BMC Medical Genomics最新文献

{"title":"Novel compound heterozygous DOCK6 variants expand the mutational spectrum in prenatal diagnosis of Adams-Oliver syndrome 2.","authors":"Xue Zhong, Xuan Zheng, Yinglei Xv, Kangxi Cai, Qianqian Wang, Shiguo Liu","doi":"10.1186/s12920-025-02157-w","DOIUrl":"10.1186/s12920-025-02157-w","url":null,"abstract":"<p><strong>Background: </strong>Adams-Oliver syndrome (AOS) is a rare developmental disorder, and the DOCK6 gene is an identified AOS gene. This report highlights the prenatal diagnosis of AOS-2 by ultrasonography and genetic testing.</p><p><strong>Methods: </strong>A growth-restricted fetus with bilateral ventriculomegaly, paraventricular calcifications, and ventricular septal defect underwent trio-whole-exome sequencing (trio-WES). Functional validation of the splice-altering variant was performed via minigene assays and protein structural modeling.</p><p><strong>Results: </strong>Trio-WES revealed compound heterozygous DOCK6 variants: a paternal frameshift (c.3190_3191del; p. Leu1064Valfs60) and a maternal splice-site variant (c.3241-1G > T). Minigene assays demonstrated that c.3241-1G > T caused intron 26 retention (486 bp), introducing a premature termination codon (p. Val1081Glufs37). Structural modeling confirmed the loss of critical DHR2 domains in both truncated proteins.</p><p><strong>Conclusions: </strong>This study expands the mutational spectrum of DOCK6 and underscores the importance of combining prenatal imaging with functional genomics for early diagnosis of AOS2.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"104"},"PeriodicalIF":2.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosomal instability by low-coverage whole-genome sequencing assay predicts prognosis in bladder cancer patients underwent radical cystectomy.","authors":"Qi Ding, Hailiang Zhu, Bo Fan, Lisheng Wang, Xiaohua Jin, Cheng Cao, Ying Shi, Zhijiang Fan, Wenjian Tu, Feng Li","doi":"10.1186/s12920-025-02172-x","DOIUrl":"10.1186/s12920-025-02172-x","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate chromosomal instability (CIN) in tumor tissue from radical bladder resection and to evaluate whether it can be used as a biomarker for the molecular typing of (BC).</p><p><strong>Methods: </strong>DNA was extracted from formalin-fixed paraffin-embedded samples of 50 BC patients who were followed up to March 23 2023 using the Qiagen nucleic acid kits. We analyzed CIN in tumor of bladder by low-coverage whole genome sequencing (LC-WGS). Kaplan-Meier log-rank test was used to perform survival analysis. The association between variables and overall and progression-free survival was analyzed using the Cox proportional hazards model.</p><p><strong>Results: </strong>There were 44 genome segments with statistically significant changes in copy number. CIN was significantly correlated with tumor stage, lymph node metastasis, relapse and survival status. Patients with high CIN were found to have a worse survival, with a median overall survival (OS) of 15 months. In addition, patients with high CIN were more likely to relapse, with a median progression-free survival (PFS) of 7 months. Patients with low CIN showed better OS and PFS. However, there was no significant difference in OS and PFS between T2 and T3-T4 patients. Multivariate cox regression analysis showed that high CIN was an independent predictor of OS, and high CIN and muscle invasion were independent predictors of PFS. Furthermore, patients with abnormal copy number of a single chromosome also had a poor prognosis, with a median survival of 14-30 months for OS and 5-10 months for PFS, while negative patients had a better prognosis.</p><p><strong>Conclusion: </strong>CIN was significantly correlated with tumor stage, lymph node metastasis, relapse and survival status of BC. Patients with high CIN or abnormal copy numbers of a single chromosome have a poor prognosis. CIN might be better than T stage in predicting the prognosis of patients with BC. Molecular typing of CIN can be used as an independent prognostic factor for BC.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"103"},"PeriodicalIF":2.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ABO exon polymorphisms are related to ischemic stroke in a Chinese Han population.","authors":"Yi Zhong, Mei Lin, Xiaoli Zhou, Chanyi He, Qi Lin, Quanni Li, Yipeng Ding","doi":"10.1186/s12920-025-02170-z","DOIUrl":"10.1186/s12920-025-02170-z","url":null,"abstract":"<p><strong>Background: </strong>Recent research have underscored the relation of ABO blood group system to cerebrovascular disorders predisposition. The present investigation endeavors to delve into the relationship between ABO polymorphisms and ischemic stroke (IS) risk.</p><p><strong>Methods: </strong>A cohort of 646 IS patients and 649 matched healthy controls was recruited. Genotyping of five SNPs within ABO were conducted by Agena MassARRAY platform. Logistic regression models were employed to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Additionally, SNP-SNP interaction was assessed by multifactor dimensionality reduction (MDR) method. Furthermore, Analysis of Variance (ANOVA) was utilized to explore the association between genotypes and blood lipid profiles.