined with whole-genome sequencing (WGS) was applied to identify the causative gene in two unrelated Chinese families with autosomal dominant progressive sensorineural HL (SNHL) accompanied by incomplete penetrance nystagmus. Functional evaluation of <i>TBX2</i> variants was performed through protein expression, localisation and transcriptional activity analysis <i>in vitro</i>, phenotypic analysis and mechanism study in knockout and knock-in mice model <i>in vivo</i>.</p><p><strong>Results: </strong>Linkage analysis in Family 1 mapped SNHL to chr17q23.2 (maximum logarithm of odds=3.01), WGS identified two rare heterozygous <i>TBX2</i> variants (c.977delA, p.Asp326Alafs*42 and c.987delC, p.Ala330Argfs*38) each segregating with the phenotype in a separate family. Affected individuals exhibited isolated auditory and oculomotor phenotypes, without additional syndromic features seen in previously described <i>TBX2</i>-associated disorders. <i>In vitro</i> assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity. <i>In vivo</i>, heterozygous <i>Tbx2</i> knockout mice (<i>Tbx2^+/-</i> ) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.</p><p><strong>Conclusion: </strong>These findings establish <i>TBX2</i> as a novel gene for syndromic HL, defining a new autosomal dominant disorder characterised by progressive HL with variable nystagmus. This discovery expands the spectrum of T-box transcription factor disorders and informs molecular diagnosis and genetic counselling in hereditary HL.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GAPO syndrome: a comprehensive examination and review of 105 clinical cases.","authors":"Clarissa Modafferi, Pino D'Ambrosio, Silvia Andaloro, Giulia Lauretti, Fulvia Antignani, Maurizio Pompili, Felice Giuliante, Marco Biolato, Benedetta Niccolini, Arcangelo Fargnoli, Francesco Bogliardi, Paola Concolino, Giuseppe Zampino, Angelo Minucci, Maurizio Genuardi, Elisabetta Tabolacci, Pietro Chiurazzi","doi":"10.1136/jmg-2025-110832","DOIUrl":"https://doi.org/10.1136/jmg-2025-110832","url":null,"abstract":"<p><p>Growth retardation, alopecia, pseudoanodontia and optic atrophy (GAPO) syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the <i>ANTXR1</i> gene. While significant progress has been made in understanding its molecular basis, no systematic description of the clinical phenotype is available.We conducted a comprehensive review of 105 cases reported in the available literature since the first description of GAPO syndrome in 1947. We summarise here the current understanding of the clinical phenotype and the genetic basis of the condition.Our findings point out the multisystemic nature of GAPO syndrome, primarily featuring skeletal, dermatological and ophthalmological manifestations. The condition is caused by the biallelic loss-of-function of <i>ANTXR1</i> Histological findings throughout the reported cases underscore the critical role of excessive extracellular matrix deposition in the pathogenesis of GAPO syndrome. The evidence gathered suggests <i>ANTXR1</i> as an important regulator of extracellular matrix homeostasis.This study highlights the clinical and molecular spectrum of GAPO syndrome. Early recognition, multidisciplinary care and genetic counselling are essential for improving patient outcomes. Future studies should focus on targeted therapies addressing extracellular matrix dysregulation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<b>Heterozygous alterations of</b> <i>GTF2I</i> <b>at the Williams-Beuren syndrome's locus cause a neurodevelopmental disorder</b>.","authors":"Jeanne Jury, Thomas Besnard, Wallid Deb, Annick Toutain, Paul Gueguen, Ange-Line Bruel, Arjan Bouman, Danielle Veenma, Tahsin Stefan Barakat, Laura Do Souto Ferreira, Petra J G Zwijnenburg, Sarah Schuhmann, Georgia Vasileiou, Matthieu Egloff, Frédéric Bilan, Anne Mercier, Pascaline Letard, Elsa Leitão, Christopher Schroeder, Christel Depienne, Pierre Blanc, Stéphane Bézieau, Benjamin Cogné, Bertrand Isidor","doi":"10.1136/jmg-2024-110471","DOIUrl":"https://doi.org/10.1136/jmg-2024-110471","url":null,"abstract":"<p><strong>Purpose: </strong>Williams-Beuren syndrome (WBS) is a well-known neurodevelopmental disorder caused by a copy-number loss at the 7q11.23 locus. Although the 1.5-1.8 Mb recurrent deletion carries several genes of interest, no single gene has been identified in which pathogenic variants cause a neurodevelopmental phenotype. At this locus, <i>GTF2I,</i> encoding the general transcription factor II-I, has been considered as the main candidate gene for the cognitive and behavioural phenotype of WBS, based on clinical observations of cases with atypical 7q.11.23 deletions and functional studies in humans and mice.