HGG Advances最新文献

{"title":"The rate of identical-by-descent segment sharing between close and distant relatives.","authors":"Amy L Williams","doi":"10.1016/j.xhgg.2026.100576","DOIUrl":"10.1016/j.xhgg.2026.100576","url":null,"abstract":"<p><p>Genetic relatives share long stretches of DNA they co-inherited from a common ancestor in identical-by-descent (IBD) segments. Because children inherit half their parents' genomes, the expected amount of DNA relatives share drops by 12 for each generation that separates them, being 2^-d for d-degree relatives. Even so, there is substantial variance in sharing rates so that most distant relatives share zero IBD segments. I characterized IBD segment sharing between relatives by simulating 100,000 pairs for each of first through eighth cousins, including once-removed and half-cousins, while modeling both crossover interference and sex-specific genetic maps. My results show that 98.5% of third cousins share at least one IBD segment, while only 32.7% of fifth cousins and 0.96% of eighth cousins have such sharing. These sharing rates are slightly higher than those that arise from models that ignore the more elaborate crossover features and can be filtered by segment length. The resulting segment count distributions are available with an interactive segment length threshold online.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100576"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12930157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146126648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic variants in AP5Z1 and AP5B1 lead to retinal degeneration.","authors":"Hafiz Muhammad Jafar Hussain, Meng Wang, Paul Yang, Behnoosh Tasharrofi, Yumei Li, Rebecca Lynn Clark, Emma Fale-Olsen, Grace Waldow, Mohammad Keramatipour, Mostafa Asadollahi, Mark E Pennesi, Rui Chen","doi":"10.1016/j.xhgg.2026.100584","DOIUrl":"10.1016/j.xhgg.2026.100584","url":null,"abstract":"<p><p>Inherited retinal diseases (IRDs) comprise a diverse group of disorders that frequently lead to progressive vision impairment and blindness. Despite advances in genetic testing, a significant number of IRD cases remain genetically unsolved, often due to unidentified disease-associated genes or variants. This study reports additional cases for the newly discovered IRD genes of the AP-5 complex. A comprehensive ophthalmological evaluation was performed for all patients, including retinal imaging (multimodal imaging), visual field testing, and electroretinogram (ERG) testing. Whole-genome and -exome sequencing (WGS and WES) were performed for clinically unsolved IRD patients, and data were analyzed to identify underlying causal variants. The identified variants were subsequently validated using Sanger sequencing. Five unrelated patients from Europe and Iran were identified with a distinctive macular degeneration associated with bi-allelic variants in AP5Z1 (HGNC: 22197) and AP5B1 (HGNC: 25104), subunits of the vesicular fifth adaptor protein (AP-5) complex. The AP-5 complex is the part of the intracellular trafficking machinery thought to be involved in cellular homeostasis and lysosomal functioning in the retinal pigment epithelium (RPE). The identification of bi-allelic variants in two proteins of the AP-5 complex expand the characterization of AP-5 genes in sustaining and preserving normal macular function.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100584"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13050037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147460565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenome-wide association study of blood proteome in the Atherosclerosis Risk in Communities study.","authors":"Yang Li, Aditya Surapaneni, Zulema Rodriguez-Hernandez, Pascal Schlosser, Eugene P Rhee, Eric Boerwinkle, Bing Yu, Megan L Grove, Kelly V Ruggles, Josef Coresh, Morgan Grams","doi":"10.1016/j.xhgg.2026.100585","DOIUrl":"10.1016/j.xhgg.2026.100585","url":null,"abstract":"<p><p>Characterizing the relationship between DNA methylation and circulating proteins is critical to understanding the epigenetic regulation of the human plasma proteome. Here, we performed an epigenome-wide association study of 5,032 circulating proteins in 1,449 White and 315 Black participants from the Atherosclerosis Risk in Communities cohort. We identified 12,500 significant protein quantitative trait methylation (pQTM)-protein associations involving 1,647 proteins. Among 7,796 unique pQTMs, 14.7% were classified as cis-pQTMs, which were enriched for fundamental cellular processes, whereas trans-pQTMs were predominantly linked to immune-related