</p><p><strong>Results: </strong>The study identified an elevated IS risk associated with rs8176740 and rs8176720 in the overall population. Notably, ABO rs8176720 emerged as the most informative single-locus model for IS susceptibility. These variants were related to an elevated IS risk, specifically in female subjects, the subgroup aged > 64 years, non-smokers, drinkers or non-drinkers. Moreover, rs8176749 and rs8176745 were associated with red blood cell count levels and total bilirubin levels.</p><p><strong>Conclusion: </strong>This study firstly demonstrated the association of ABO rs8176740 and rs8176720 with IS incidence, which increased the understanding regarding the effect of ABO on IS pathogenesis.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"102"},"PeriodicalIF":2.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania.","authors":"Zhi Ming Xu, Michaela Zwyer, Hellen Hiza, Sarah Schmidiger, Mohamed Sasamalo, Miriam Reinhard, Anna Doetsch, Sonia Borrell, Olivier Naret, Sina Rüeger, Dylan Lawless, Simon Tang, Faima Isihaka, Hosiana Temba, Thomas Maroa, Rastard Naftari, Christian Beisel, Jerry Hella, Klaus Reither, Daniela Brites, Damien Portevin, Sebastien Gagneux, Jacques Fellay","doi":"10.1186/s12920-025-02164-x","DOIUrl":"10.1186/s12920-025-02164-x","url":null,"abstract":"<p><p>The risk and prognosis of tuberculosis (TB) are influenced by a complex interplay between human and bacterial genetic factors. While previous genomic studies have largely examined human and bacterial genomes separately, we adopted an integrated approach to uncover host-pathogen interactions. We leveraged paired human and Mycobacterium tuberculosis (M.tb) genomic data from 1000 adult TB patients from Tanzania and used a \"genome-to-genome\" approach to search for associations between human and M.tb genetic variants and to identify interacting genetic loci. Our analyses revealed two significant host-pathogen genetic associations. The first significant association (p = 4.7e-11) links a human intronic variant in PRDM15 (rs12151990), a gene involved in apoptosis regulation, with an M.tb variant in Rv2348c (I101M), which encodes a T cell-stimulating antigen. The second significant association (p = 6.3e-11) connects a human intergenic variant near TIMM21 and FBXO15 (rs75769176) - also associated with TB severity (p = 0.04) - with an M.tb variant in FixA (T67M). While FBXO15 is involved in the regulation of antigen processing and TIMM21 affects mitochondrial function, FixA's role remains undefined due to limited functional characterization. Additionally, we observed that a group of M.tb T cell epitope variants were significantly associated with HLA-DRB1 variation, suggesting that, despite their rarity, certain epitopes may still be subjected to immune selective pressure. Together, these findings identify previously unknown sites of genomic conflicts between humans and M.tb, advancing our understanding of how this pathogen evades selection pressure and persist in human populations.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"99"},"PeriodicalIF":2.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MDA5 variants trade antiviral activity for protection from autoimmune disease.","authors":"Chris Wallace, Rahul Singh, Yorgo Modis","doi":"10.1186/s12920-025-02171-y","DOIUrl":"10.1186/s12920-025-02171-y","url":null,"abstract":"<p><p>Loss-of-function variants in MDA5, a key sensor of double-stranded RNA from viruses and retroelements, have been associated with protection from type 1 diabetes (T1D) in genome-wide association studies (GWAS). MDA5 loss-of-function variants have also been reported to increase the risk of inflammatory bowel disease (IBD). Whether these associations are linked or extend to other diseases remains unclear. Here, fine-mapping analysis of four large GWAS datasets shows that T1D-protective loss-of-function MDA5 variants also protect against psoriasis and hypothyroidism, while increasing the risk of IBD. The degree of autoimmune protection and IBD risk were linearly proportional. The magnitudes of the odds ratios for autoimmune protection and IBD risk were larger for rare MDA5 variants than for common variants, which were differentially expressed in different geographic populations. Our analysis suggests MDA5 genetic variants offer a direct fitness trade-off between viral clearance and autoimmune tissue damage.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"101"},"PeriodicalIF":2.