Human Genomics最新文献

{"title":"National genomic projects in Asia and Africa: a review.","authors":"Aisha Hanaya Alsuwaidi, Mira Mousa, Michael Olbrich, Nour Al Dain Marzouka, Inken Wohlers, Saleh Ibrahim, Habiba Alsafar","doi":"10.1186/s40246-026-01007-9","DOIUrl":"10.1186/s40246-026-01007-9","url":null,"abstract":"<p><p>National genome projects (NGPs) are increasingly shaping precision medicine by improving representation of population-specific genetic diversity. This review compiles findings from NGPs across Asia and Africa, regions that remain underrepresented in global genomic databases despite their extensive demographic and genetic diversity. A total of 53 studies from 24 countries were identified to understand (1) the genomic approach utilized, (2) novel findings that have emerged, and (3) strategies for improving research in these regions. The NGPs implement population-based variome databases (20 NGPs), linear reference genome assemblies (8 NGPs), and graph-based pangenome assemblies (1 NGP). Novel variants ranged between 0.28% (China) and 19.6% (Iran), whereas rare variants accounted for up to 88.9% of the detected variants in the Chinese population. Each NGP documents its country's evolutionary and migration history, which impacts disease frequency and pharmacogenomic variants. Clinically, NGPs revealed strong population stratification in disease-associated and pharmacogenomic variants. For example, the GJB2 rs72474224 hearing-loss variant ranged from 13% in Vietnam and 12% in Hong Kong to 0.0894% in Turkey, while the VKORC1 rs9923231 pharmacogenomic variant reached 89.2% in Taiwan but was 20%-25% in European-related Russian subpopulations. These findings demonstrate that clinically relevant allele frequencies, pathogenicity assessments, and drug-response markers differ substantially across ancestries. This review highlights ongoing efforts and strategies to enhance the representativeness of genomic data through NGPs in Asia and Africa. We also suggest future directions for national projects, including integrating family-based studies, multi-omic data, and standardized pipelines to accelerate discovery and support the equitable implementation of precision medicine.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of whole-exome sequencing data from nearly 10,000 Iranian individuals: identification of recessive mitochondrial disease variants and proposal of a population-specific carrier screening panel.","authors":"Mohadeseh Fathi, Parvaneh Karimzadeh, Farzad Ahmadabadi, Damoun Nashta Ali, Narjes Jafari, Raheleh Tangestani, Shadab Salehpour, Toktam Moosavian, Soudeh Ghafouri-Fard, Mohammad Miryounesi","doi":"10.1186/s40246-026-01011-z","DOIUrl":"10.1186/s40246-026-01011-z","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial diseases, often stemming from recessive nuclear gene mutations, represent a heterogeneous group of disorders with significant morbidity and mortality. Carrier screening for these conditions is population-specific, yet data on the pathogenic variant burden in the Iranian population remain limited. This study aimed to analyze whole-exome sequencing (WES) data from 9989 Iranian individuals to identify the spectrum and frequency of recessive mitochondrial disease variants and to develop a population-specific carrier screening panel.</p><p><strong>Methods: </strong>We analyzed WES data from 9989 unrelated Iranian individuals. Variants in 1,564 nuclear genes associated with mitochondrial function were filtered for rarity (minor allele frequency < 0.01 in public databases), predicted pathogenicity, and recessive inheritance patterns (homozygous or compound heterozygous). Clinically relevant variants were manually curated, and carrier frequencies for significant recessive mitochondrial conditions were calculated.</p><p><strong>Results: </strong>Our analysis identified variants across 15 groups of mitochondrial-related nuclear genes in 345 individuals recognized as carriers. Of these, 123 variants (35.6%) were classified as Pathogenic, and 154 variants (44.6%) were classified as Likely Pathogenic according to ACMG guidelines.