functions. Trans-pQTMs also exhibited stronger associations with demographic, lifestyle, and clinical traits as compared with cis-pQTMs. We identified proteins such as GM2A and EPHB6, whose expression appears to be strongly associated with DNA methylation, suggesting potential as targets for epigenetic-based therapeutic interventions. These findings demonstrate the extensive impact of DNA methylation on the circulating proteome through cis- and trans-regulatory mechanisms and underscore the influence of population-level traits on epigenetic regulation. These findings highlight a broad impact of DNA methylation on circulating proteins through both cis- and trans-regulatory mechanisms and the roles of population-level phenotypes.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100585"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13014933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147356345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of the STAAR framework in detecting rare variant associations with Alzheimer disease and related dementias: Insights and implications.","authors":"Dongyu Wang, Sabrina Abbruzzese, Nancy Heard-Costa, Andy Rampersaud, Eden Martin, Adam Naj, Bilcag Akgun, Brian Kunkle, Sudha Seshadri, Gina Peloso, Anita L DeStefano, Zilin Li, Xihao Li, Seung Hoan Choi","doi":"10.1016/j.xhgg.2026.100574","DOIUrl":"10.1016/j.xhgg.2026.100574","url":null,"abstract":"<p><p>Rare genetic variation is considered a potential source of heritability in individuals with sporadic Alzheimer disease and related dementias (ADRD). The Variant-set test for association using annotation information (STAAR) framework leverages multiple functional annotations of genetic variants and combines association statistics from multiple variant aggregation-based methods, including burden, sequence kernel association test (SKAT), and aggregated Cauchy association test (ACAT-V), into a single measure of significance. Using whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP), we comprehensively examined the association of rare genetic variation with ADRD in 23,454 individuals (37% individuals affected by ADRD) and with cognitively healthy elder status in 13,292 individuals (13% cognitively healthy elders) from diverse populations via the STAAR framework. We identified several genes significantly associated with ADRD or cognitively healthy status. However, our analysis revealed several limitations within the STAAR framework incorporating ultra-rare variants with dichotomous outcomes. To enhance the robustness of the framework, we proposed several computational refinements, including creating a burden of ultra-rare variants and employing more precise annotations to match the expected mechanism. After implementing the proposed modifications, the association with ADRD for ZNF200 was no longer statistically significant (α = 1 × 10^-7), while TBX19, PLXNB2, CARD11, and LINC01880 remained significantly associated with cognitively healthy status. We identified and addressed the computational limitations in the STAAR framework that could lead to potential spurious results for ultra-rare variant aggregates with an extremely low cumulative minor-allele count. Our proposed refinements produced more robust results for associations with rare variants in the context of dichotomous outcomes.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100574"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12934298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146012311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paternal age effect in autosomal dominant or X-linked de novo variants identified by genome-wide sequencing.","authors":"Ella Beraldo, Shelin Adam, Colleen Guimond, Jan M Friedman","doi":"10.1016/j.xhgg.2026.100577","DOIUrl":"10.1016/j.xhgg.2026.100577","url":null,"abstract":"<p><p>An increased frequency of sporadic autosomal dominant disorders has been observed among children born to older fathers. This paternal age effect is thought to reflect an accumulation of new mutations in the male germ line as DNA replication and cell division continue to occur as men age. Genome-wide sequencing is useful for identifying disease-causing genetic variants in patients with suspected genetic diseases and for determining inheritance or de novo mutation of the variants when done in patient-parent trios. We analyzed paternal ages in 593 families who received trio or quad exome or genome sequencing for suspected genetic disease. The mean age of fathers of children with de novo disease-causing variants (35.09 years) was significantly greater than that of children with