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of genetic factors of humans, mosquitoes and parasites, on the evolution of Plasmodium falciparum infections, malaria transmission and genetic control methods: a review of the literature.","authors":"Seni Nikiema, Issiaka Soulama, Gifty Dufie Ampofo, Moustapha Nikiema, Abdou Azaque Zouré, Salif Sombié, Salam Sawadogo, Nicolas Ouedraogo, Samuel Sindie Sermé, Haffsatou Sawadogo, Raïssa Ily, Guillène Y N Tibiri, Djamila O A Zouré, Nassandba Julien Yanogo, Farida C A Kaboré, Chanolle Tchekounou, Adama Zida, Issoufou Tao, Oumarou Ouedraogo, Dramane Zongo, Florencia Wendkuuni Djigma, Alfred B Tiono, Sodiomon B Sirima, Athanase Badolo, Jacques Simporé","doi":"10.1186/s12920-025-02165-w","DOIUrl":"10.1186/s12920-025-02165-w","url":null,"abstract":"<p><p>Despite significant progress, malaria remains a public health problem in many regions, particularly in sub-Saharan Africa. This situation is partly explained by the mosquito's resistance to insecticides and the emergence of parasite resistance to antimalarial drugs. Indeed, in spite of the various vectors' controls, insecticide resistance emerges from multi-generational selection and poses worldwide concern. In parallel, artemisinin resistance unfortunately emerged independently in multiple countries in eastern Africa. Since 2014, artemisinin resistance has been observed in 6 countries in Africa and, more concerningly, the evidence from longitudinal molecular surveys in these countries suggests that it is spreading. While phenotypic evidence of treatment failure is still limited, the increasing reports of validated artemisinin resistance mutations are alarming. Unlike the emergence of artemisinin resistance in South-East Asia, our understanding of the genetic determinants of artemisinin resistance and our ability to sequence and map the spread of resistance are significantly greater. In addition to mosquito and parasite genetics affecting malaria evolution, many human individual variants have been identified that are associated with malaria protection, but the most important of all relates to the structure or function of red blood cells, the classical polymorphisms that causes sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. In that biological complex context, there is a need to characterize the various genetic factors in Plasmodium falciparum, humans and mosquitoes that are potentially associated with resistance to antimalarial drugs and insecticides, and their involvement in the evolution, severity and transmission of malaria. In this direction, A comprehensive literature review was conducted to capture the objectives highlighted above. The advances in genomic surveillance and emerging genetic control strategies, such as gene drive technology were also considered in this review. We used search engines such as PubMed and Google scholar to retrieve articles useful to the objective of this paper and information on the knowledge of genetic factors and methods that contributed to malaria control were synthesized.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"100"},"PeriodicalIF":2.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome.","authors":"Amika Singla, Carolyn Rogers, Mary-Joe Touma, Yassin El-Najjar, Alison Colley, Daniel J Boesch, Daniel D Billadeau, Jozef Gecz, Baoyu Chen, Ezra Burstein","doi":"10.1186/s12920-025-02168-7","DOIUrl":"10.1186/s12920-025-02168-7","url":null,"abstract":"<p><p>The CCC complex, composed of CCDC22, CCDC93, and ten proteins of the COMMD family, coordinates several critical steps required to recycle internalized plasma membrane proteins from endosomes to the cell surface. CCC interacts with Retriever, a trimeric cargo recognition complex comprising VPS35L, VPS26C, and VPS29, and works closely with the WASH complex, a crucial regulator of branched actin polymerization at endosomal membranes. Mutations in genes encoding subunits of these three complexes, CCDC22, VPS35L, and WASHC5, have been linked with a developmental syndrome known as 3 C (cranio-cerebello-cardiac) or Ritscher-Schinzel syndrome. Here, we report a new CCDC22 missense mutation, p.E208K, that results in attenuated 3 C syndrome, without cardiac or neuroanatomical abnormalities. We show that this mutation impairs CCC complex assembly by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding. We also review previously described cases and identify that CCDC22 p.P172R has a similar attenuated phenotype and impairs complex assembly in a similar fashion as p.E208K. The characterization of these mutations adds to our understanding of the clinical and molecular spectrum of these disorders.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"98"},"PeriodicalIF":2.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining three dimensional chromatin structures of pediatric and adolescent B cells using primary B cell and EBV-immortalized B cell reference genomes.","authors":"Kaiyu Jiang, Yao Fu, Jennifer A Kelly, Patrick M Gaffney, Lucy C Holmes, James N Jarvis","doi":"10.1186/s12920-025-02166-9","DOIUrl":"10.1186/s12920-025-02166-9","url":null,"abstract":"<p><strong>Background/purpose: </strong>Knowledge of the 3D genome is essential to elucidate genetic mechanisms driving autoimmune diseases. The 3D genome is distinct for each cell type, and it is uncertain whether cell lines faithfully recapitulate the 3D architecture of primary human cells or whether developmental aspects of the pediatric immune system require use of pediatric samples. We undertook a systematic analysis of B cells and B cell lines to compare 3D genomic features encompassing risk loci for juvenile idiopathic arthritis (JIA), systemic lupus (SLE), and type 1 diabetes (T1D).