Human Genetics最新文献_第5页

Large-scale mitogenome analysis reveals complex maternal genetic connections between Sino-Tibetan- and Altaic-speaking populations. 大规模的有丝分裂基因组分析揭示了汉藏语系和阿尔泰语系人口之间复杂的母系遗传联系。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-06-13 DOI: 10.1007/s00439-026-02842-5

Yutong Jiang, Lintao Luo, Yunhui Liu, Lingqing Ou, Jiayan Liang, Limei Zhang, Moru Guo, Yanling Liu, Jie Zhong, Bowen Li, Zihao Zhu, Yuzhu Wang, Yuguo Huang, Chao Liu, Yuhang Feng, Guanglin He, Mengge Wang, Renkuan Tang

{"title":"Large-scale mitogenome analysis reveals complex maternal genetic connections between Sino-Tibetan- and Altaic-speaking populations.","authors":"Yutong Jiang, Lintao Luo, Yunhui Liu, Lingqing Ou, Jiayan Liang, Limei Zhang, Moru Guo, Yanling Liu, Jie Zhong, Bowen Li, Zihao Zhu, Yuzhu Wang, Yuguo Huang, Chao Liu, Yuhang Feng, Guanglin He, Mengge Wang, Renkuan Tang","doi":"10.1007/s00439-026-02842-5","DOIUrl":"10.1007/s00439-026-02842-5","url":null,"abstract":"The Sino-Tibetan and Altaic groups have played central roles in shaping the human demographic history of populations at the crossroads of East Asia and Siberia. However, their matrilineal relationships and links to complex cultural interactions remain poorly resolved. Here, we reported 344 newly sequenced complete mitogenomes from representative populations and integrated them with a curated dataset of more than 53,000 reference sequences. We uncovered a highly structured maternal genetic landscape, in which Sino-Tibetan and Altaic groups shared some maternal lineages despite distinct demographic trajectories, including East Asian haplogroups D4 and A. Sino-Tibetan-speaking populations showed elevated frequencies of B4, F1, and M7, whereas Altaic-speaking populations were enriched for C, H, and U. These observed genomic diversity patterns were jointly shaped by linguistic affiliation and geography. High-resolution phylogeographic analyses further showed that Tibeto-Burman groups from the Qinghai-Tibetan Plateau (QTP) carried distinctive maternal components, including region-specific sub-lineages within A, M9, and R32. Phylogenetic reconstructions dated the maternal lineages shared by Sino-Tibetan- and Altaic-speaking populations to 56.87-10.86 thousand years ago (kya), indicating that these early divergences formed the primary genetic foundation of both groups, whereas later Neolithic expansions contributed only modestly. Mongolic groups from the Inner Mongolian Plateau shared some maternal lineages with QTP populations, largely dating to 26.83-12.72 kya, indicating deep maternal connections despite substantial geographic separation.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: A comprehensive and accessible model for co-segregation analysis in BRCA1, BRCA2, and PALB2 variant classification. 更正：BRCA1、BRCA2和PALB2变体分类中共分离分析的一个全面和可访问的模型。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-06-10 DOI: 10.1007/s00439-026-02844-3

Setareh Moghadasi, Ramin Monajemi, Merel E Braspenning, Maaike P G Vreeswijk, Mar Rodríguez-Girondo

引用次数: 0

The 2023 clinical laboratory genetics workforce in the United States: trends, challenges, and evolving practices. 2023年美国临床实验室遗传学劳动力：趋势、挑战和不断发展的实践。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-06-05 DOI: 10.1007/s00439-026-02834-5

Cinthya J Zepeda-Mendoza, Rhonda West, Yassmine Akkari, Erica F Andersen, Miriam G Blitzer, Jennelle C Hodge, Honey V Reddi, Marci K Sontag, Megan Lyon

