Journal of Medical Genetics最新文献

{"title":"Identification of <i>MACF1</i> as a causative gene of generalised epilepsy.","authors":"Xiao-Yun Lei, Meng-Wen Zhang, Hui Sun, Wang Song, Xiao-Yu Liang, Cui-Shan Wang, Sheng Luo, Bing-Mei Li, Xiao-Rong Liu, Yao Wang, Yang Tian, Qian Peng, Jie Wang, Heng Meng, Na He, Wei-Ping Liao","doi":"10.1136/jmg-2025-110699","DOIUrl":"10.1136/jmg-2025-110699","url":null,"abstract":"<p><strong>Background: </strong>The microtubule actin crosslinking factor 1 (<i>MACF1)</i> gene encodes microtubule-microfilament cross-linking factor 1 that plays an essential role in the embryonic brain development. <i>MACF1</i> variants were associated with lissencephaly-9 (LIS9). However, the <i>MACF1</i>-epilepsy relationship was unknown.</p><p><strong>Methods: </strong>Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of <i>MACF1</i> in epilepsy and neurodevelopment.</p><p><strong>Results: </strong>Two de novo heterozygous and eight biallelic <i>MACF1</i> variants were identified in 10 unrelated patients. The variants presented significantly high excess by multiple statistical analyses. All patients were diagnosed with generalised epilepsy, among whom three patients presented with neurodevelopmental delay. <i>MACF1</i> was expressed throughout the lifespan, with three major peaks in the fetal, early childhood and adulthood stages, consistent with seizure onset ages of the patients. The highest expression in adulthood was in the thalamus nucleus, potentially associated with the pathogenesis of generalised epilepsy. The single-cell sequencing in organoids showed <i>MACF1</i> is widely expressed in the developing brain, especially in the early stage, suggesting a vital role in neurodevelopment. Genotype-phenotype association analysis revealed that LIS9-associated variants were featured by de novo monoallelic variants clustered within the C-terminal; the autism spectrum disorder-associated variants were mainly de novo monoallelic variants located at the spectrin-repeat rod domains. In contrast, the epilepsy-associated variants were biallelic missense variants, and those in the plakin domain were potentially associated with neurodevelopment delay.</p><p><strong>Significance: </strong><i>MACF1</i> is potentially a novel causative gene of generalised epilepsy.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"484-493"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021446","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":"Rare missense variants in <i>FNDC1</i> are associated with severe adolescent idiopathic scoliosis.","authors":"Wu-Lin Charng, Gabe Haller, Julia Whittle, Momchil Nikolov, Addison Avery, Jose Morcuende, Philip Giampietro, Cathy Raggio, Nancy Miller, Anne E Justice, Natasha T Strande, Mark Seeley, Dale L Bodian, Carol A Wise, Diane S Sepich, Matthew B Dobbs, Christina A Gurnett","doi":"10.1136/jmg-2024-110586","DOIUrl":"10.1136/jmg-2024-110586","url":null,"abstract":"<p><strong>Background: </strong>Scoliosis is the most common paediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve >35 degrees) are largely unknown.</p><p><strong>Methods: </strong>To explore the role of rare variants in severe AIS, exome sequence data from 1221 individuals with AIS were compared with both 1397 in-house European ancestry controls and 56885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritised genes was performed in additional family members. A replication study was performed using the Geisinger MyCode cohort. <i>FNDC1</i> function was investigated in <i>fndc1</i> null mutant zebrafish.</p><p><strong>Results: </strong>Rare variants were enriched in 84 genes, including <i>RAF1</i> (Noonan syndrome), <i>FBN1</i> (Marfan syndrome) and <i>FNDC1,</i> in individuals with severe AIS. <i>FNDC1</i>, which had previously been associated with joint hypermobility, harboured missense variants in 4.0% of individuals with AIS compared with 2.3% of controls (p=0.00764, OR=1.78). <i>FNDC1</i> variants segregated with AIS in five multiplex families with incomplete penetrance. In addition, <i>FNDC1</i> rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the <i>fndc1</i> locus in zebrafish resulted in increased bone mineral density.</p><p><strong>Conclusion: </strong>We broadened the phenotype associated with <i>RAF1</i> and <i>FBN1</i> variants and identified <i>FNDC1</i> as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of <i>FNDC1</i> missense variants with AIS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"427-435"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electronic health record-based registry for identification of individuals at risk for hereditary cancer syndromes.","authors":"Vinit Singh, Thomas E Rafter, Mohamad Sharbatji, Jing Liu, Quiana Brown, Karina Brierley, Claire Healy, Rosa M Xicola, Nitu M Kashyap, Xavier Llor","doi":"10.1136/jmg-2025-110718","DOIUrl":"10.1136/jmg-2025-110718","url":null,"abstract":"<p><strong>Background: </strong>Despite well-established criteria for genetic testing to rule out hereditary cancer syndromes (HCSs), most pathogenic variant (PV) carriers are not being tested. Thus, mechanisms that allow for better identification and a streamlined process for testing need to be implemented. The main purpose was to develop a self-updating, guideline-driven tool integrated with the electronic health record (EHR) to prospectively identify at-risk individuals and facilitate outreach and diagnosis.