Human Genomics最新文献

{"title":"Identification and experimental validation of ulcerative colitis-associated hub genes through integrated WGCNA and lysosomal autophagy analysis.","authors":"Yuanpei Zhao, Yijun Li, Qingwen Xu, Lili Ding, Weiming Li, Qinghua Zou, Yichen Hu, Kaiwen Shi, Hongyuan Liu","doi":"10.1186/s40246-025-00783-0","DOIUrl":"10.1186/s40246-025-00783-0","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to systematically identify differentially expressed genes associated with lysosomal autophagy in ulcerative colitis (UC) and validate key candidate genes in an animal model, thereby providing novel insights driving UC pathogenesis.</p><p><strong>Methods: </strong>The GSE47908 dataset from the Gene Expression Omnibus (GEO) was subjected to principal component analysis (PCA), followed by stratified identification of differentially expressed genes (DEGs) across UC subtypes. Immune cell infiltration of these gene sets was evaluated using the CIBERSORT algorithm. Lysophagy-related genes set were retrieved from the GeneCards database. Bioinformatics methods were employed to stratify UC DEGs, weighted gene co-expression network analysis (WGCNA) module genes, and lysophagy-associated DEGs, which were then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A protein-protein interaction (PPI) network was constructed via the STRING database, and Cytoscape was used to identify core genes highly associated with lysophagy. Core genes were validated using external datasets, and experimental UC mouse model was established to confirm their expression levels by real-time quantitative reverse transcription PCR (RT-qPCR).</p><p><strong>Results: </strong>PCA of the GSE47908 dataset across UC subtypes revealed distinct spatial separation, integrated and subgroup analyses identified lysophagy-related key genes, and enrichment analyses demonstrated differences in core genes and pathways between overall UC and its subtypes. A PPI network highlighted five hub genes in UC (CASP1, CXCL1, LCN2, PSMB9, AGT). Upregulation of these genes was confirmed via external datasets and animal experiments. Moreover, immune infiltration analysis of UC samples demonstrated immune dysregulation during disease progression, underscoring the interplay between lysophagy and inflammation in UC.</p><p><strong>Conclusion: </strong>The five genes identified-CASP1, CXCL1, LCN2, PSMB9, and AGT-exhibit strong associations with lysosomal autophagy. Our findings suggest that these genes may function as critical regulators of lysosomal autophagy in UC.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"74"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540063","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":"Prevalence and impact of molecular variation in the three-prime repair exonuclease 1 TREX1 and its implications for oncology.","authors":"Marwa Shekfeh, Mariam M Konaté, Julia Krushkal","doi":"10.1186/s40246-025-00785-y","DOIUrl":"10.1186/s40246-025-00785-y","url":null,"abstract":"<p><strong>Background: </strong>The three-prime repair exonuclease 1, TREX1, degrades cytosolic DNA to prevent aberrant immune activation. Its inactivation results in DNA accumulation in the cytosol and induction of the cGAS-STING DNA sensing pathway, interferon signaling, and inflammation. Germline pathogenic TREX1 mutations are known to lead to hereditary autoimmune and autoinflammatory disorders, whereas the consequences of TREX1 mutations in cancer remain poorly understood.</p><p><strong>Results: </strong>To assess the importance of human TREX1 amino acid variants, we analyzed protein sequences of the functional TREX1b isoform from 168 mammalian species and integrated available data on TREX1 sequence and copy number alterations in hereditary autoimmune and autoinflammatory disorders, cancer, and in human populations. While the entire TREX1b protein was conserved in placental mammals, egg-laying mammals and marsupials had their own unique C-terminal regions, with each predicted to contain a transmembrane domain. We modeled human TREX1 variants occurring in autoimmune disease and cancer samples at 12 protein positions to evaluate their predicted impact on protein stability and function.</p><p><strong>Conclusions: </strong>Our findings provide novel insight into the role of TREX1 molecular variation in cancer, where genetic or epigenetic loss of TREX1 activity may improve susceptibility to treatment. However, TREX1 gene deletion in tumors was associated with unfavorable patient outcomes, most likely due its frequent co-occurrence with the loss of the entire 3p chromosomal arm, which contains known cancer-related genes.