Human Genomics最新文献

{"title":"Comprehensive transcriptomics and proteome analysis to identify prognostic risk factors for MYCN non-amplified high-risk neuroblastoma.","authors":"Shan Liu, Zhihong Wang, Jianzhen Shen, Lizhi Li, Yaobin Lin","doi":"10.1186/s40246-026-00973-4","DOIUrl":"10.1186/s40246-026-00973-4","url":null,"abstract":"<p><strong>Background: </strong>MYCN non-amplified (MYCN-NA) neuroblastoma (NB) demonstrates considerable heterogeneity in both biological and clinical aspects, and its molecular and biological characteristics remain inadequately defined.</p><p><strong>Methods: </strong>A comprehensive multi-omics analysis was performed on transcriptome and proteome data from 20 MYCN-NA NB tissues, including 11 low- and intermediate-risk neuroblastoma (LIR-NB) cases and 9 high-risk neuroblastoma (HR-NB) cases. Additionally, the expression levels and survival prognostic significance of key candidate genes were systematically assessed using public datasets (GSE85047 and TARGET-NB).</p><p><strong>Results: </strong>Transcriptomic analysis revealed 1,955 differentially expressed genes (DEGs), with 899 upregulated and 1,056 downregulated in HR-NB (P < 0.05, |log₂FC| ≥ 1.5). Pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes identified significant associations of these DEGs with glycolipid metabolism, signal transduction, and transcriptional regulation. Proteomic profiling identified 609 differentially expressed proteins (DEPs), with 24 upregulated and 585 downregulated in HR-NB. These DEPs were predominantly enriched in metabolic pathways, axon guidance, and Rho GTPase signaling. Integrated omics analysis revealed that both mRNA and protein expression of DPEP1 and FILIP1 were co-upregulated in HR-NB, while seven genes-ICA1L, KCNH2, LGI3, FAM184A, INPP5F, NELL2, and VKORC1L1-were co-downregulated. Genes exhibiting consistent changes in both protein and mRNA levels were primarily involved in glycerophospholipid metabolism and regulation of transport. Moreover, the top five genes (ICA1L, KCNH2, LGI3, FAM184A, and INPP5F) with the most significant concurrent changes were further validated for their expression levels and association with survival prognosis in GSE85047 and TARGET-NB datasets. Notably, increased expression of INPP5F and LGI3 correlated with an improvement in overall survival rate (P < 0.05).</p><p><strong>Conclusion: </strong>MYCN-NA HR-NB demonstrates metabolic reprogramming characterized by disorders in glucose and lipid metabolism. Notably, the elevated expression of INPP5F and LGI3 is linked to improved overall survival and may serve as potential therapeutic targets.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770101","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":"A consensus model for implementation of genomics in Queensland Health - a Delphi study.","authors":"Minh Viet Bui, Zoe Fehlberg, Mathilde Desselle, Saras Menon, Senel Idrisoglu, Andrew Mallett, Stephanie Best","doi":"10.1186/s40246-026-00941-y","DOIUrl":"10.1186/s40246-026-00941-y","url":null,"abstract":"<p><p>BACKGROUND: As genomic technologies in healthcare expand, health systems face integration challenges. This study aimed to consolidate collective expertise, experiences, and existing knowledge from local, statewide, and national genomics projects to inform a model of care for integrating and delivering genomic services in the Queensland public health system. METHODS: We used a modified Delphi methodology with three survey rounds to achieve expert consensus on the model of care. We analysed quantitative data using descriptive statistics and qualitative data using content analysis. RESULTS: From 112 invited experts, 43 participants took part. The model of care comprised 30 actions across three phases: pre-test, testing, and post-test. Consensus (≥ 75% agreement) was achieved on 25 of the actions, with 5 included with specific considerations. Ten recommendations were developed, including building sustainability, improving access to specialists through a distributed model, and investing in clinical-pathology partnerships and infrastructures. CONCLUSION: These findings may inform a comprehensive, stakeholder-informed, system-level implementation effort for mainstreaming genomic medicine that is practical, feasible, and acceptable to key stakeholders across the system. The three-phase model of care provides a structured approach to genomic service delivery and has the potential to significantly improve patient access and healthcare delivery. