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

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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Journal
Advanced Science
Published
2024-12-31
DOI
https://doi.org/10.1002/advs.202410992
Citations
2
Primary Topic
Hemoglobinopathies and Related Disorders
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article
Field-Weighted Citation Impact
0.88

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article

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

Jiahan Zhan, Jiaofeng Qin, Jufang Tan, Tiantian Xie et al.
2 citations
Advanced Science
Hemoglobinopathies and Related Disorders
0.88
article

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

Jiahan Zhan, Jiaofeng Qin, Jufang Tan, Tiantian Xie, Yuhua Ye, Tianyu Zhong, Hong‐Yan Qin, Lixiang Yan, Yaoyun Li, Riyang Liu, Lihong Zeng, Liuhua Liao, Zhilin Ren, Aiping Mao, Wanli Meng, Deguo Tang, Jinquan Lao, Qiujun Liu, Jiaqi Li, Qianqian Zhang, Kui Li, Chao Shi Niu, Yumeng Liu, Weijie Chen, Li Huang, Juanjuan Chen, Chengwu Fan, Xiaoqin Feng, Binbin Huang, Wanying Lin, Weijian Zhu, Xiaoman Zhou, Xing‐Jiang Long, Zhijing Huang, Zhentian Liu, Xiangmin Xu, Jinfu Cai, Lian Yu, Yidan Liang, Xiaoyun Hua, Xiang Qu, Yueyan Huang, Lang Qin, Xinhua Zhang, Bin Lin
article en
2 citations

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.

Advanced ScienceVol. 12(9)
Fujian Medical University (CN), Jinan University (CN), Guilin Medical University (CN), Liuzhou Maternal and Child Health Hospital (CN), Liuzhou General Hospital (CN), Nanfang Hospital (CN), Zhuhai People's Hospital (CN), Songshan Lake Materials Laboratory (CN), First Affiliated Hospital of Fujian Medical University (CN), Affiliated Hospital of Youjiang Medical University for Nationalities (CN), First Affiliated Hospital of Gannan Medical University (CN), The Second Nanning People's Hospital (CN), Fourth Affiliated Hospital of Guangxi Medical University (CN), Huizhou Central People's Hospital (CN), Berry Oncology (China) (CN), Chenzhou First People's Hospital (CN), 303 Hospital of People's Liberation Army (CN), Shenzhen Second People's Hospital (CN), Hunan Provincial Maternal and Child Health Hospital (CN), Southern Medical University (CN)
Northeast Normal University, National Natural Science Foundation of China, Soochow University, Southern Medical University, Shanghai University of Traditional Chinese Medicine, Guangxi Medical University, Chinese People’s Liberation Army, National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 22%
Hemoglobinopathies and Related Disorders
0.88
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