</p><p><strong>Methods: </strong>We isolated B cells from four healthy individuals, ages 9-17. HiChIP was performed using a CTCF antibody, and CTCF peaks were called within each sample separately. Peaks observed in all four samples were identified. CTCF loops were called within the pediatric samples using three CTCF peak datasets: 1) self-called CTCF consensus peaks called within the pediatric samples, 2) ENCODE's publicly available GM12878 CTCF ChIP-seq peaks, and 3) ENCODE's primary B cell CTCF ChIP-seq peaks from two adult females. Differential looping was assessed within the pediatric samples and each of the three peak datasets.</p><p><strong>Results: </strong>The number of consensus peaks called in the pediatric samples was similar to that identified in ENCODE's GM12878 and primary B cell datasets. We observed < 1% of loops that demonstrated significantly differential looping between peaks called within the pediatric samples themselves and when called using ENCODE GM12878 peaks. Significant looping differences were even fewer when comparing loops of the pediatric called peaks to those of the ENCODE primary B cell peaks. When querying loops found in juvenile idiopathic arthritis, type 1 diabetes, or systemic lupus erythematosus risk haplotypes, we observed significant differences in only 2.2%, 1.0%, and 1.3% loops, respectively, when comparing peaks called within the pediatric samples and ENCODE GM12878 dataset. The differences were even less apparent when comparing loops called with the pediatric vs ENCODE adult primary B cell peak datasets.</p><p><strong>Conclusion: </strong>The 3D chromatin architecture in B cells is similar across pediatric, adult, and EBV-transformed cell lines. This conservation of 3D structure includes regions encompassing autoimmune risk haplotypes. Thus, even for pediatric autoimmune diseases, publicly available adult B cell and cell line datasets may be sufficient for assessing effects exerted in the 3D genomic space.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"97"},"PeriodicalIF":2.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Different mutations in TBL1XR1 lead to diverse phenotypes of neurodevelopmental disorder: two case reports.","authors":"Linlin Wei, Yonghui Yang, Tiejia Jiang, Chaolang Zhang, Cuiying Chen, Mingwei Huang, Nannan Li, Huachun Xiong, Feng Gao","doi":"10.1186/s12920-025-02169-6","DOIUrl":"10.1186/s12920-025-02169-6","url":null,"abstract":"<p><p>The TBL1XR1 gene (Transducin beta-like 1X-linked receptor 1) is responsible for encoding the TBL1XR1 protein, an important component of the NCoR and SMRT corepressor complexes. 48 missense variants of the TBL1XR1 gene have been reported, which are associated with various phenotypes of neurodevelopmental disorders, including West syndrome, Pierpont syndrome, and others. However, given the important role of TBL1XR1 in neurological diseases, it is still necessary to further explore the variation of TBL1XR1. In this study, we present two patients with distinct variants and phenotypes. Patient 1 exhibits global developmental delay, intellectual disability, delayed language development, and seizures. While patient 2 displays mild facial dysmorphism, significant developmental delay, feeding difficulties, and increased muscle tone. Through trio whole-exome sequencing, two novel pathogenic variants in the TBL1XR1 gene were identified: A heterozygous NM_024665.6:c.940G > T (p.Val314Phe) variant in patient 1 and a heterozygous NM_024665.6:c.1387G > T (p.Asp463Tyr) in patient 2. Discovery of these two novel variant sites expands the mutation spectrum associated with the TBL1XR1 gene.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"96"},"PeriodicalIF":2.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of a novel LYST mutation in a Tunisian patient with Chediak-Higashi syndrome.","authors":"Yessine Amri, Saoussen Chouchene, Hajer Foddha, Amani Abderahmene, Ikbel Kooli, Adnen Toumi, Kawthar Hadj Khalifa, Rihem Mezrigui, Taieb Messaoud, Mohsen Hassine, Rym Dabboubi","doi":"10.1186/s12920-025-02145-0","DOIUrl":"10.1186/s12920-025-02145-0","url":null,"abstract":"<p><strong>Background: </strong>Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking.</p><p><strong>Objective: </strong>This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient's clinical presentation.</p><p><strong>Methods: </strong>A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient's blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations.</p><p><strong>Results: </strong>The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein's C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking.</p><p><strong>Conclusion: </strong>The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"95"},"PeriodicalIF":2.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}