inherited disease-causing variants (33.78 years, p = 0.04). The mean age of mothers of children with de novo disease-causing variants (31.86 years) was not significantly greater than that of children with inherited disease-causing variants (30.80 years, p = 0.09). Interestingly, when the de novo disease-causing variants were broken down into subgroups by variant type, both mean paternal age and mean maternal age of children with de novo indel variants (paternal = 36.33 years, maternal = 33.34 years) were significantly higher than in children identified to have de novo single-nucleotide variants (paternal = 34.35 years, p = 0.03; maternal = 31.15 years, p = 0.004). This observation, which may have implications for how indels arise, requires further study.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100577"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12934291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simple approach for multiple observations improves power to detect genetic effects and genomic prediction accuracy.","authors":"Luke M Evans, Christopher H Arehart, Raine A Gibson, Grace I Bowman, Christopher R Gignoux","doi":"10.1016/j.xhgg.2026.100586","DOIUrl":"10.1016/j.xhgg.2026.100586","url":null,"abstract":"<p><p>Many datasets, including widely used biobanks, have more than one observation of numerous phenotypes for at least a portion of their sample. The majority of genome-wide association studies (GWASs) utilize only a single observation per individual, even when more than one observation may be available, and apply a standard model in which the additive allelic effect being estimated is assumed to be constant across the age or time range in the sample. Here, we test a set of simple approaches to utilize multiple observations per individual, under this same assumption, to characterize effects on GWAS power, SNP heritability, gene set enrichment, and polygenic prediction. We find that utilizing the mean or median of the available observations rather than a single observation improves the power to detect associated loci and enriched gene sets and yields higher out-of-sample polygenic score prediction accuracy. Despite growing biobanks, many deeply phenotyped samples are relatively small but have multiple observations. While explicitly modeling age- or time-dependent genetic effects can add nuance to genetic studies and estimates, most GWASs apply a standard, additive-only model; a simple approach of using the mean or median can improve power by reducing \"noise\" in the phenotype, utilize standard, optimized software, and be particularly impactful for smaller samples, including samples of diverse genetic ancestry existing in widely used biobanks such as the UK Biobank and the Health and Retirement Study.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100586"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13081671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale blood pressure GWAS accounting for gene-depression interactions in 564,680 individuals from diverse populations.","authors":"Songmi Lee, Clint L Miller, Amy R Bentley, Michael R Brown, Pavithra Nagarajan, Raymond Noordam, John L Morrison, Karen Schwander, Kenneth Westerman, Minjung Kho, Aldi T Kraja, Paul S de Vries, Farah Ammous, Hughes Aschard, Traci M Bartz, Anh Do, Charles T Dupont, Mary F Feitosa, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E Harris, Keiko Hikino, Zhijie Huang, Christophe Lefevre, Leo-Pekka Lyytikäinen, Yuri Milaneschi, Giuseppe Giovanni Nardone, Aurora Santin, Helena Schmidt, Botong Shen, Tamar Sofer, Quan Sun, Ye An Tan, Jingxian Tang, Sébastien Thériault, Peter J van der Most, Erin B Ware, Stefan Weiss, Wang Ya Xing, Chenglong Yu, Wei Zhao, Md Abu Yusuf Ansari, Pramod Anugu, John R Attia, Lydia A Bazzano, Joshua C Bis, Max Breyer, Brian Cade, Guanjie Chen, Stacey Collins, Janie Corley, Gail Davies, Marcus Dörr, Jiawen Du, Todd L Edwards, Tariq Faquih, Jessica D Faul, Alison E Fohner, Amanda M Fretts, Srushti Gangireddy, Adam Gepner, MariaElisa Graff, Edith Hofer, Georg Homuth, Michelle M Hood, Xu Jie, Mika Kähönen, Sharon L R Kardia, Carrie A Karvonen-Gutierrez, Lenore J Launer, Daniel Levy, Maitreiyi Maheshwari, Lisa W Martin, Koichi Matsuda, John J McNeil, Ilja M Nolte, Tomo Okochi, Laura M Raffield, Olli T Raitakari, Lorenz Risch, Martin Risch, Ana Diez Roux, Edward A Ruiz-Narvaez, Tom C Russ, Takeo Saito, Pamela J Schreiner, Rodney J Scott, James Shikany, Jennifer A Smith, Harold Snieder, Beatrice Spedicati, E Shyong Tai, Adele M Taylor, Kent D Taylor, Paola Tesolin, Rob M van Dam, Rujia Wang, Wei Wenbin, Tian Xie, Jie Yao, Kristin