</p><p><strong>Methods: </strong>National Comprehensive Cancer Network/American College of Medical Genetics criteria for genetic testing were translated into three distinct rule-based conditional logic statements in the EHR from 218 rules that serially evaluate each aspect of individual criteria, which together roll up into a logic statement of 'at-risk'. The rules evaluate personal or family history, determine age at onset and categorise family relationships. This tool is applied to a system-wide registry of active patients.</p><p><strong>Results: </strong>Out of 1 325 545 individuals, 59 377 (4.48%) were identified as at-risk and thus constitute the At-Risk Cancer Genetic Syndrome Identification (ARCAGEN-ID) registry. Of those, only 12 377 (20.9%) had previously been evaluated, and 2506 had a PV. ARCAGEN-ID appropriately included 96.2% of cases. ARCAGEN-ID individuals not previously evaluated were more often included based on family history criteria (79.8% vs 49.3%), and less often because of both personal and family history of cancer (13% vs 41%) (p<0.001).</p><p><strong>Conclusions: </strong>This study is the first to use an EHR-based registry for the automatic and prospective identification of individuals eligible for genetic testing based on current criteria for all major HCS. By streamlining the identification process, this approach has the potential to dramatically increase diagnostic rates and improve cancer-related survival.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"457-463"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996437","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":"Short stature, brachydactyly and joint contractures associated with novel <i>FBN2</i> variants in two families.","authors":"Petra Loid, Fan Wang, Otto Lennartsson, Mari Muurinen, Alice Costantini, Sakshi Vats, Maria Lodefalk, Ola Nilsson, Outi Mäkitie","doi":"10.1136/jmg-2024-110533","DOIUrl":"10.1136/jmg-2024-110533","url":null,"abstract":"<p><strong>Background: </strong>Fibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by <i>FBN2</i>, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly.</p><p><strong>Methods and results: </strong>We recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the <i>FBN2</i> gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9-11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The <i>FBN2</i> deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain.</p><p><strong>Conclusion: </strong>Our findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of <i>FBN2-</i>related phenotypes. The study supports the role of <i>FBN2</i> variants in growth failure and expands the molecular spectrum of <i>FBN2</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"436-440"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811499","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":"Phenotypic heterogeneity in <i>DYNC2H1</i>-related short-rib thoracic dysplasia: antenatal indicators and postnatal outcomes.","authors":"Nikhil Pattani, Nour Elkhateeb, Aakash Joshi, Juan Carlos Del Rey Jimenez, Joy L Barber, Pilar Palmrich, Helen Firth, Sarju G Mehta, Leila Amel Riazat Kesh, Jennifer Campbell, Jenny Carmichael, Sahar Mansour","doi":"10.1136/jmg-2024-110369","DOIUrl":"10.1136/jmg-2024-110369","url":null,"abstract":"<p><strong>Introduction: </strong><i>DYNC2H1</i>-related short-rib thoracic dysplasia with/without polydactyly (SRTD), formerly asphyxiating thoracic dystrophy-Jeune syndrome, is a rare genetic skeletal disorder characterised by a narrow thorax, short ribs, shortened long bones and brachydactyly/polydactyly. <i>DYNC2H1</i>-related SRTD shows significant phenotypic variability. There is limited information regarding correlations between genotypes, antenatal ultrasound findings and clinical phenotypes and severity.</p><p><strong>Methods: </strong>A retrospective study of confirmed <i>DYNC2H1</i>-related SRTD cases was conducted through paper and digital medical records. Data collected included patient demographics, initial presentation, postnatal progression, childhood follow-up, antenatal ultrasound imaging, postnatal skeletal surveys and genetic variant analysis.