</p><p><strong>Conclusions: </strong>This study provides the first large-scale WES-derived assessment of recessive mitochondrial disease carrier burden in the Iranian population. The high estimated carrier rate supports implementing population-specific preconception screening. The results of this study can be used for design of targeted panels of nuclear mitochondrial genes to identify at-risk couples, facilitating genetic counseling and reproductive decision-making in Iran.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Replicating lipid micelles: a feasible precursor to the origin of life and the earliest appearance of genomes.","authors":"Daniel W Nebert, Zijuan Liu, Vasilis Vasiliou","doi":"10.1186/s40246-026-01005-x","DOIUrl":"10.1186/s40246-026-01005-x","url":null,"abstract":"<p><p>The most commonly accepted scenario of early Earth includes: creation of the universe around 13.8 Ga (Giga-annus; or 10⁹ years ago); establishment of our solar system ~ 4.60 Ga; and formation of Earth ~ 4.54 Ga. The earliest life forms on our planet so far observed to have existed, are microbes that left signals of their presence in rocks ~ 3.6 Ga - suggesting that Life forms existed within the first 940 million years after Earth's formation. However, an intriguing recent publication [1] infers that the last universal common ancestor (LUCA) likely existed by 4.2 Ga, and that the inferred LUCA had a genome of at least 2.5 Mb of DNA, encoding around 2,600 proteins; this suggests that sophisticated Life might have existed within the first 340 million years after Earth was formed. The commonly accepted geological history of early Earth suggests that the turbulent Hadean Eon lasted until 4.0 Ga, with the Late Heavy Bombardment (LHB) period occurring around 4.1 to 3.8 Ga. If Earth during the Hadean exhibited a molten surface, intense volcanic activity, and constant bombardment by asteroids and comets - how were sensitive molecules (e.g., nucleic acids, proteins) able to survive? Considering the \"Lipid First\" hypothesis [2], we propose that replicating lipid micelles are feasible candidates for having populated much of Earth's deep hydrothermal vents and turbulent surface within the first 340 million years of Earth's existence. These lipid micelles could therefore have provided a plausible form of \"protective capsules\" inside which early Life's sensitive molecules were able to evolve.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beckwith-Wiedemann spectrum exhibiting a 46,XY karyotype caused by genome-wide paternal uniparental heterodisomy: a case report.","authors":"Satoshi Hara, Tomohiko Sato, Osamu Shimokawa, Ritsuko Pooh, Yayoi Watanabe, Musashi Kubiura-Ichimaru, Hidenobu Soejima","doi":"10.1186/s40246-026-01009-7","DOIUrl":"10.1186/s40246-026-01009-7","url":null,"abstract":"<p><strong>Backgrounds: </strong>Patients with genome-wide paternal uniparental disomy (GWpUPD) usually exhibit clinical features of Beckwith-Wiedemann syndrome (BWS) and a 46,XX karyotype, with all chromosomes showing isodisomy. To date, male patients with GWpUPD and a complete 46,XY karyotype, specifically involving heterodisomy, have not been described.</p><p><strong>Results: </strong>We report a male infant exhibiting classical BWS clinical features. DNA methylation analyses showed paternal-specific methylation across multiple imprinted loci, suggesting GWpUPD. Genetic analysis of autosomes and sex chromosomes indicated two distinct paternal genomes in peripheral blood leukocytes, whereas a normal biparental genome was detected in other tissues under chimeric conditions. These findings indicated that the patient had genome-wide paternal uniparental heterodisomy (GWpUPhD). The SNP array revealed the presence of one copy of the X chromosome and one copy of the Y chromosome, the patient is a chimera composed of 46,XY biparental cells (with maternal X) and 46,XY GWpUPhD cells (with paternal X).</p><p><strong>Conclusions: </strong>This is the first report of a male patient with a GWpUPhD chimera. We propose a potential mechanism of GWpUPhD formation. Our findings expand the molecular spectrum of GWpUPD and provide valuable insights into its pathogenesis in chimeric conditions. Furthermore, the potential for clinical manifestations unique to 46,XY heterodisomy warrants careful long-term follow-up.