Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing
Abstract Despite the well‐documented mutation spectra of β‐thalassemia, the genetic variants and haplotypes of globin gene clusters modulating its clinical heterogeneity remain incompletely illustrated. Here, a targeted long‐read sequencing (T‐LRS) is demonstrated to capture 20 genes/loci in 1,020 β...
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2025-03-01
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| Online Access: | https://doi.org/10.1002/advs.202410992 |
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| author | Yuhua Ye Chao Niu Aiping Mao Lang Qin Jiahan Zhan Weijie Chen Zhentian Liu Tiantian Xie Qianqian Zhang Jiaqi Li Li Huang Wanli Meng Yumeng Liu Liuhua Liao Junqin Cai Riyang Liu Xinhua Zhang Lihong Zeng Yaoyun Li Bin Lin Kui Li Xiaoyun Hua Binbin Huang Honggui Qin Yueyan Huang Zhijing Huang Jinquan Lao Xiang Qu Juanjuan Chen Xiaoqin Feng Qiujun Liu Wanying Lin Xiaoman Zhou Yidan Liang Xingjiang Long Jiaofeng Qin Lixiang Yan Weijian Zhu Lian Yu Chengwu Fan Deguo Tang Tianyu Zhong Jufang Tan Zhilin Ren Xiangmin Xu |
| author_facet | Yuhua Ye Chao Niu Aiping Mao Lang Qin Jiahan Zhan Weijie Chen Zhentian Liu Tiantian Xie Qianqian Zhang Jiaqi Li Li Huang Wanli Meng Yumeng Liu Liuhua Liao Junqin Cai Riyang Liu Xinhua Zhang Lihong Zeng Yaoyun Li Bin Lin Kui Li Xiaoyun Hua Binbin Huang Honggui Qin Yueyan Huang Zhijing Huang Jinquan Lao Xiang Qu Juanjuan Chen Xiaoqin Feng Qiujun Liu Wanying Lin Xiaoman Zhou Yidan Liang Xingjiang Long Jiaofeng Qin Lixiang Yan Weijian Zhu Lian Yu Chengwu Fan Deguo Tang Tianyu Zhong Jufang Tan Zhilin Ren Xiangmin Xu |
| author_sort | Yuhua Ye |
| collection | DOAJ |
| description | Abstract Despite the well‐documented mutation spectra of β‐thalassemia, the genetic variants and haplotypes of globin gene clusters modulating its clinical heterogeneity remain incompletely illustrated. Here, a targeted long‐read sequencing (T‐LRS) is demonstrated to capture 20 genes/loci in 1,020 β‐thalassemia patients. This panel permits not only identification of thalassemia mutations at 100% of sensitivity and specificity, but also detection of rare structural variants (SVs) and single nucleotide variants (SNVs) in modifier genes/loci. The highly homologous regions of α‐/β‐globin gene clusters are then phased and 3 novel haplotypes in HBG1/HBG2 region are reported in this population of β‐thalassemia patients. Furthermore, one of the haplotypes is associated with ameliorated symptoms of β‐thalassemia. Similarly, 5 major haplotypes are identified in HBA1/HBA2 homologous region while one of them is found highly linked with deletional α‐thalassemia mutations. Finally, rare mutations in erythroid transcription factors in DNMT1 and KLF1 associated with increased expression of fetal hemoglobin and reduced transfusion dependencies are identified. This study presents the largest T‐LRS study for β‐thalassemia patients to date, facilitating precise clinical diagnosis and haplotype phasing of globin gene clusters. |
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| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-f80e64c84d914be1bd945f75d5a5e85f2025-06-27T08:21:37ZengWileyAdvanced Science2198-38442025-03-01129n/an/a10.1002/advs.202410992Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read SequencingYuhua Ye0Chao Niu1Aiping Mao2Lang Qin3Jiahan Zhan4Weijie Chen5Zhentian Liu6Tiantian Xie7Qianqian Zhang8Jiaqi Li9Li Huang10Wanli Meng11Yumeng Liu12Liuhua Liao13Junqin Cai14Riyang Liu15Xinhua Zhang16Lihong Zeng17Yaoyun Li18Bin Lin19Kui Li20Xiaoyun Hua21Binbin Huang22Honggui Qin23Yueyan Huang24Zhijing Huang25Jinquan Lao26Xiang Qu27Juanjuan Chen28Xiaoqin Feng29Qiujun Liu30Wanying Lin31Xiaoman Zhou32Yidan Liang33Xingjiang Long34Jiaofeng Qin35Lixiang Yan36Weijian Zhu37Lian Yu38Chengwu Fan39Deguo Tang40Tianyu Zhong41Jufang Tan42Zhilin Ren43Xiangmin Xu44Innovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaInnovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Long‐Read Sequencing Research and Development Berry Genomics Corporation Beijing 102200 ChinaInnovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Long‐Read Sequencing Research and Development Berry Genomics Corporation Beijing 102200 ChinaInnovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Long‐Read Sequencing Research and Development Berry Genomics Corporation Beijing 102200 ChinaDepartment of Long‐Read Sequencing Research and Development Berry Genomics Corporation Beijing 102200 ChinaInnovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Long‐Read Sequencing Research and Development Berry Genomics Corporation Beijing 102200 ChinaInnovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Long‐Read Sequencing Research and Development Berry Genomics Corporation Beijing 102200 ChinaInnovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Pediatrics Huizhou Central People's Hospital Huizhou Guangdong 516001 ChinaDepartment of Pediatrics Huizhou Central People's Hospital Huizhou Guangdong 516001 ChinaDepartment of Pediatrics Huizhou Central People's Hospital Huizhou Guangdong 516001 ChinaDepartment of Hematology 923(rd) Hospital of the People's Liberation Army Nanning Guangxi 530021 ChinaDepartment of Hematology 923(rd) Hospital of the People's Liberation Army Nanning Guangxi 530021 ChinaDepartment