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770068","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 variants identification through whole-genome sequencing based on dried blood spots in 92 Chinese children with Autism.","authors":"Lulu Wang, Haixin Li, Yuqi Yang, Bin Zhang, Bin Yu","doi":"10.1186/s40246-026-00971-6","DOIUrl":"10.1186/s40246-026-00971-6","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a group of neurodevelopmental disorder with high heterogeneity. We hence to investigate the genetic etiology of ASD and the potential of whole-genome sequencing (WGS) from dried blood spots for the presymptomatic risk assessment. Total 92 individuals diagnosed with ASD were recruited to identify the genetic etiologies of ASD using WGS of newborn dried blood spots. Variants were verified with a minigene splicing assay and the construction of three-dimensional protein models. Overall, a positive molecular diagnosis was obtained for 10 cases, a rate of 10.87%. Among the 10 cases, five cases (50.0%, 5/10) were identified with likely pathogenic exon-level CNVs, two cases (20.0%, 2/10) were identified with pathogenic large CNVs, one case (10%, 1/10) was identified with the chromosomal translocation t(8;9)(q13.3;q21.13), and 2 cases (20.0%, 2/10) were identified with likely pathogenic SNVs/Indels. Total 245 variants of 173 genes were classified as \"VUS\". Further functional analysis showed that one splicing variant were predicted to generate a truncated protein. Our study demonstrated the utility of WGS derived from dried blood spots for identifying ASD-associated risk genes and variants. The introduction of ASD to the newborn genetic screening should be considered, which may facilitate presymptomatic risk identification and enable earlier, more personalized interventions for high-risk infants.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770056","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":"Serum ferritin and delirium risk: an integrative genomic analysis of causal inference and multi-tissue regulatory signals.","authors":"Amirhossein Saed, Mahdi Akbarzadeh, Fatemeh Gohari, Nafiseh Asadrouh, Amir Mohammad Jahromizadeh, Hani Sabaie, Maryam Zarkesh, Mehdi Hedayati, Fereidoun Azizi, Maryam Sadat Daneshpour","doi":"10.1186/s40246-026-00972-5","DOIUrl":"10.1186/s40246-026-00972-5","url":null,"abstract":"<p><p>BACKGROUND: Delirium is an acute neuropsychiatric syndrome characterized by disrupted attention and cognition, often triggered by systemic inflammation and physiological stress. Elevated serum ferritin is frequently observed in patients with delirium. Since ferritin couples iron handling to inflammatory signaling during acute-phase responses, it remains unclear whether genetically influenced baseline serum ferritin is a modifiable causal risk factor for delirium, or whether ferritin elevations observed during illness mainly reflect downstream systemic states leading to brain network failure. We used genetic triangulation to assess baseline causality and identify regulatory mechanisms influencing delirium susceptibility. RESULTS: Using harmonized GWAS summary statistics for ferritin (GCST90270865; N = 270,794) and delirium (GCST90473243; 8461 cases, 449,979 controls), we found no evidence that genetically proxied increases in ferritin causally raise delirium risk (primary MR: IVW random-effects OR = 1.09 per 1/SD ferritin, 95% CI 0.93–1.26; p = 0.282). Genome-wide overlap was limited, with weak, non-significant cross-trait genetic correlation and minimal shared polygenic signal. Mechanistic follow-up at the locus level across multi-tissue QTL resources identified widespread ferritin-linked cis-QTL signals (255 probes, 126 genes), while delirium showed sparse mediator signals (four probes, three genes), all on chromosome 19. At 19q13, ferritin strongly colocalized with an APOE plasma pQTL (PP.H4 = 0.999; SuSiE PP.H4 ≈ 1.00), whereas delirium colocalized with a cortex CEACAM19 eQTL (PP.H4 = 0.9983). Outside 19q13, ferritin colocalized with iron regulation signals at SLC11A2 whole-blood eQTL (PP.H4 = 0.853) and TF liver sQTL (PP.H4 = 0.966), with no evidence of ferritin–delirium colocalization. CONCLUSIONS: Genetic evidence does not support baseline ferritin as a primary, modifiable causal factor for delirium risk. Instead, inherited susceptibility appears locus-specific and seems to align with brain regulatory mechanisms, including a cortical signal at 19q13, distinct from iron homeostasis. These findings emphasize the need for mechanistic and preventive research targeting brain-relevant pathways other than systemic iron management for delirium prevention. