Human Genomics最新文献

{"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}

{"title":"Editing regulatory network in non-small cell lung cancer: implications for immunity and metastasis.","authors":"Jiajin Zhang, Liyu Huang, Sijia Wu","doi":"10.1186/s40246-026-00999-8","DOIUrl":"10.1186/s40246-026-00999-8","url":null,"abstract":"<p><strong>Background: </strong>RNA editing plays critical roles in cancer development, and multiple editing events collectively exert greater effects than individual events. However, the coordinated impact of RNA editing remains poorly understood.</p><p><strong>Methods: </strong>A comprehensive framework was proposed to investigate interactions among RNA editing events, capturing both the global editing landscape and site-specific functional effects. The resulting RNA editing modules were further explored to reveal gene interactions and regulatory mechanisms from the perspective of RNA editing.</p><p><strong>Results: </strong>Using non-small cell lung cancer as an example, we identified more than 12 modules involved in immune regulation and metastasis-related processes, demonstrating their clinical relevance. Mechanistically, RNA editing influenced miRNA-mediated regulation of EIF2AK2 and PRKAR2A, transcription factor activity of AHR, and RNA-binding regulation of DDX3X, highlighting its role in shaping gene regulatory networks.</p><p><strong>Conclusions: </strong>Collectively, this study provides a systematic, module-based framework for understanding coordinated RNA editing, offering new insights into RNA editing-mediated gene interactions and revealing a complementary approach to study molecular mechanisms of diseases.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217605","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":"An example for potentially underrated causes of recessive disease in the Greater Middle East: integrative long-read genome and transcriptome sequencing pinpoint a deep-intronic homozygous HEXB candidate founder variant in GM2-gangliosidosis.","authors":"Angelika Bolte, Clara Velmans, Christian Netzer, Eva Thimm, Ali Tunҫ Tuncel, Friederike Bürger, Milan Hiersche, Christian Betz, Hanno Jörn Bolz","doi":"10.1186/s40246-026-00995-y","DOIUrl":"10.1186/s40246-026-00995-y","url":null,"abstract":"<p><strong>Background: </strong>Consanguinity provides shortcuts to identify homozygous recessive mutations. However, deep-intronic variants escape standard sequencing (panel; exome/WES), and their pathogenicity cannot be inferred from genomic data. We applied WES, long-read genome and long-read-RNA-sequencing (LR-WGS, LR-RNA-Seq) in a Syrian patient with biochemically evident GM2-gangliosidosis.</p><p><strong>Results: </strong>No exonic HEXA, HEXB and GM2A mutations were found. LR-WGS/LR-RNA-Seq revealed a homozygous HEXB variant, c.771 + 985G > A, activating a 97 bp pseudo-exon.</p><p><strong>Conclusions: </strong>Integrative genome and transcriptome sequencing unlocked a deep-intronic, database-annotated HEXB mutation and proved causality. This illustrates the diagnostic challenges in patients from the Middle East with its prevalent consanguinity and hidden (candidate founder) mutations which are potential targets for splice-modulating therapies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"20 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13251226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217582","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":"Clinical and functional characterization of a novel homozygous non-canonical splice mutation (c.1910-15_1910-11delinsTTACA) in CEP290 causing Joubert syndrome.","authors":"Valeriia A Kovalskaia, Dmitriy N Maslennikov, Ksenia A Svirepova, Vyacheslav Y Tabakov, Polina N Tsabai, Evgenii V Shchoka, Nikita S Beskorovainiy, Jekaterina Shubina, Dmitry Y Trofimov, Oxana P Ryzhkova","doi":"10.1186/s40246-026-01002-0","DOIUrl":"https://doi.org/10.1186/s40246-026-01002-0","url":null,"abstract":"<p><strong>Background: </strong>Joubert syndrome (JS) is a rare, predominantly autosomal recessive neurodevelopmental disorder characterized by hypotonia, motor delay, intellectual disability, oculomotor apraxia, and the hallmark \"molar tooth sign\" on axial view of MRI. JS is genetically heterogeneous, with pathogenic variants identified in more than 40 genes involved in primary cilia function. Among these, CEP290 is one of the most frequently mutated genes.</p><p><strong>Results: </strong>In this study, we investigated two children-an 11-year-old boy (the proband) and his 5-year-old sister-both presenting with a similar phenotype consistent with JS. The parents, who self-identified as Chechen, reported distant consanguinity. The family also included a healthy 13-year-old daughter. The proband had previously been evaluated by a neurologist and underwent whole-genome sequencing (WGS); however, no causative variants were identified initially. After phenotype reassessment by a clinical geneticist, we performed a reanalysis of the raw WGS data and identified a novel homozygous intronic variant of uncertain significance (VUS), c.1910-15_1910-11delinsTTACA in CEP290 (NM_025114.4). Sanger sequencing confirmed that both the proband and his affected sister were homozygous for this variant, which they inherited from their heterozygous parents. Their healthy sister did not carry the variant. mRNA-sequencing and targeted cDNA sequencing (read depth ~ 100,000x) demonstrated that this intronic variant causes completely aberrant splicing of CEP290 pre-mRNA. Predominantly this variant causes the skipping of exon 20 in the main CEP290 transcript. Alternatively, the variant results in partial inclusion of intron 19 into the mRNA, elongation of exon 20 by 58 nucleotides, and a homozygous substitution chr12:88114573 (ACTGTGTA> TTACAGTA). No canonical mRNA isoform was detected when the variant was homozygous. Both the predicted severe truncation and the likely degradation of aberrant transcripts through nonsense-mediated decay (NMD) would correspond to complete loss of CEP290 function. Following the reclassification of this VUS to likely pathogenic, the family was able to pursue in vitro fertilization (IVF) with preimplantation genetic testing for monogenic disorders (PGT-M).</p><p><strong>Conclusion: </strong>Our study highlights the critical importance of proper phenotyping prior to referral for WES/WGS as well as of combining NGS with functional mRNA studies to achieve a molecular diagnosis for patients with predicted splice-site mutations in JS-associated genes. It also emphasizes the need for functional reassessment of VUS when genomic data are expected to guide reproductive decision-making within affected families.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}