{"title":"The 2023 clinical laboratory genetics workforce in the United States: trends, challenges, and evolving practices.","authors":"Cinthya J Zepeda-Mendoza, Rhonda West, Yassmine Akkari, Erica F Andersen, Miriam G Blitzer, Jennelle C Hodge, Honey V Reddi, Marci K Sontag, Megan Lyon","doi":"10.1007/s00439-026-02834-5","DOIUrl":"10.1007/s00439-026-02834-5","url":null,"abstract":"This study analyzed data from the National Coordinating Center for the Regional Genetics Networks (NCC) 2023 electronic survey to gather insights on current workforce trends and challenges faced by clinical laboratory geneticists in the United States. The analysis included demographics, certifications, career stages, practice patterns, staffing, reimbursement practices, and burnout levels. A total of 375 clinical laboratory geneticists responded to the survey (36.9% response rate). The workforce predominantly identifies as White and female, with limited representation from African-American/Black, Latinx/Hispanic, and Native American groups. The field includes both experienced professionals and newer entrants, with up to 25% of respondents anticipating retirement within the next decade and another 27% uncertain of retirement timeline. Technician/technologist staffing shortages were reported by over half of respondents and included other key laboratory roles such as genetic counselors and variant scientists. Concerns about reimbursement practices for new technologies and increased complexity in test interpretation were expressed by nearly 33% of respondents. Inequities in reimbursement for PhD-trained clinical laboratory directors were identified, along with increased staff strain and heightened burnout, especially among mid-career professionals. Together, these findings underscore the urgent need for dedicated strategic initiatives to enhance workforce diversity, address staffing and compensation disparities, improve resource allocation, and alleviate burnout to ensure a sustainable future for clinical laboratory geneticists.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex differences and alcohol modulation in the heritability of MASLD: a twin study of the 2023 definition. 性别差异和酒精调节在MASLD遗传力中的作用：2023年定义的双胞胎研究

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-06-05 DOI: 10.1007/s00439-026-02837-2

Jingxian Li, Jiping Zhong, Jia Luo, Tong Wang, Chunsheng Xu, Weijing Wang, Xiaocao Tian, Dongfeng Zhang

{"title":"Sex differences and alcohol modulation in the heritability of MASLD: a twin study of the 2023 definition.","authors":"Jingxian Li, Jiping Zhong, Jia Luo, Tong Wang, Chunsheng Xu, Weijing Wang, Xiaocao Tian, Dongfeng Zhang","doi":"10.1007/s00439-026-02837-2","DOIUrl":"10.1007/s00439-026-02837-2","url":null,"abstract":"The baseline heritability of the newly defined metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown. Given that sex and alcohol consumption are well-recognized determinants of fatty liver disease, it is important to understand whether they are also associated with variation in its underlying genetic susceptibility. We aimed to quantify the baseline heritability and investigate these potential effects in a classical twin study of 710 Chinese adults using structural equation modeling. We observed a baseline narrow-sense heritability (A) of 0.57 (95% CI 0.46-0.67) in the lower alcohol intake group. This genetic contribution was not uniform and showed a potential difference by sex, with heritability tending to be higher in females (0.63) than in males (0.30). Furthermore, the genetic architecture appeared to vary across alcohol exposure levels. In contrast to the additive (AE) model observed in lower drinkers, the higher alcohol intake group was better fitted by a dominant/non-additive (DE) model, yielding a broad-sense heritability (D) of 0.60 (95% CI 0.34-0.77). In conclusion, our findings suggest that the genetic architecture of MASLD may vary according to sex and alcohol consumption, highlighting potential gene-environment interactions and the context-dependent nature of genetic susceptibility. These results may have implications for future risk stratification and targeted prevention strategies.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ScSpTITH: a rank-correlation framework for robust quantification of multi-dimensional tumor heterogeneity. ScSpTITH：用于多维肿瘤异质性稳健量化的秩相关框架。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-06-01 DOI: 10.1007/s00439-026-02841-6