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"73"},"PeriodicalIF":3.8,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527670","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":"Identification and functional analysis of a novel TBC1D23 pathogenic variant in a Chinese family with pontocerebellar hypoplasia.","authors":"Kangyu Liu, Yu Chen, Yunlong Meng, Xinyao Wang, Xingkun Tang, Haining Li, Jianjun Chen, Zilin Zhong","doi":"10.1186/s40246-025-00782-1","DOIUrl":"10.1186/s40246-025-00782-1","url":null,"abstract":"<p><strong>Background: </strong>Pontocerebellar hypoplasia type 11 (PCH11) is an autosomal recessive disorder caused by variants in TBC1D23. The molecular basis for its clinical heterogeneity remains poorly understood. Here, we identified a novel TBC1D23 variant in a Chinese family, investigated its underlying pathogenic mechanisms, and systematically reviewed the clinical phenotypes of all reported cases of PCH11.</p><p><strong>Results: </strong>We identified a novel homozygous frameshift variant, c.511_512delTT (p.F171Qfs*8), in TBC1D23. The patient exhibited a severe phenotype, including marked pontocerebellar hypoplasia, a thinned corpus callosum, global developmental delay, and severe language and motor impairments. Mechanistic studies in a zebrafish model revealed that the mutant transcript partially escaped nonsense-mediated decay (NMD), with expression levels at approximately 50% of the wild-type. In vitro, the resultant truncated protein showed enhanced stability and aberrant cytoplasmic distribution instead of its normal Golgi localization. Furthermore, its expression significantly inhibited cell proliferation.</p><p><strong>Conclusion: </strong>Our study identifies c.511_512delTT as a novel pathogenic variant in TBC1D23. We propose the severe phenotype stems from a primary loss-of-function (LoF), which is likely exacerbated by the cytotoxic effect of the truncated protein produced via partial NMD escape. Our findings suggest this mutant protein exhibits increased stability. This model provides a novel explanation for the phenotypic heterogeneity in PCH11 and expands the mutational spectrum of this disorder.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"72"},"PeriodicalIF":3.8,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527669","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":"Pharmacists' perspectives on integrating pharmacogenetics in clinical practice.","authors":"Najmaddin A H Hatem, Wafa Badullah, Seena A Yousuf, Mohamed Izham Mohamed Ibrahim, Waleed A Haidar, Mohammed Zawiah","doi":"10.1186/s40246-025-00780-3","DOIUrl":"10.1186/s40246-025-00780-3","url":null,"abstract":"<p><strong>Introduction: </strong>The successful implementation of pharmacogenetics (PGx) in many developed countries has significantly enhanced personalized care and improved both clinical and financial outcomes. This study was designed to evaluate the current knowledge, prevailing attitudes, and perceived ability of pharmacists to actively participate in the integration of PGx into their practice settings.</p><p><strong>Methods: </strong>A cross-sectional study was conducted among pharmacists in Yemen using convenience sampling. Data was collected through an online-based questionnaire using the Google Forms platform. Both descriptive and inferential analyses were employed.</p><p><strong>Results: </strong>With a total of 211 participants involved. Most participants held a bachelor's degree in pharmacy (45%, n = 95). Approximately 70% of respondents reported having between one and five years of experience in pharmacy practice. About three-quarters of pharmacists showed high knowledge score regarding PGx (74.4%; 95% CI: 68.47 - 80.34), with overall pharmacists' knowledge score had a median and IQR of 4( 3-5). The score of knowledge exhibited statistical significance in relation to participants' years of professional experience (p = 0.005). Overall, pharmacists expressed positive attitudes toward PGx. The top two challenges reported for the adoption of PGx in practice were \"high cost\" and \"limited availability of tests\". Additionally, about 70% agreed that they lacked knowledge about the specific PGx tests required.</p><p><strong>Conclusion: </strong>Pharmacists exhibit promising attitudes towards PGx. Nevertheless, there is a clear need to reinforce their foundational knowledge and enhance their confidence in the practical application of PGx principles. Effective integration of personalized medicine will necessitate collaborative efforts among key stakeholders, including the Ministry of Health, academic institutions, and professional pharmacy associations.