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic responses in the human methylome to exertional heat exhaustion, heat injury, and heat stroke.","authors":"Brandon M Roberts, Ruoting Yang, Kari C Goodwin, Aarti Gautam, Stacy Miller, Ida Nela Crespo Rosales, David W DeGroot, Rasha Hammamieh, Nisha Charkoudian","doi":"10.1186/s40246-026-01008-8","DOIUrl":"10.1186/s40246-026-01008-8","url":null,"abstract":"<p><p>Exertional heat illness encompasses a continuum from heat exhaustion (EHE) to heat stroke (EHS), yet the molecular mechanisms remain poorly understood. DNA methylation offers a stable epigenetic signature linking environmental stress to gene regulation and long-term physiological outcomes. We profiled genome-wide DNA methylation in blood from active-duty service members hospitalized for EHE (n = 36), heat injury (EHI; n = 18), or EHS (n = 50). Blood was collected longitudinally and analyzed using the Illumina 850 K array, with normalization and time-course clustering (TCseq) to identify co-regulated CpG networks. Ingenuity Pathway Analysis was applied differentially methylated probes (p < 0.01, Δβ > 0.04). At diagnosis, both EHI and EHS shared hypomethylation in pathways regulating heat sensing, oxidative defense, and vascular tone. Over time, EHI exhibited adaptive methylation changes supporting neuronal repair, glucocorticoid regulation, and cytoskeletal stability. In contrast, EHS demonstrated sustained downregulation of metabolic and cardiovascular regulators, persistent inflammasome activation, and oxidative imbalance. Early patterns were shared between EHI and EHS, reflecting a common acute stress response, but later responses diverged: EHI showed partial epigenetic recovery, while EHS exhibited sustained metabolic suppression and inflammasome activation. These time-dependent methylation signatures identify potential molecular targets for promoting recovery and preventing long-term complications of heat illnesses.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variant-specific SF3B1 mutations drive distinct splicing and mitochondrial dysfunction in myelodysplastic neoplasms.","authors":"Andrea Hruštincová, Iva Trsová, David Kundrát, Monika Beličková, Monika Kaisrlíková, Jitka Veselá, Zdeněk Krejčík, Alžběta Hlaváčková, Jiří Suttnar, Hana Štufková, Nikol Volfová, Hana Hansíková, Tatiana Aghová, Zuzana Zemanová, Anna Jonášová, Jaroslav Čermák, Markéta Šťastná Marková, Michaela Dostálová Merkerová","doi":"10.1186/s40246-026-01000-2","DOIUrl":"10.1186/s40246-026-01000-2","url":null,"abstract":"<p><strong>Background: </strong>SF3B1 spliceosome mutations are among the most common genetic lesions in myelodysplastic neoplasms (MDS). The canonical hotspot K700E variant is generally associated with a favorable prognosis, whereas the impact of other recurrent variants is poorly defined. We investigated the clinical, transcriptomic, and functional consequences of distinct SF3B1 mutations in MDS patients and isogenic cell models.</p><p><strong>Methods: </strong>Clinical data from 121 SF3B1-mutated MDS patients were analyzed. RNA sequencing was performed on CD34⁺ patient bone marrow cells and CRISPR-engineered NALM-6 lines harboring individual SF3B1 variants. Comprehensive profiling of splicing, gene expression, and mitochondrial bioenergetic parameters was performed.</p><p><strong>Results: </strong>Compared with K700E, the K666 variant was associated with shorter progression-free survival, distinct splicing abnormalities, and a higher frequency of retained introns, showing partial overlap with the H662 variant. Mitochondria-related genes were frequently mis-spliced and differentially expressed in K666-variant cells. In isogenic models, reduced complex IV activity and marked OXPHOS impairment were observed, with the most pronounced effects seen in K666N. Overall, SF3B1 variants confer heterogeneous biological and clinical effects. The K666N variant, in particular, is associated with adverse prognosis and profound bioenergetic dysfunction.