L Young, Ruiyuan Zhang, Alan B Zonderman, Maria Pina Concas, David Conen, Simon R Cox, Michele K Evans, Ervin R Fox, Lisa de Las Fuentes, Ayush Giri, Giorgia Girotto, Hans J Grabe, Charles Gu, Vilmundur Gudnason, Sioban D Harlow, Elizabeth Holliday, Jonas B Jost, Paul Lacaze, Seunggeun Lee, Terho Lehtimäki, Changwei Li, Ching-Ti Liu, Alanna C Morrison, Kari E North, Brenda W J H Penninx, Patricia A Peyser, Michael M Province, Bruce M Psaty, Susan Redline, Frits R Rosendaal, Charles N Rotimi, Jerome I Rotter, Reinhold Schmidt, Xueling Sim, Chikashi Terao, David R Weir, Xiaofeng Zhu, Nora Franceschini, Jeffrey R O'Connell, Cashell E Jaquish, Heming Wang, Alisa Manning, Patricia B Munroe, Dabeeru C Rao, Han Chen, W James Gauderman, Laura J Bierut, Thomas W Winkler, Myriam Fornage","doi":"10.1016/j.xhgg.2026.100566","DOIUrl":"10.1016/j.xhgg.2026.100566","url":null,"abstract":"<p><p>Gene-environment interactions may enhance our understanding of blood pressure (BP) biology. We conducted a meta-analysis of multi-population genome-wide association studies (GWASs) of BP traits accounting for gene-depressive symptomatology (DEPR) interactions. Our study included 564,680 adults from 67 cohorts and four population backgrounds: African (5%), Asian (7%), European (85%), and Hispanic (3%). We discovered seven previously unreported BP loci showing gene-DEPR interaction. These loci mapped to genes implicated in neurogenesis (TGFA and CASP3), lipid metabolism (ACSL1), neuronal apoptosis (CASP3), and synaptic activity (CNTN6 and DBI). We also showed evidence for gene-DEPR interaction at nine known BP loci, further suggesting links between mood disturbance and BP regulation. Of the 16 identified loci, 11 were derived from non-European populations. Post-GWAS analyses prioritized 36 genes, including genes involved in synaptic functions (DOCK4 and MAGI2) and neuronal signaling (CCK, UGDH, and SLC01A2). Integrative druggability analyses identified 11 druggable candidate gene targets linked to pathways involved in mood disorders as well as known anti-hypertensive drugs. Our findings emphasize the importance of considering gene-DEPR interactions on BP, particularly in non-European populations. Our prioritized genes and druggable targets highlight biological pathways connecting mood disorders and hypertension and suggest opportunities for BP drug repurposing and risk factor prevention, especially in individuals with DEPR.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100566"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12874302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome-wide association study of cardiovascular outcomes in chronic kidney disease: The chronic renal insufficiency cohort.","authors":"Bridget M Lin, Jia Wen, Andrea R V R Horimoto, Lingbo Zhou, Shuai Huang, Mirela Dobre, Alan S Go, Yun Li, Nora Franceschini","doi":"10.1016/j.xhgg.2026.100562","DOIUrl":"10.1016/j.xhgg.2026.100562","url":null,"abstract":"<p><p>Transcriptome-wide association studies (TWASs) are powerful for identifying gene-trait associations by integrating gene expression and genome-wide association data, but findings may be impacted by the choice of gene expression reference. We performed TWAS of cardiovascular outcomes using multi-tissue and ancestry-matched gene expression references. We used data from the Chronic Renal Insufficiency Cohort Study for participants of African (AFR, n = 1,512) and European (EUR, n = 2,067) ancestry and three outcomes: all-cause stroke, coronary heart disease, and heart failure. We performed TWASs using EUR and AFR predicted gene expression reference panels and multi-tissue TWAS by integrating gene expression from 10 GTEx selected tissues. TWAS identified KDELR2 associated with heart failure in AFR participants using matched AFR reference panel (p = 4.7 × 10^-6), although findings were near significant using the EUR mismatched reference panel (p = 5.6 × 10^-6). PSMC1 was associated with coronary heart disease in TWAS of CRIC EUR using AFR reference panel, and this gene was not present in the EUR-trained gene expression model. Multi-tissue TWASs identified KHDRBS2 significantly associated with all-cause stroke in CRIC AFR participants (p = 4.0 × 10^-6). Variants near KDELR2 have been associated with coronary artery disease, which is a main cause of heart failure, while KHDRBS2 has been associated with cardiovascular risk factors in genome-wide association studies. Our findings highlight differences in gene discovery for TWAS of cardiovascular disease applied to high-risk participants based on participant ancestry and gene expression reference panels, and gains to identify genes compared with traditional genome-wide association approaches.