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770095","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":"Multigenerational evidence of X-linked adrenal hypoplasia congenita due to a novel NR0B1 frameshift.","authors":"Lang Tian, Jie Mei, Xi Zheng, Hong-Mei Dai","doi":"10.1186/s40246-026-00955-6","DOIUrl":"10.1186/s40246-026-00955-6","url":null,"abstract":"<p><strong>Backgroud: </strong>Pathogenic NR0B1 variants, encoding DAX-1, are a major cause of X-linked adrenal hypoplasia congenita (AHC), yet genotype-phenotype variability persists.</p><p><strong>Results: </strong>In a Chinese four-generation pedigree, two affected males carried a novel NR0B1 frameshift, c.573_576dup4 (p.T193Gfs*13). Segregation showed wild-type fathers and heterozygous carrier mothers, and unaffected male relatives lacked the variant. The duplication shifts the reading frame from residue 193 and introduces a premature stop at residue 205, truncating DAX-1. Pedigree analysis supports NR0B1 c.573_576dup4 (p.T193Gfs*13) as a novel AHC-causing variant.</p><p><strong>Conclusions: </strong>This maternally inherited frameshift underlies AHC in this family, expanding the NR0B1 mutational spectrum and underscoring genetic testing.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13248395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770079","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":"Sex-aware genome-wide assessment of de novo variants in autism across coding and noncoding regions.","authors":"Tychele N Turner","doi":"10.1186/s40246-026-00961-8","DOIUrl":"10.1186/s40246-026-00961-8","url":null,"abstract":"<p><p>BACKGROUND: Autism spectrum disorder (ASD) shows a consistent sex bias, yet how sex shapes de novo variant (DNV) risk across coding and noncoding sequence remains unclear. I analyzed DNVs in > 41,000 parent–child sequenced trios from three ASD family-based cohorts and compared DNV characteristics and enrichment patterns in males and females. Notably, these trios included individuals with ASD as well as those without ASD. I developed a new sex-aware DNV caller (HAT-FLEX) and thoroughly evaluated each candidate DNV using an additional tool introduced in this study, SNOW, to generate a high-confidence callset. RESULTS: I identified enrichment of missense and loss-of-function (LOF) DNVs both overall and within known ASD-related genes (i.e., SFARI genes). Gene-specific enrichment analyses revealed twelve genes that were exome-wide significant and specific to males, for significance, including FOXP1, SMAD6, AUTS2, CCDC168, PIEZO1, EML6, ZNF84, IGSF23, OTOG, NHSL1, ADNP, and FREM3 and three genes that were specific to females, for significance, including TAOK1, MECP2, and DDX3X within a variant class. Direct comparisons of DNVs in males and females revealed MECP2 as the only exome-wide significant gene; however, GABBR2 was also trending toward enrichment in the direct males with ASD comparison to females with ASD. Furthermore, probit analyses support a female protective effect and demonstrates that damaging DNVs, particularly LOF variants, including potentially stronger X-linked effects in females, are associated with increased ASD liability, whereas synonymous variants are not. Finally, I analyzed promoters and identified a single significant promoter region (p = 3.8 × 10−13), associated with the WDR74 gene, with the signal driven by DNVs observed in males with ASD. Surprisingly, the noncoding RNA gene RNU2-2 lies within this significant WDR74 promoter and accounted for most of the DNVs in the region. RNU2-2 DNVs were present in 0.2% of individuals with ASD in comparison to 0.05% of individuals without ASD. CONCLUSIONS: These findings show that ASD DNV risk differs by sex at both the gene and liability levels, supporting a female protective effect while highlighting sex-specific patterns in coding variation. They also identify RNU2-2 as a noncoding contributor to ASD risk, expanding the landscape of ASD-associated variation beyond protein-coding genes. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13248286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770139","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":"Progranulin genetic variant rs5848 displays ancestry-specific associations with Alzheimer's disease.","authors":"Benjamin E Life, Erick I Navarro-Delgado, Oriol Fornes, Jan M Friedman, Wyeth W Wasserman, Keegan Korthauer, Blair R Leavitt","doi":"10.1186/s40246-026-00958-3","DOIUrl":"10.1186/s40246-026-00958-3","url":null,"abstract":"<p><p>BACKGROUND: Progranulin is a molecular modifier of Alzheimer’s disease (AD). However, its cis-regulatory region remains under-characterized. Association studies of genetic variants in this region with AD have obtained conflicting results across different human populations. METHODS: We define the cis-regulatory region of the progranulin gene (GRN). Querying the genetically admixed Alzheimer’s Disease Sequencing Project whole-genome sequencing dataset (n = 9,416 cases; 13,603 controls), we conduct ancestry-specific analyses of AD association with GRN genetic variants. RESULTS: We report predicted impacts of genetic variation on transcription factor binding for 150 unique transcription factors across the GRN cis-regulatory region. We identify 99 common variants (MAF > 0.005) in one or more superpopulations (African, Admixed American, East Asian, European, and South Asian). The common GRN variant rs5848 is significantly associated with AD only in East Asian ancestry. CONCLUSIONS: Ancestry-specific effects may contribute to discordant findings in the literature. European-centric results in AD might not be generalizable to other populations. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13200471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147672794","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":"Prenatal and postnatal manifestations of WBP11-related disorder in Chinese patients: expanding the phenotypic and mutational spectrum.","authors":"Tingbin Ma, Jinyu Liu, Yuqi Wang, Haibo Zhu, Yihong Qin, Ruizhi Liu, Hongtao Yuan, Baoying Ye, Renyi Hua, Shuyuan Li, Hui Xi, Jian Wang, Niu Li","doi":"10.1186/s40246-026-00966-3","DOIUrl":"10.1186/s40246-026-00966-3","url":null,"abstract":"<p><p>BACKGROUND: Heterozygous pathogenic variants in WBP11, a spliceosome-associated gene, have recently been linked to VACTERL syndrome, yet prenatal manifestations and genotype–phenotype correlations remain poorly characterized. METHODS: Genomic DNA was extracted from fetal tissues, amniotic fluid cells, or peripheral blood samples for trio-based whole-exome sequencing (WES) to identify potential genetic etiologies. The structural stability of the WBP11 protein associated with missense variants was characterized using 3D protein structural modeling. The impact of splicing variant was further evaluated through TA cloning coupled with Sanger sequencing. RESULTS: Here, we report the first case series of WBP11-related disorder in Chinese patients, comprising four fetuses and one postnatal child from five unrelated families. Whole-exome sequencing identified five previously unreported heterozygous WBP11 variants (NM_016312.3), including three nonsense (p.Arg55*, p.Lys83*, p.Ser279*), one canonical splice-site (c.1310-1G > A), and one missense (p.Arg91Cys). Three occurred de novo, while two were paternally inherited from clinically unaffected or mildly affected carriers, supporting incomplete penetrance. Crucially, RNA analysis of amniocytes carrying the c.1310-1G > A variant revealed only 4% aberrant splicing (c.1310del, p.Gly437Glufs*6), explaining the mild fetal phenotype of isolated femoral shortening and challenging conventional assumptions about the pathogenicity of canonical splice-site variants. The postnatal patient primarily presents with retinal pigmentary degeneration, hearing impairment, bilateral cryptorchidism, short stature, and global developmental delay. Most of these features have been reported in WBP11-related cases but are not considered classic diagnostic criteria for VACTERL. Notably, prenatal cases predominantly presented with cardiac malformations, whereas vertebral anomalies, common postnatally, were absent prenatally, suggesting age-dependent phenotypic evolution. CONCLUSIONS: We have documented the retinal pigment phenotype in WBP11 mutant patients for the first time. Our findings expand the mutational and clinical spectrum of WBP11-related disease, highlight the limitations of sequence-based variant interpretation without functional or transcriptomic validation, and underscore the necessity of integrating detailed phenotypic correlation into prenatal genetic counseling. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13200368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147672855","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, genetic and bioinformatic analysis of Saudi families with Joubert syndrome and related disorders.","authors":"Riman Alafghani, Deema Aljeaid, Noor Ahmad Shaik, Babajan Banaganapalli, Ramu Elango, Ghayah Khard, Wisam Habhab, Ghada Jadkarim, Dalal Sameer Alshaer, Mahmoud Almutadares, Nuha Mohammad Alrayes, Noha M Issa","doi":"10.1186/s40246-026-00953-8","DOIUrl":"10.1186/s40246-026-00953-8","url":null,"abstract":"<p><p>BACKGROUND: Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies caused by pathogenic variants in over 40 genes, mainly encoding ciliary proteins. However, data on JSRD in the Saudi population remain limited. This study aimed to identify novel and reported JSRD-causing variants in Saudi families and analyze their potential functional impact on protein structure using advanced computational tools. METHODS: Patients with genetically or clinically confirmed/suspected JSRD were recruited according to ethical protocols. Clinical data were collected, and exome sequencing was performed, followed by Sanger validation of identified variant. Pathogenicity was assessed using bioinformatics tools, while conservation, expression and RNA structure analyses were conducted to evaluate the potential functional consequences. RESULTS: Homozygous variants were identified in three consanguineous Saudi families, including a novel stop-gain variant in KIF7 (c.2992 C > T; p.(Gln998Ter)), and novel splice-site variant in CEP104 (c.489 + 1G > A) and a previously reported splice-site variant in TMEM237 (c.869 + 1G > A). All variants were predicted to be pathogenic as per ACMG criteria and located in highly conserved regions, suggesting potential functional impact. RNA analysis suggested possible alterations in folding. CONCLUSION: This study identified three pathogenic variants in JSRD-related genes in Saudi families, including two novel variants. These findings expand the variant spectrum for JSRD, particularly in the Saudi population. Establishing a comprehensive regional variant database is essential for improving molecular diagnosis and genetic counseling in population with high consanguinity. Finally, these results highlight the need for further functional studies to validate their pathogenicity and elucidate their role in JSRD pathogenesis. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13200349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662470","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":"Leveraging a spectrum of cytogenomics methods for profiling complex karyotypes in chronic lymphocytic leukemia.","authors":"Karolina Cernovska, Sabina Penazova, Kamila Stranska, Jakub Paweł Porc, Patricie Skalakova, Eva Ondrouskova, Tobias Rausch, Jan Svaton, Kristyna Tausova, Natalie Kazdova, Karol Pal, Jakub Hynst, Vladimir Benes, Marie Jarosova, Sarka Pospisilova, Jana Kotaskova, Karla Plevova","doi":"10.1186/s40246-026-00957-4","DOIUrl":"10.1186/s40246-026-00957-4","url":null,"abstract":"<p><p>BACKGROUND: A highly complex karyotype (high-CK) is a key biomarker of poor prognosis in chronic lymphocytic leukemia (CLL). While conventional methods lack the resolution to fully characterize complex structural variants (SVs), emerging technologies such as short-read WGS (sr-WGS), nanopore sequencing (ONT), optical genome mapping (OGM), and chromatin conformation capture (Micro-C) offer powerful tools for high-resolution SVs analysis, illuminating the genomic architecture underlying CLL. METHODS: We selected nine CLL cases bearing diverse genomic alterations. Each underwent routine diagnostic evaluation via chromosome banding analysis (CBA), multicolor fluorescence in situ hybridization (mFISH), and chromosomal microarray (CMA) and was further analyzed using sr-WGS, ONT, OGM, and Micro-C. We performed a comprehensive comparison of copy number variants (CNVs) and SVs across all methods. RESULTS: Across five methods (CMA, ONT, OGM, sr-WGS, Micro-C), 56.3% (179/318) of CNVs were consistently detected. A high-confidence CNV set, defined as those identified by ≥ 3 methods, comprised 70.4% (224/318). SV detection varied by genome complexity: 2910 unique breakends (BNDs) were identified, with only 10.9% (320/2910) supported by all methods. A high-confidence SV set, supported by ≥ 3 methods, included 20.4% (595/2910) of BNDs. Dicentric chromosomes (DICs) and complex derivative chromosomes (CDERs), particularly those involving BNDs near centromeric or telomeric regions, were the most difficult to resolve. Micro-C fully confirmed 71.4% (5/7) of CDERs and all ten DICs. Overall, Micro-C aligned best with classical cytogenetics, confirming 85.5% (47/55) of aberrations, followed by OGM (65.5%) and both ONT and sr-WGS (56.4%). CONCLUSION: Each technology offers unique insights into the leukemia genome. Combining classical cytogenetics with high-throughput methods improves the detection of structural complexity and clinically relevant alterations. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13195900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662452","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}