</p><p><strong>Conclusions: </strong>These results support a refined view of SF3B1-mutated MDS as a biologically heterogeneous entity and suggest that variant-specific mitochondrial vulnerabilities may represent exploitable targets for precision-based therapeutic strategies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148277260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking exposure alters splicing of the nicotinic acetylcholine receptor subunit CHRNA5.","authors":"Maxwell H Hogshead, Atuahene Adu-Gyamfi, Brenen W Papenberg, Wusheng Yan, Chia-Han Lee, Oscar Florez-Vargas, Ludmila Prokunina-Olsson","doi":"10.1186/s40246-026-01004-y","DOIUrl":"10.1186/s40246-026-01004-y","url":null,"abstract":"<p><strong>Background: </strong>Cigarette smoking is the major preventable cancer risk factor. The missense variant rs16969968 (G > A, D398N) in exon 5 of CHRNA5 on chromosome 15q25.1 alters activity of the nicotinic acetylcholine receptor (α5-nAChR) and is associated with increased smoking intensity and cancer risk. We hypothesized that smoking exposure might affect alternative splicing of CHRNA5, which is mainly limited to exon 5, and thereby modulate genetic associations reported for rs16969968.</p><p><strong>Results: </strong>In human tissues and cell lines, we detected five main alternative CHRNA5 isoforms, each lacking 130-786 bp of exon 5, including the region with rs16969968. In tumors from The Cancer Genome Atlas (TCGA), only 52.4% of all exon 5 splice junctions corresponded to the full-length isoform. We modeled cigarette smoking exposure by treating cell lines representing smoking-related cancers - A549 (lung) and UMUC3 (bladder) - with cigarette smoke concentrate (CSC). Splicing of CHRNA5-exon 5 was evaluated in the context of a transiently expressed Exontrap-CHRNA5-exon5 minigene using long-read targeted cDNA sequencing and RT-qPCR. Long-term, but not short-term, smoking exposure significantly altered the relative abundance of several CHRNA5 splice isoforms, but independently of rs16969968 alleles.</p><p><strong>Conclusions: </strong>Smoking exposure can modulate CHRNA5 splicing and, consequently, the composition and function of α5-nAChR, the receptor regulating the response to smoking. Thus, smoking-induced alterations of CHRNA5-exon 5 splicing can influence nicotine dependence and cancer risk, acting both independently of and complementary to the genetic risk conferred by the rs16969968-A variant.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic evidence elucidates the mediating role of sex hormone-binding globulin in the causal relationship linking insomnia to carpal tunnel syndrome.","authors":"Junming Huang, Mingxing Chen, Song Zhou, Jun Liu, Jiangxi Li, Shanhu Huang, Zhiyuan Zou, Kui Deng","doi":"10.1186/s40246-026-01006-w","DOIUrl":"10.1186/s40246-026-01006-w","url":null,"abstract":"<p><strong>Background: </strong>Carpal tunnel syndrome (CTS) is the most prevalent type of entrapment neuropathy and is frequently associated with sleep disturbances. However, the directionality of this association remains ambiguous, necessitating an exploration of potential mediators. Sex hormone-binding globulin (SHBG) may affect the risk of CTS by modulating the sex hormone milieu within the carpal tunnel. This study seeks to elucidate the causal relationship between sleep disturbances and CTS and to assess the mediating role of SHBG.</p><p><strong>Method: </strong>Comprehensive summary-level data on sleep traits and CTS from Genome-wide association studies (GWAS) were gathered in this study. The causal analysis between sleep traits and CTS was carried out using two-sample MR. Additionally, two-step MR analysis was employed to study the mediating effect of SHBG on the causal relationship between sleep traits and CTS.</p><p><strong>Results: </strong>We examined the genetic causal relationships between nine sleep traits and CTS. Only insomnia genetically predicted the increased risk of CTS. The backward MR analyses showed no causal associations of CTS with any sleep traits. Exploratory mediation analysis suggested that SHBG may represent a putative partial explanatory pathway between insomnia and CTS, accounting for approximately 2.1% of the total association.</p><p><strong>Conclusion: </strong>This genetic evidence demonstrates that insomnia is an independent risk factor for CTS, with SHBG acting as a putative hormonal mediator or genetically correlated pathway in this relationship. The findings highlight sleep management as a potential preventive strategy for CTS and warrant mechanistic and clinical validation.