DataVXAdvanced SciencePaper
journal article·2025-03Open access

Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing

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

Advanced Science· Volume 12· Issue 9
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Source abstract

Abstract

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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Research context

OpenAlex topics: Hemoglobinopathies and Related Disorders · Iron Metabolism and Disorders · Genomics and Rare Diseases

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Innovation Center for Diagnostics and Treatment of Thalassemia Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 China

Department of Medical Genetics School of Basic Medical Sciences Southern Medical University Guangzhou Guangdong 510515 China

Department of Long‐Read Sequencing Research and Development Berry Genomics Corporation Beijing 102200 China

Department of Pediatrics Huizhou Central People's Hospital Huizhou Guangdong 516001 China

Department of Hematology 923(rd) Hospital of the People's Liberation Army Nanning Guangxi 530021 China

Department of Pediatrics 923(rd) Hospital of the People's Liberation Army Nanning Guangxi 530021 China

Guangzhou Huayinkang Healthcare Group Co., Ltd. Guangzhou Guangdong 510663 China

Department of Internal Medicine Sixth People's Hospital of Nanning Nanning Guangxi 530022 China

Department of Pediatrics Affiliated Hospital of Youjiang Medical University for Nationalities Baise Guangxi 533000 China

Department of Pediatrics Liuzhou Worker's Hospital Liuzhou Guangxi 545005 China

Department of Pediatrics The Second People's Hospital of Shenzhen The First Affiliated Hospital of Shenzhen University Shenzhen Guangdong 518035 China

Department of Pediatrics Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 China

Department of Laboratory Medicine Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 China

Central Laboratory Dongguan Songshan Lake Central Hospital Dongguan Guangdong 523808 China

Department of Pediatrics Liuzhou People's Hospital Liuzhou Guangxi 545001 China

Medical Genetics Laboratory Heyuan Maternal and Child Health Care Hospital Heyuan Guangdong 517000 China

Department of Hematology and Oncology Zhuhai People's Hospital The Third Affiliated Hosptial Jinan University Medical College Zhuhai Guangdong 519000 China

Department of Hematology and Rheumatology Longyan First Hospital Affiliated to Fujian Medical University Longyan Fujian 364000 China

Department of Pediatrics Second people's hospital of Guilin Guilin Guangxi 541001 China

Department of Genetics and Laboratory Medicine Maternal and Child Health Hospital of Yongzhou City Yongzhou Hunan 425000 China

Department of Clinical Laboratory The First Affiliated Hospital of Gannan Medical University Ganzhou Jiangxi 341000 China

Prenatal Diagnosis Center Chenzhou First People's Hospital Chenzhou Hunan 423000 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China

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