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"71"},"PeriodicalIF":3.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144496095","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":"Toward streamline variant classification: discrepancies in variant nomenclature and syntax for ClinVar pathogenic variants across annotation tools.","authors":"Yu-An Chen, Tzu-Hang Yuan, Jia-Hsin Huang, Yu-Bin Wang, Tzu-Mao Hung, Chien-Yu Chen, Pei-Lung Chen, Jacob Shujui Hsu","doi":"10.1186/s40246-025-00778-x","DOIUrl":"10.1186/s40246-025-00778-x","url":null,"abstract":"<p><strong>Background: </strong>High-throughput sequencing has revolutionized genetic disorder diagnosis, but variant pathogenicity interpretation is still challenging. Even though the human genome variation society (HGVS) provides recommendations for variant nomenclature, discrepancies in annotation remain a significant hurdle.</p><p><strong>Results: </strong>In this study, we evaluated the annotation concordance between three tools-ANNOVAR, SnpEff, and variant effect predictor (VEP)-using 164,549 two-star variants from ClinVar. The analysis used HGVS nomenclature string-match comparisons to assess annotation consistency from each tool, corresponding coding impacts, and associated ACMG criteria inferred from the annotations. The analysis revealed variable concordance rates, with 58.52% agreement for HGVSc, 84.04% for HGVSp, and 85.58% for the coding impact. SnpEff showed the highest match for HGVSc (0.988), while VEP bettered for HGVSp (0.977). The substantial discrepancies were noted in the loss-of-function (LoF) category. Incorrect PVS1 interpretations affected the final pathogenicity and downgraded PLP variants (ANNOVAR 55.9%, SnpEff 66.5%, VEP 67.3%), risking false negatives of clinically relevant variants in reports.</p><p><strong>Conclusions: </strong>These findings highlight the critical challenges in accurately interpreting variant pathogenicity due to discrepancies in annotations. To enhance the reliability of genetic variant interpretation in clinical practice, standardizing transcript sets and systematically cross-validating results across multiple annotation tools is essential.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"70"},"PeriodicalIF":3.8,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336483","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":"Update of the sideroflexin (SLC56) gene family.","authors":"Angeliki I Katsafadou, Daniel W Nebert, Sergey A Krupenko, David C Thompson, Vasilis Vasiliou","doi":"10.1186/s40246-025-00779-w","DOIUrl":"10.1186/s40246-025-00779-w","url":null,"abstract":"<p><p>The human sideroflexin (SFXN) gene family, also classified as solute carrier family 56 (SLC56), encodes a group of five mitochondrial transmembrane proteins (SFXN1-SFXN5) involved in key aspects of mitochondrial metabolism, cellular homeostasis, and development. SFXNs are highly conserved across eukaryotic species, with evolutionary the origin traced back to the earliest metazoans. Functionally, each of the five family members exhibits distinct functional specialization. Particularly, SFXN1 and SFXN3 facilitate mitochondrial serine transport, supporting one-carbon metabolism. SFXN2 and SFXN4 are implicated in mitochondrial iron regulation, heme biosynthesis, and iron-sulfur cluster assembly. SFXN5, predominantly expressed in the brain, is proposed to regulate citrate metabolism and immune cell functions. Mutations or dysregulation of SFXN genes have been linked to certain human diseases, including congenital sideroblastic anemia, oxidative phosphorylation disorders, neurodegenerative conditions, and cancers. Structurally, SFXNs share conserved transmembrane domains and key motifs critical for substrate transport, mitochondrial iron homeostasis, and overall mitochondrial function. The evolutionary trajectory of the SFXN family-from amino acid transport to functionally specialized roles in higher organisms-highlights their biological and clinical significance. Comparative studies across model organisms reveal both conserved and divergent functions, emphasizing their importance in health and disease. A comprehensive understanding of the SFXN family not only advances fundamental mitochondrial research but also opens avenues for novel therapeutic interventions.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"69"},"PeriodicalIF":3.