Jiangti Luo, Qiqi Lu, Xiaobo Zhang, Xiaosheng Wang

{"title":"ScSpTITH: a rank-correlation framework for robust quantification of multi-dimensional tumor heterogeneity.","authors":"Jiangti Luo, Qiqi Lu, Xiaobo Zhang, Xiaosheng Wang","doi":"10.1007/s00439-026-02841-6","DOIUrl":"10.1007/s00439-026-02841-6","url":null,"abstract":"Intra- and inter-tumoral heterogeneity (ITH) is a fundamental hallmark of cancer, driving spatial, temporal, cellular, and tumor microenvironmental (TME) complexity and critically contributing to therapeutic resistance. Single-cell RNA sequencing (scRNA-seq) provides unprecedented resolution for dissecting tumor heterogeneity; however, its accuracy is severely compromised by pervasive \"dropout\" artifacts, resulting in zero-inflation rates of 70-95% in typical scRNA-seq datasets. To address this limitation, we introduce ScSpTITH (Single-cell and Spatial Transcriptomic Intra-/inter-Tumoral Heterogeneity), a robust computational framework for quantifying ITH in both scRNA-seq and spatial transcriptomic data. ScSpTITH first selects highly variable genes based on standard deviation to prioritize biologically informative features, and then computes pairwise Spearman rank correlations across cells. This rank-based strategy confers inherent robustness to technical noise, non-normality, and high dropout rates, enabling stable and interpretable quantification of transcriptional heterogeneity. Across diverse cancer and developmental datasets, elevated ScSpTITH scores are strongly associated with active tumor evolution, advanced disease stage, pronounced cellular plasticity, therapeutic resistance, and poor clinical outcomes. ScSpTITH is scalable and flexible, allowing heterogeneity to be quantified across inter-tumoral and intra-tumoral dimensions, including spatial regions, cell populations, and treatment conditions. Collectively, ScSpTITH provides a unified and robust framework for dissecting multi-dimensional heterogeneity in single-cell and spatial transcriptomic studies.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148137537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Contrasting ancestry patterns inferred from Y chromosome and mitochondrial DNA in Nanjing people from southwestern China. 从中国西南南京人的Y染色体和线粒体DNA推断的祖先模式对比。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-05-23 DOI: 10.1007/s00439-026-02836-3

Lintao Luo, Yunhui Liu, Yutong Jiang, Minzhu Zhao, Zihao Zhu, Yuzhu Wang, Limei Zhang, Renkuan Tang, Guanglin He, Mengge Wang, Jianbo Li, Chao Liu, Shixiong Deng

{"title":"Contrasting ancestry patterns inferred from Y chromosome and mitochondrial DNA in Nanjing people from southwestern China.","authors":"Lintao Luo, Yunhui Liu, Yutong Jiang, Minzhu Zhao, Zihao Zhu, Yuzhu Wang, Limei Zhang, Renkuan Tang, Guanglin He, Mengge Wang, Jianbo Li, Chao Liu, Shixiong Deng","doi":"10.1007/s00439-026-02836-3","DOIUrl":"10.1007/s00439-026-02836-3","url":null,"abstract":"Whole Y-chromosome and mitochondrial variations provide insights into deep demographic histories and sex-biased admixture that often remain undetected through autosomal-based analyses. The Nanjing people, an unofficially recognized group in western Guizhou, have historically been described as migrant soldiers from coastal Jiangsu and classified as Bai, exhibiting a complex and poorly understood genetic origin. To investigate their demographic history, we analyzed genetic variation in a large-scale, ethnolinguistically diverse Chinese genomic resource, including 42 newly sequenced genomes from the Nanjing people and 1,454 ancient and modern reference whole-genome sequences. Phylogenetic and demographic analyses revealed that both northern and southern Chinese Y-chromosome lineages contributed to the paternal ancestry of the Nanjing people. We identified one dominant paternal lineage, O2a2b1a1a1c1a1a, that likely originated in northern and eastern China, underwent a bottleneck ~ 1,700 years before present (YBP), and expanded around 600 YBP. In contrast, maternal lineages, particularly F1, M7, and B4, showed strong affinities with southern Chinese and northern Vietnamese populations, indicating a southwestern indigenous maternal origin. The discordant paternal and maternal origin patterns indicate that male migrant soldiers from coastal northern China interbred with indigenous southwestern Chinese females, supporting a strongly sex-biased model of admixture formation. These findings shed new light on the genetic origins and evolution of the Nanjing people, underscoring the power of uniparental markers in disentangling complex and sex-biased demographic processes.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of a question prompt list to support Consent for Genomic Testing (CoGenT) and research. 开发一个问题提示列表，以支持基因组测试同意（CoGenT）和研究。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-05-21 DOI: 10.1007/s00439-026-02839-0

Jolyn Hersch, Lauren O'Hara, Phyllis Butow, Mandy Ballinger, Rebekah Laidsaar-Powell, Nicci Bartley, Kirsten McCaffery, Anastasia Latin, Christine Cockburn, Caitlin Delaney, Katherine M Tucker, Ilona Juraskova