of Pediatrics 923(rd) Hospital of the People's Liberation Army Nanning Guangxi 530021 ChinaGuangzhou Huayinkang Healthcare Group Co., Ltd. Guangzhou Guangdong 510663 ChinaGuangzhou Huayinkang Healthcare Group Co., Ltd. Guangzhou Guangdong 510663 ChinaGuangzhou Huayinkang Healthcare Group Co., Ltd. Guangzhou Guangdong 510663 ChinaDepartment of Internal Medicine Sixth People's Hospital of Nanning Nanning Guangxi 530022 ChinaDepartment of Internal Medicine Sixth People's Hospital of Nanning Nanning Guangxi 530022 ChinaDepartment of Pediatrics Affiliated Hospital of Youjiang Medical University for Nationalities Baise Guangxi 533000 ChinaDepartment of Pediatrics Affiliated Hospital of Youjiang Medical University for Nationalities Baise Guangxi 533000 ChinaDepartment of Pediatrics Liuzhou Worker's Hospital Liuzhou Guangxi 545005 ChinaDepartment of Pediatrics Liuzhou Worker's Hospital Liuzhou Guangxi 545005 ChinaDepartment of Pediatrics The Second People's Hospital of Shenzhen The First Affiliated Hospital of Shenzhen University Shenzhen Guangdong 518035 ChinaDepartment of Pediatrics Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Pediatrics Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Laboratory Medicine Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaCentral Laboratory Dongguan Songshan Lake Central Hospital Dongguan Guangdong 523808 ChinaInnovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaDepartment of Pediatrics Liuzhou People's Hospital Liuzhou Guangxi 545001 ChinaDepartment of Pediatrics Liuzhou People's Hospital Liuzhou Guangxi 545001 ChinaMedical Genetics Laboratory Heyuan Maternal and Child Health Care Hospital Heyuan Guangdong 517000 ChinaDepartment of Hematology and Oncology Zhuhai People's Hospital The Third Affiliated Hosptial Jinan University Medical College Zhuhai Guangdong 519000 ChinaDepartment of Hematology and Rheumatology Longyan First Hospital Affiliated to Fujian Medical University Longyan Fujian 364000 ChinaDepartment of Pediatrics Second people's hospital of Guilin Guilin Guangxi 541001 ChinaDepartment of Genetics and Laboratory Medicine Maternal and Child Health Hospital of Yongzhou City Yongzhou Hunan 425000 ChinaDepartment of Clinical Laboratory The First Affiliated Hospital of Gannan Medical University Ganzhou Jiangxi 341000 ChinaPrenatal Diagnosis Center Chenzhou First People's Hospital Chenzhou Hunan 423000 ChinaDepartment of Long‐Read Sequencing Research and Development Berry Genomics Corporation Beijing 102200 ChinaInnovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 ChinaAbstract Despite the well‐documented mutation spectra of β‐thalassemia, the genetic variants and haplotypes of globin gene clusters modulating its clinical heterogeneity remain incompletely illustrated. Here, a targeted long‐read sequencing (T‐LRS) is demonstrated to capture 20 genes/loci in 1,020 β‐thalassemia patients. This panel permits not only identification of thalassemia mutations at 100% of sensitivity and specificity, but also detection of rare structural variants (SVs) and single nucleotide variants (SNVs) in modifier genes/loci. The highly homologous regions of α‐/β‐globin gene clusters are then phased and 3 novel haplotypes in HBG1/HBG2 region are reported in this population of β‐thalassemia patients. Furthermore, one of the haplotypes is associated with ameliorated symptoms of β‐thalassemia. Similarly, 5 major haplotypes are identified in HBA1/HBA2 homologous region while one of them is found highly linked with deletional α‐thalassemia mutations. Finally, rare mutations in erythroid transcription factors in DNMT1 and KLF1 associated with increased expression of fetal hemoglobin and reduced transfusion dependencies are identified. This study presents the largest T‐LRS study for β‐thalassemia patients to date, facilitating precise clinical diagnosis and haplotype phasing of globin gene clusters.https://doi.org/10.1002/advs.202410992fetal hemoglobinthalassemiathird‐generation sequencing |
| spellingShingle | Yuhua Ye Chao Niu Aiping Mao Lang Qin Jiahan Zhan Weijie Chen Zhentian Liu Tiantian Xie Qianqian Zhang Jiaqi Li Li Huang Wanli Meng Yumeng Liu Liuhua Liao Junqin Cai Riyang Liu Xinhua Zhang Lihong Zeng Yaoyun Li Bin Lin Kui Li Xiaoyun Hua Binbin Huang Honggui Qin Yueyan Huang Zhijing Huang Jinquan Lao Xiang Qu Juanjuan Chen Xiaoqin Feng Qiujun Liu Wanying Lin Xiaoman Zhou Yidan Liang Xingjiang Long Jiaofeng Qin Lixiang Yan Weijian Zhu Lian Yu Chengwu Fan Deguo Tang Tianyu Zhong Jufang Tan Zhilin Ren Xiangmin Xu Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing Advanced Science fetal hemoglobin thalassemia third‐generation sequencing |
| title | Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing |
| title_full | Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing |
| title_fullStr | Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing |
| title_full_unstemmed | Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing |
| title_short | Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing |
| title_sort | haplotype resolved genotyping and association analysis of 1 020 β thalassemia patients by targeted long read sequencing |
| topic | fetal hemoglobin thalassemia third‐generation sequencing |
| url | https://doi.org/10.1002/advs.202410992 |
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