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336484","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":"CHEK1 variant is a risk factor for premature ovarian insufficiency by mis- regulating metabolism and inflammation-related genes.","authors":"Jianying Guo, Yali Fan, Zifan Song, Lin Li, Meng Fu","doi":"10.1186/s40246-025-00774-1","DOIUrl":"10.1186/s40246-025-00774-1","url":null,"abstract":"<p><strong>Background: </strong>Premature ovarian insufficiency (POI) is affecting approximately 1% of females and increasingly contributing to female infertility. The etiology of POI is heterogeneous. CHEK1, a critical component of the DNA damage and replication stress response, has recently been linked to female reproductive biology.</p><p><strong>Results: </strong>We identified a CHEK1 variant c.77C > G; p.A26G in a POI patient through whole-exome sequencing. Protein structure prediction and pathogenicity analysis suggested that the CHEK1 A26G variant may affect protein stability. RNA sequencing results of 293FT cells overexpressing wild-type and A26G CHEK1 revealed altered expression and alternative splicing of genes involved in metabolism and inflammation.</p><p><strong>Conclusion: </strong>CHEK1 may be involved in ovarian aging and the A26G variant may increase susceptibility to POI.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"67"},"PeriodicalIF":3.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325533","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":"Outcomes of genetic testing for Usher syndrome in a diverse population cohort from South Florida.","authors":"Zachary J Cromar, Ryan Chen, Tamara Juvier Riesgo, Denise Yan, Lindsay Dawn Verma, Zhengyi Chen, Susan H Blanton, Byron L Lam, Xue Zhong Liu","doi":"10.1186/s40246-025-00775-0","DOIUrl":"10.1186/s40246-025-00775-0","url":null,"abstract":"<p><strong>Background: </strong>Usher syndrome (USH) is the leading genetic cause of congenital deaf blindness worldwide. USH is an autosomal recessive disorder clinically characterized by partial or complete congenital sensorineural hearing loss followed by progressive vision loss due to retinitis pigmentosa. There are three main subtypes (USH1, USH2, USH3) with different genetic causes categorized by age of symptom onset and severity. Understanding the genetic epidemiology of USH can help identify novel mutations and facilitate definitive diagnosis and treatment. This retrospective study characterizes the mutation spectrum of USH in an ethnically diverse South Florida population.</p><p><strong>Results: </strong>Of the 148 patients assessed for this study, 67 were male and 81 were female. In this population, one identified as American Indian or Alaska Native, 6 identified as Asian (A), eight identified as Black or African American (AA), eight identified as More than One Race, 26 were identified as Unknown or Not Reported, and 99 were identified as white. In addition, 42 identified as Hispanic or Latino, 87 identified as Non-Hispanic or Latino, and 19 were identified as Unknown or Not Reported; all individuals identifying as Hispanic or Latino were either White or Unknown. One American Indian or Alaska Native patient, two Asian patients, two Black or African American Patients, and 15 white patients had inconclusive molecular testing results. In our population, White Non-Hispanics were more likely to receive a conclusive molecular diagnosis for their hearing loss.</p><p><strong>Conclusions: </strong>This is the first genetic characterization of an ethnically diverse South Florida population with USH, which can help direct patient diagnosis and medical care. As clinical trials for treatment increases, molecular testing in all individuals is imperative.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"68"},"PeriodicalIF":3.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325534","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":"Correlation between clinical classification and genetic analysis of familial hypercholesterolemia in premature coronary artery disease in a cohort of Egyptian patients.","authors":"Rania A Zahwo, Ziad N Rezk, Tamer M Elwasify, Amr M Zaki, Hoda M El Assi, Eman Ramadan, Abdallah Y Habib, Wael A Hassan, Ahmed Abdel-Raouf, Ameera Ragheb, Amin F Shaker, Khaled E Amer, Heba Sh Kassem","doi":"10.1186/s40246-025-00769-y","DOIUrl":"10.1186/s40246-025-00769-y","url":null,"abstract":"<p><strong>Background: </strong>Familial Hypercholesterolemia (FH) is a major risk factor for premature Coronary Artery Disease (CAD). Genetic testing is the gold standard for FH diagnosis. The purpose of this Observational Analytical Cross-sectional study was to estimate the proportion of genetically confirmed Familial Hypercholesterolemia in Patients with premature Coronary Artery Disease in a cohort of Egyptian patients.