{"title":"Development of a question prompt list to support Consent for Genomic Testing (CoGenT) and research.","authors":"Jolyn Hersch, Lauren O'Hara, Phyllis Butow, Mandy Ballinger, Rebekah Laidsaar-Powell, Nicci Bartley, Kirsten McCaffery, Anastasia Latin, Christine Cockburn, Caitlin Delaney, Katherine M Tucker, Ilona Juraskova","doi":"10.1007/s00439-026-02839-0","DOIUrl":"10.1007/s00439-026-02839-0","url":null,"abstract":"While genomic testing is increasingly utilised to personalise cancer treatment, its complexity creates challenges in achieving informed consent. Partnering with patients, carers, researchers and health professionals, we developed a Question Prompt List (QPL) aiming to support communication and informed consent for tumour profiling and genomic research in oncology. Participants (n = 38) included cancer patients participating (or not) in genomic research, carers, researchers and clinicians. Two rounds of interviews elicited information needs and suggested questions, followed by feedback on the draft QPL and its potential value. We produced concise answers for all questions, edited wording using health literacy principles, and refined according to feedback. The QPL includes 29 items arranged into three sections: Comprehensive Genomic Profiling (CGP), Results of CGP, and About the Genomic Research Study. Participants believed the QPL would empower patients and carers, support clinicians and researchers to engage with patient/family queries, and enable better informed consent in genomic oncology. The Consent in Genomic Testing (CoGenT) Question Prompt List, including evidence-based answers, has been developed rigorously and collaboratively. This simple and flexible tool is perceived as acceptable and useful for patients, carers, clinicians, and research personnel engaging in informed consent for genomic research including tumour profiling.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13194191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tracing the genetic legacy of Altaic-speaking populations suggested long-distance migration and multi-source admixture shape the genomic diversity of Xibe and Daur. 对阿尔泰语人群遗传遗产的追踪表明，远距离迁移和多源混合形成了锡伯族和达斡尔族的基因组多样性。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-05-19 DOI: 10.1007/s00439-026-02835-4

Yuzhu Wang, Limei Zhang, Yutong Jiang, Sijia Zhu, Yufeng Liu, Qiuxia Sun, Didi Yuan, Moru Guo, Jiayan Liang, Lingqing Ou, Shuhan Duan, Lintao Luo, Chao Liu, Yun Liu, Yan Liu, Renkuan Tang, Mengge Wang, Guanglin He

{"title":"Tracing the genetic legacy of Altaic-speaking populations suggested long-distance migration and multi-source admixture shape the genomic diversity of Xibe and Daur.","authors":"Yuzhu Wang, Limei Zhang, Yutong Jiang, Sijia Zhu, Yufeng Liu, Qiuxia Sun, Didi Yuan, Moru Guo, Jiayan Liang, Lingqing Ou, Shuhan Duan, Lintao Luo, Chao Liu, Yun Liu, Yan Liu, Renkuan Tang, Mengge Wang, Guanglin He","doi":"10.1007/s00439-026-02835-4","DOIUrl":"10.1007/s00439-026-02835-4","url":null,"abstract":"Long-distance migrations across Eurasia have led to extensive admixture among ethnolinguistically diverse Altaic speakers and their Indo-European neighbors; however, the population histories of the Xibe and Daur in northern China remain poorly understood. We address this gap by analyzing genome-wide SNP data from 324 individuals to characterize genetic structure, admixture, and migration. Both groups cluster with East Asian populations, particularly Altaic-speaking groups, consistent with a shared origin of the geographically distinct Xibe and Daur populations. We identify divergent post-migration histories, in which northwestern Chinese Xibe show distinct profiles and stronger genetic ties to the Daur, while northeastern Xibe have substantial contributions from indigenous ancient Northeast Asian (ANA) and Sino-Tibetan speakers. Admixture modeling indicates that Daur and the majority of Xibe populations are best described as two-way mixtures with Han and ANA groups; a distinct West Eurasian/Steppe signal persists in specific Shandong subgroups, reflecting historical trans-Eurasian cultural interactions and gene flow. Notably, Xinjiang Xibe share a high-ANA genetic profile, whereas other Xibe groups possess additional Han-related ancestry. Shared-segment analyses support a northeastern origin for the Xinjiang Xibe, where subsequent westward migration served as a complementary event that preserved this ancestral diversity, whereas the Daur retains strong ties to ANA, especially those from Inner Mongolia. Together, these results clarify the layered demographic histories of Xibe and Daur, refine models of population structure in northern East Asia, and illustrate how repeated movements and regional interactions generate present-day genomic diversity at the crossroads between North China and Siberia.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147972123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bringing environment back into human evolution: why human genetics needs genome-environment association studies. 将环境带回人类进化：为什么人类遗传学需要基因组-环境关联研究。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-05-08 DOI: 10.1007/s00439-026-02838-1