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100562"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12857338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145935579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired retinoic acid receptor-γ signaling underlies a heritable form of urothelial keratinizing squamous metaplasia.","authors":"Kaya Fukushima, Nicole Avery, Jade Desjardins, Benjamin J Halliday, Zandra A Jenkins, Robert Porteous, Tim Morgan, Padmini Parthasarathy, Michael Lau, Michael W Vincent, Karen J Liu, Stephen R F Twigg, Stephen P Robertson","doi":"10.1016/j.xhgg.2026.100590","DOIUrl":"10.1016/j.xhgg.2026.100590","url":null,"abstract":"<p><p>Keratinizing desquamative squamous metaplasia (KDSM) of the urinary tract is typically a sporadic condition with unclear etiology and treatment options. It is characterized by either a focal or widespread transition of normal urothelium of the bladder and ureters to a stratified squamous keratinizing epithelium. Four individuals from three generations of a single family were ascertained with a likely autosomal dominant form of syndromic KDSM. Whole-genome sequencing was performed on three affected individuals and a truncating variant (RARG NM_000966.6:c.1237C>T; NP_000957.1:p.Arg413∗) in the gene encoding retinoic acid receptor gamma (RARγ) was identified to be segregating with the phenotype. The truncating variant does not destabilize the transcript or protein produced from this allele but instead predicts the loss of half of helix 12 of RARγ, leading to reduced responsiveness of the receptor to all-trans retinoic acid via a dominant-negative mechanism. Mice heterozygous for the variant demonstrated upregulation of cytokeratin-10 in the bladder and ureteric epithelium consistent with keratinizing squamous metaplasia of the urothelium. The implicated dominant-negative mechanism reduces retinoic acid signaling via heterodimeric receptors that incorporate the variant γ subunit and indicates that this condition may be addressable with high-dose retinoic acid receptor agonists.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100590"},"PeriodicalIF":3.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13050057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147460536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detailed assessment of rare and common TERT variation in a family with a telomere biology disorder.","authors":"Logan P Zeigler, Oscar Florez-Vargas, Burak Altintas, Marena R Niewisch, Weiyin Zhou, Neelam Giri, Maryam Rafati, Michael Poeschla, Vijay G Sankaran, Tsung-Po Lai, Abraham Aviv, Kristine Jones, Wen Luo, Jia Liu, Lisa J McReynolds, Tianna Zhao, Ludmila Prokunina-Olsson, Sharon A Savage","doi":"10.1016/j.xhgg.2025.100536","DOIUrl":"10.1016/j.xhgg.2025.100536","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) are caused by rare pathogenic variants in telomere maintenance genes and often present with variable penetrance of multi-organ system manifestations. We evaluated a family with 14 individuals heterozygous for TERT c.2591T>C (p.L864P) and 13 non-carriers. TRAP assays showed that p.L864P causes a complete loss of telomerase activity. Carriers had shorter lymphocyte telomeres than non-carriers. Carriers presented different TBD manifestations, but had similar telomere length (TL) distributions, suggesting variable penetrance and possible genetic anticipation. Somatic TERT promoter mutations were detected in four carriers aged >50 years (variant allele fractions <4% in three and 18%-19% in one). Exome sequencing did not identify other variants of interest. Although not statistically significant, polygenic scores derived from common TL-associated genetic variation were lower in c.2591T>C carriers with more TBD clinical manifestations. Alleles associated with alternative TERT splicing, VNTR6-1-Long and rs10069690-T, co-segregated with c.2591T>C. This haplotype was associated with a reduction in TL Z score (β = -1.81, p < 0.0001). Another haplotype, c.2591T, VNTR6-1-Long, and rs10069690-T, demonstrated an independent reduction of TL Z score (β = -0.84, p = 0.0111). The TBD manifestations in this family may relate to common TL-associated genetic variation and alternative TERT splicing, emphasizing the importance of investigations into TBD manifestations within and between TBD families.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100536"},"PeriodicalIF":3.6,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12639602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}