</p><p><strong>Methods: </strong>Individuals with a neurodevelopmental disorder were identified through a multicentre collaboration using GeneMatcher and the ERN-ITHACA network. They remained undiagnosed following genome/exome sequencing. Clinical evaluations were performed in each participating centre.</p><p><strong>Results: </strong>We identified seven unrelated individuals with <i>de novo</i> variants in <i>GTF2I</i> (two non-sense, two splice-site, one missense, one indel and one intragenic deletion). We also identified one individual with a WBS phenotype and low <i>GTF2I</i> expression identified by RNA sequencing. All eight individuals presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in seven cases. The effect of the two splice-site variants was confirmed by RNA sequencing.</p><p><strong>Conclusion: </strong>Pathogenic heterozygous <i>GTF2I</i> variants cause a neurodevelopmental disorder characterised by global developmental delay with facial dysmorphic features, partly resembling the phenotype observed in individuals affected with WBS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Further evidence of <i>RNU4ATAC</i> variants causing Joubert syndrome with skeletal involvement.","authors":"Fulvio D'Abrusco, Simone Gana, Enrico Alfei, Emanuela Scarano, Francesco Nicita, Enrico Silvio Bertini, Maria Cristina Digilio, Ginevra Zanni, Domenico Barbuti, Eleonora Carlicchi, Anna Pichiecchio, Stefano D'Arrigo, Valentina Serpieri, Enza Maria Valente","doi":"10.1136/jmg-2025-110987","DOIUrl":"https://doi.org/10.1136/jmg-2025-110987","url":null,"abstract":"<p><p><i>RNU4ATAC</i> is a non-coding gene involved in the minor spliceosome, and is mutated in a spectrum of syndromic skeletal disorders with recessive inheritance. Recently, biallelic <i>RNU4ATAC</i> pathogenic variants were detected in five patients presenting a complex syndromic phenotype and a brain malformation resembling the 'molar tooth sign' (MTS). This is the hallmark of Joubert syndrome (JS), a neurodevelopmental ciliopathy with multiorgan involvement.We reanalysed exome sequencing (ES) from 53 patients with JS, who lacked coding variants in known JS-associated genes. Four <i>RNU4ATAC</i> variants (n.16G>A, n.51G>A, n.13C>T and n.30G>A) were identified in compound heterozygosity in three probands, accounting for 5.6% of negative cases. All patients displayed the MTS and clinical features overlapping those of JS and <i>RNU4ATAC</i>-related skeletal disorders.These findings expand the phenotypic spectrum of <i>RNU4ATAC</i>-related disorders to include a complex neurological-skeletal ciliopathy phenotype, and highlight the relevance of ES reanalysis to uncover non-coding variants often undetected by conventional diagnostics.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mixed functional consequences of the N651D <i>GRIA3</i> variant: a case of early-onset developmental and epileptic encephalopathy with parkinsonism.","authors":"Carmen Fons, Yu-Han Ge, Laura Kristine Rasmussen, Yun Stone Shi, Allan Bayat","doi":"10.1136/jmg-2025-110855","DOIUrl":"https://doi.org/10.1136/jmg-2025-110855","url":null,"abstract":"<p><p>Rare variants in <i>GRIA3</i>, the gene encoding the GluA3 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs), are associated with defects in early brain development. Disease-causing variants are generally categorised as either loss of function (LoF) or gain of function (GoF) that appear to be linked to different symptoms. Here, we reported a de novo variant (N651D) that has mixed LoF and GoF in a female patient with a devastating developmental and epileptic encephalopathy, parkinsonism and cortical malformation. N651D is located in the M3 segment, which forms the filter pore of AMPAR tetramers. Interestingly, functional assays revealed that glutamate induced no currents in GluA3_N651D homomeric receptors, likely indicating an LoF effect. However, when co-expressed with the GluA2 subunit, the GluA2/A3_N651D heteromeric receptors showed slower deactivation and desensitisation curves, along with elevated non-desensitising steady-state currents, features typically observed in GoF variants. We speculate that variants with mixed LoF and GoF effects may lead to a more devastating phenotype compared with variants with GoF effects only.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}