</p><p><strong>Methods: </strong>Next generation sequencing (NGS) was conducted for 7 genes (LDLR, PCSK9, APOB, APOE, ABCG5, ABCG8 and LDLRAP1) commonly associated with FH in 94 patients with Premature CAD from 2 tertiary hospitals in Cairo and Alexandria, Egypt. Individuals were clinically assessed using the Dutch Lipid Network criteria and genetically-confirmed FH prevalence was analyzed.</p><p><strong>Results: </strong>Fourteen patients had pathogenic or likely pathogenic mutations in LDLR, APOB, PCSK9 and LDLRAP1 genes. Three patients had homozygous autosomal dominant FH and another 3 patients had autosomal recessive hypercholesterolemia. In addition, 10 patients had rare variants of uncertain significance in LDLR, APOB, APOE, ABCG5 and ABCG8 genes.</p><p><strong>Conclusions: </strong>The prevalence of genetically confirmed FH in premature CAD (PCAD) patients in this study was found to be 14.89%. The Dutch Lipid Clinic Network (DLCN) scoring system is suggested as a good screening tool for familial hypercholesterolemia but confirmatory genetic testing is essential for the accurate diagnosis and management of the patients. In Egypt, the high rate of consanguinity contributes to the high prevalence of both homozygous autosomal dominant and recessive FH.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"66"},"PeriodicalIF":3.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293674","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":"Improved breast cancer risk prediction using chromosomal-scale length variation.","authors":"Yasaman Fatapour, James P Brody","doi":"10.1186/s40246-025-00776-z","DOIUrl":"10.1186/s40246-025-00776-z","url":null,"abstract":"<p><strong>Introduction: </strong>Early diagnosis of breast cancer leads to higher long-term survival rates. The development of a germline genetic test, or polygenic risk score, to identify women at high risk of breast cancer holds the potential to reduce cancer deaths. However, current tests based on SNPs do not perform much better than predictions based on family history and perform significantly worse in populations with non-European ancestry. We have developed an alternative method to characterize a genome, called chromosomal-scale length variation, which can be applied to polygenic risk scores.</p><p><strong>Objective: </strong>The objective of this paper is to characterize a breast cancer genetic risk score based on chromosomal-scale length variation using the NIH All of Us dataset in different self-identified racial groups when trained on different populations.</p><p><strong>Methods: </strong>We used the NIH All of Us dataset to compile a dataset with 4,533 women who have been diagnosed with breast cancer (including 440 who self-identified as Black) and 44,518 women who have not. We acquired, through All of Us, genetic information for each of these women. We computed a set of 88 values for each woman in the dataset, representing the chromosomal-scale length variation parameters. These numbers are average log R ratios for four different segments from each of the 22 autosomes. We used machine learning algorithms to find a model that best differentiates the women with breast cancer from the women without breast cancer based on the set of 88 numbers that characterize each woman's germline genome.</p><p><strong>Results: </strong>The best model had an AUC of 0.70 (95% CI, 0.67-0.73) in the All of Us population. Women who scored in the top quintile by this model were nine times more likely to have breast cancer when compared to women who scored in the lowest quintile.</p><p><strong>Conclusion: </strong>In conclusion, we found that this method of computing genetic risk scores for breast cancer is a substantial improvement over SNP-based polygenic risk scores. In addition, we compared models trained on populations of only White women and only Black women. We found that the models trained only on White women performed better than models trained only on Black women when tested on only White women. We did not see a significant difference between the two models when tested on only Black women.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"65"},"PeriodicalIF":3.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274669","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}