</p><p><strong>Results: </strong>Nine individuals from eight families across three tertiary genetic centres in England were included in the study. Eight presented in the antenatal period (gestation 14-36 weeks) and one in the postnatal period at 6 weeks. All nine displayed a narrow thorax and eight displayed shortened long bones (humerus and/or femur). Polydactyly was less common and seen in only four individuals. Phenotypic severity was variable, including mild (n=4), moderate requiring respiratory support (n=2) and severe/lethal (n=3) cases. Earlier antenatal presentation and more significant femur shortening and bowing were predictive of poor postnatal prognosis, and there were no clear genotype-phenotype correlations. We also report seven novel <i>DYNC2H1</i> variants, not previously reported.</p><p><strong>Conclusion: </strong><i>DYNC2H1</i>-related SRTD exhibits significant phenotypic variability which cannot be reliably predicted by genotype but has some correlation with time of gestational presentation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"476-483"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010606","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 <i>SIDT2</i> loss-of-function in a child with cerebellar ataxia and lysosomal dysfunction mimics impairment of <i>SIDT2</i> in mice.","authors":"Tan Nguyen, Grace Yoon, Blake R C Smith, Martine Tétreault, Jeiwook Chae, Sean Massey, Simranpreet Kaur, John Christodoulou, Craig P Hunter, Ken C Pang","doi":"10.1136/jmg-2025-110654","DOIUrl":"10.1136/jmg-2025-110654","url":null,"abstract":"<p><p>SIDT2 (Systemic Interference Deficient 1 Transmembrane Family Member 2) is a lysosomal membrane protein involved in RNA degradation via RNAutophagy. While animal models have indicated a link between SIDT2 deficiency and lysosomal storage disorders, no human cases have been reported. Here, we report a child with biallelic <i>SIDT2</i> missense variants (p.Arg529Trp, p.Arg678Trp), who developed progressive neurological decline with cerebellar atrophy and Parkinsonian features. Functional studies revealed that the affected individual's variants disrupted the ability of SIDT2 to interact with RNA. Fibroblasts from the affected individual showed impaired autophagy, characterised by abnormal accumulation of autophagy markers. In mouse models, Sidt2 was found to be highly expressed in the brain, particularly in the hippocampus and cerebellum. Sidt2 loss-of-function in mice resulted in not only impaired autophagy in the brain but also neurological dysfunction, including motor incoordination and eventual seizures. These findings suggest that SIDT2 deficiency contributes to both autophagic dysfunction and neurodegenerative processes, providing insight into a potential role in human neurological disease.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336688","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":"Reproductive decision-making and pregnancy in germline <i>CDH1</i> variant carriers.","authors":"Amber Famiglietti Gallanis, Cassidy Bowden, Rachael Lopez, Jessica Turner, Grace-Ann Fasaye, Shruthi Reddy Perati, Jonathan M Hernandez, Andrew Blakely, Jeremy L Davis","doi":"10.1136/jmg-2025-110857","DOIUrl":"10.1136/jmg-2025-110857","url":null,"abstract":"<p><strong>Background: </strong>Diagnosis of a hereditary cancer syndrome may impact family planning, particularly in reproductive age individuals. Factors influencing reproductive decision-making are understudied in individuals with germline <i>CDH1</i> pathogenic or likely pathogenic (P/LP) variants.</p><p><strong>Methods: </strong>We characterised reproductive decision-making and perinatal outcomes in 121 individuals aged 18-49 with hereditary diffuse gastric and lobular breast cancer syndrome due to a germline <i>CDH1</i> P/LP variant.</p><p><strong>Results: </strong>Half of individuals (50%, 60/121) reported their <i>CDH1</i> diagnosis impacted family planning. Psychosocial and economic barriers to reproduction were encountered by 47% (56/119) of patients. Additionally, 12% (15/121) of individuals delayed pregnancy to prioritise personal cancer risk management with either endoscopic surveillance, prophylactic total gastrectomy (PTG) or mastectomy. Women were more likely to experience guilt about passing their <i>CDH1</i> variant to offspring compared with men. Perinatal and fetal outcomes were investigated in six women who gave birth at a median time of 24 months (IQR 20-44) after PTG. Maternal micronutrient deficiencies were not uncommon in pregnant women after PTG despite compliance with a bariatric, prenatal multivitamin. Majority of women who became pregnant after PTG reported worsening post-gastrectomy syndromes. Most infants (90%, 9/10) born after PTG were full-term and no fetal complications were reported.</p><p><strong>Conclusion: </strong>Reproductive decision-making is complex in individuals with germline <i>CDH1</i> variants, who often encounter psychosocial and physical challenges during family planning and pregnancy. However, successful pregnancy is possible after PTG with the guidance of a multidisciplinary team including maternal fetal medicine specialists and a registered dietitian.</p><p><strong>Trial registration number: </strong>NCT03030404.