Pei-Wei Sun

{"title":"Bringing environment back into human evolution: why human genetics needs genome-environment association studies.","authors":"Pei-Wei Sun","doi":"10.1007/s00439-026-02838-1","DOIUrl":"10.1007/s00439-026-02838-1","url":null,"abstract":"Understanding the genetic basis of human adaptation to environmental pressures is a central question in evolutionary biology. Recent advancements in genome-environment association (GEA) methods have provided novel insights into how genetic variation is shaped by climate, diet, altitude, pathogens, and other environmental factors. However, despite significant progress in non-human studies, the application of GEA in human populations remains underused. This article synthesizes recent GEA methodological advancements, including redundancy analysis (RDA) and machine learning approaches, such as gradient forest (GF), to improve the detection of selection signals while accounting for demographic noise. Furthermore, I discuss the implications of historical GEA projection and genetic offset to human adaptation, particularly in the context of rapid urbanization and climate change. By integrating genomic, environmental, and epidemiological data, GEA has the potential not only to enhance our understanding of past human evolution but also to evaluate how allele-environment relationships may shift under future environmental change. By refining statistical models and expanding studies to diverse populations, GEA can play a critical role in elucidating the mechanisms underlying human adaptation and characterizing how selective forces shape the spatial distribution of adaptive alleles.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel splice site variant in DEGS1 leads to aberrant splicing and loss of DEGS1 enzyme activity, a VUS resolved. DEGS1中一个新的剪接位点变异导致异常剪接和DEGS1酶活性的丧失，这是VUS解决的问题。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-05-06 DOI: 10.1007/s00439-026-02830-9

Holly C Beale, Victor Tse, Joanna Y Lee, Jon Akutagawa, Yusuph Mavura, Brandon Saint-John, Allison Cheney, Dennis R Mulligan, Guillermo Chacaltana, Martin Gutierrez, Jessica Tenney, Joseph T Shieh, Pierre-Marie Martin, Tiffany Yip, Ugur Hodoglugil, Alex J Fay, Angela N Brooks, Jessica Van Ziffle, Michael D Stone, Neil Risch, Jeremy R Sanford, Patrick Devine, Julie D Saba, Olena M Vaske, Anne Slavotinek

{"title":"A novel splice site variant in DEGS1 leads to aberrant splicing and loss of DEGS1 enzyme activity, a VUS resolved.","authors":"Holly C Beale, Victor Tse, Joanna Y Lee, Jon Akutagawa, Yusuph Mavura, Brandon Saint-John, Allison Cheney, Dennis R Mulligan, Guillermo Chacaltana, Martin Gutierrez, Jessica Tenney, Joseph T Shieh, Pierre-Marie Martin, Tiffany Yip, Ugur Hodoglugil, Alex J Fay, Angela N Brooks, Jessica Van Ziffle, Michael D Stone, Neil Risch, Jeremy R Sanford, Patrick Devine, Julie D Saba, Olena M Vaske, Anne Slavotinek","doi":"10.1007/s00439-026-02830-9","DOIUrl":"10.1007/s00439-026-02830-9","url":null,"abstract":"Pathogenic DEGS1 variants have been reported in individuals with autosomal recessive hypomyelinating leukodystrophy 18 (HLD18; MIM# 618404). Here we describe three participants with HLD features and a previously unreported homozygous DEGS1 5' splice site variant, c.825+4_825 + 5delAGinsTT (NM_003676.4). We used next-generation DNA and transcriptome sequencing, cell-based splicing assays, and tandem mass spectrometry to detect and characterize the variant's impact on DEGS1 expression. We then performed RNA structure probing and conventional antisense oligonucleotide screening to investigate molecular mechanisms for potential therapeutic intervention. We show that the splice site variant: (1) was sufficient to induce exon two skipping in most detected transcripts; (2) resulted in structural changes to the 5' and 3' splice site regions using RNA structure probing; and (3) corresponds to plasma sphingolipid profiles consistent with loss of sphingolipid delta(4)-desaturase activity. Our RNA and lipidomic evidence proved that the DEGS1 variant c.825+4_825 + 5delAGinsTT is pathogenic and suggested a mechanistic model that explains how exon two skipping is induced.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13149559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0