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing reveals chemotherapy-induced apoptosis in acute myeloid leukemia via B cell depletion and M2 to M1 macrophage repolarization.","authors":"Di Zhou, Xue Bai, Chenchen Wang, Lintao Bi","doi":"10.1186/s40246-026-01001-1","DOIUrl":"10.1186/s40246-026-01001-1","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to investigate the dynamic changes of immune microenvironment in acute myeloid leukemia (AML) during chemotherapy, thereby, exploring the mechanism of chemotherapy resistance of AML.</p><p><strong>Methods: </strong>Single cell RNA sequencing (scRNAseq) was performed on 6 bone marrow samples from AML before or after chemotherapy (BC, AC) to obtain the fastq files. Bioinformatics analysis including GSEA, GSVA, pseudotime trajectory and cell chat analysis was used for constructing single-cell transcriptome and observing the dynamic changes of immune microenvironment. Western blot was carried out for validation.</p><p><strong>Results: </strong>A total of 11 cell subpopulations were obtained, among which B cells, HSCs, and TAMs were the significant changed between BC and AC groups. MCM7 gene was highly expressed in malignant cells, co-expressed with CD34 + pre B cells in BC groups, and decreased in AC group. The SPINK2 + B cells activated JAK-STAT pathway. Furthermore, we found that chemotherapy driven the transition for M2 to M1 in TAMs polarization.</p><p><strong>Conclusions: </strong>MCM7 and SPINK2 were the targeted genes in AML during chemotherapy, which help for providing a theoretical basis for combined immunotherapy/targeted-therapy strategies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148224871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening of autoinflammatory genes in patients with SARS-CoV-2-associated MIS-C.","authors":"Raquel Bispo São Pedro, Sâmek D Novaes, Thaís M M Barreto, Andréia S Silva, Ana L Nogueira, Ana P N Bellinat, Sara Nunes, Edson H B Amaral, Alana C M Lessa, Alberto O Moreira, Thayse S de Jesus, Bernardo Mirabal, Sandeep Tiwari, Thiago L P Castro, Natália M Tavares, Marcus V B Oliveira-Sá, Regina C F Ramos, Rodrigo F Carmo, Luydson R S Vasconcelos, Pablo R S Oliveira","doi":"10.1186/s40246-026-00985-0","DOIUrl":"10.1186/s40246-026-00985-0","url":null,"abstract":"<p><strong>Background: </strong>Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe complication of SARS-CoV-2 infection, characterized by systemic hyperinflammation. Evidence indicates innate immunity defects may predispose children to MIS-C. Host genetics may influence MIS-C susceptibility and severity, but underlying mechanisms remain incompletely understood. The aim of this study was to identify rare genetic variants in autoinflammatory genes that may contribute to MIS-C.</p><p><strong>Results: </strong>Whole-exome sequencing was performed in 21 unvaccinated Brazilian children with MIS-C, stratified as non-critical or critical. Variant prioritization focused on single nucleotide variants with minor allele frequency < 0.001 in autoinflammatory genes. Functional impact was inferred using variant pathogenicity metrics, gene constraint scores, and in silico molecular docking. Four heterozygous missense variants were prioritized in three genes (SH3BP2, CARD14, and ADAM17), all in critical patients. ADAM17 was the most constrained gene, with variants in protein maturation (P18L) and substrate recognition (T663N) domains. Docking analyses showed both substitutions could affected ADAM17 interactions. ADAM17-NOTCH1 binding was predicted to be impaired by in silico analysis.</p><p><strong>Conclusions: </strong>Rare deleterious variants in autoinflammatory genes, especially ADAM17, may influence immune regulation and MIS-C severity. Our results highlight genetic pathways underlying MIS-C and provide a framework for mechanistic studies. Understanding how ADAM17 variants affect immune regulation may improve risk stratification and guide targeted therapies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13480074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148224865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}