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336689","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":"Integration of genetic counselling into a multidisciplinary urological oncology programme enhances access and detection of hereditary prostate cancer syndromes.","authors":"Lindsey Byrne, Mckenna G Lewis, Shihua Wang, Steven K Clinton","doi":"10.1136/jmg-2025-110755","DOIUrl":"https://doi.org/10.1136/jmg-2025-110755","url":null,"abstract":"<p><strong>Background: </strong>Advances in prostate cancer (PCa) research have revealed dozens of genetic markers for inherited risk. Germline genetic testing (GGT) enhances patient care by guiding therapeutic decisions and promoting screening and surveillance for men and their families. We evaluated the impact of embedding a genitourinary (GU) specialised genetic counsellor (GC) into a multidisciplinary GU clinic on counselling referrals, genetic risk assessment and GGT uptake for men with PCa.</p><p><strong>Methods: </strong>A chart review of 2593 individuals with PCa from 2016 to 2022 was performed. Categorical data were analysed by the χ² test and predictors were identified by logistic regression.</p><p><strong>Results: </strong>Prior to the integration of a GU GC (2016-2018), 39 men were referred for genetic counselling (2%), which increased to 368 men (14%) during 2019-2022. During the pre-embedment period, GGT was completed in 9 out of 39 (23%) referrals, whereas GGT was completed in 235 out of 368 referrals (64%) in the postembedment period. Individuals with a younger age (p<0.0001), family history of PCa (p<0.0001), higher Gleason Score (p<0.0001), more advanced clinical stage (p<0.0001), metastatic disease (p<0.0001), and meeting National Comprehensive Cancer Network guidelines for prostate GGT (p<0.0001) were more likely to be referred. Forty-one tested positive for one or more pathogenic or likely pathogenic variants (17%).</p><p><strong>Conclusions: </strong>The integration of a GC dramatically increased referrals, and a greater proportion of individuals proceeded with GGT. Future studies will analyse barriers and factors promoting referrals so that individuals and their families benefit from evidence-based treatment and early detection and prevention options.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325991","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":"Correction: Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals.","authors":"","doi":"10.1136/jmg-2023-109702.corr1","DOIUrl":"https://doi.org/10.1136/jmg-2023-109702.corr1","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317081","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":"The γ-Actin with pathogenic variants of sites on actin-binding proteins caused earlier onset and more malignant progressive hearing loss.","authors":"Sijun Li, Qi Feng, Lingyun Mei, Shuai Zhang, Jian Song, Yong Feng, Xuewen Wu","doi":"10.1136/jmg-2024-110573","DOIUrl":"https://doi.org/10.1136/jmg-2024-110573","url":null,"abstract":"<p><strong>Background: </strong>The γ-actin protein, encoded by the <i>ACTG1</i> gene, is a critical cytoskeletal component in non-muscle cells. Mutations in <i>ACTG1</i> are associated with autosomal dominant, progressive sensorineural hearing loss (HL), but clinical heterogeneity remains poorly understood.</p><p><strong>Methods: </strong>We identified a novel missense variant, c.981C>G (p.Ile327Met; I327M), in a Chinese family with hereditary HL through whole exome sequencing. Functional analyses were performed to assess <i>ACTG1</i> mRNA and protein expression, F-actin organisation and subcellular localisation. Structural modelling and electrostatic analysis were used to predict the impact of the I327M substitution. Additionally, we reviewed 35 published <i>ACTG1</i>-related families involving 82 patients to explore genotype-phenotype correlations.</p><p><strong>Results: </strong>The I327M variant resulted in significantly reduced <i>ACTG1</i> transcript and protein levels, accompanied by disrupted F-actin integrity in patient-derived peripheral blood mononuclear cells. Structural modelling suggested that the variant alters the electrostatic environment near the tropomyosin-binding interface, potentially compromising filament stability. Literature review and comparative analysis revealed that variants located within actin-binding protein (ABP) interaction sites were associated with an earlier onset and more severe progression of HL compared with those located outside ABP-binding domains.</p><p><strong>Conclusion: </strong>The c.981C>G (p.Ile327Met) variant contributes to HL pathogenesis through dual mechanisms involving impaired gene expression and filament destabilisation. This study highlights the clinical relevance of variant location relative to ABP binding regions and provides new insights into genotype-phenotype relationships in <i>ACTG1</i>-associated HL.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317082","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}