The Genome Atlas of 1,020 Probands and 409 Unaffected Parents Decodes the Clinical Heterogeneity in β-thalassemia
Year: 2026
Type: article
Study design: Observational Study
Abstract: β-thalassemia is an extensively studied monogenic disorder, yet the basis of its striking phenotypic diversity remains unresolved. Here we present the 1000 β-Thalassemia Genomes Project (KbTGP), providing the first comprehensive atlas of 1,429 Chinese genomes (1,020 probands and 409 unaffected parents, 61.63× coverage) linked to 77 clinical traits. We identify 11 independent phenotype-associated loci in probands, and 15 additional loci by integrating 2,746 ethnically matched controls from the NyuWa Project and the 1000 Genomes Project. Functional experiments further highlight non-coding regions at 17p13.3 and the autophagy-related gene PIK3C3 as modulators of thalassemic phenotypes. Loss-of-function structural variants are enriched in hemoglobinopathy-related genes, and structural variants in TF and SLC25A37 are significantly associated with iron metabolism and fetal hemoglobin, respectively. Notably, de novo structural variants and clonal hematopoiesis mutations are enriched in severe cases. These findings collectively establish a phenome-genome resource that delineates the genetic architecture of β-thalassemia, offering candidate targets for precision therapies and laying the groundwork for future research into dissecting the Mendelian disease variability. The authors sequence 1020 Chinese patients with beta thalassemia and 409 unaffected parents to identify genes that modulate the phenotypes. Functional validation in mice and cultured cells confirm the role of autophagy-associated gene PIK3C3.
Source: Nature Communications
Authors: Yuhua Ye, Yushan Huang, Lian Deng, Xinyue Liu, Xiang Guo, Qianqian Zhang, Yongzhong Zhao, Dan Xie, Yong Long, Songyang Li, Mingyan Fang, Chao Niu, Peng Zhang, Lang Qin, Jingyu Zeng, Yang Gao, Yanyan Li, 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, Xianming Chen, Weijie Chen, Wanying Lin, Xiaoman Zhou, Ling Ling, Zhanping Lu, Xuemei Song, Qinlong Zeng, Yan Chen, Yidan Liang, Xingjiang Long, Jiaofeng Qin, Lixiang Yan, Weijian Zhu, Lian Yu, Chengwu Fan, Deguo Tang, Tianyu Zhong, Jufang Tan, Huanhuan Zhu, Yumeng Sun, Linxuan Li, Xia Tang, Xinjiang Tan, Ziyi Yang, Yirong Shi, Xiaoyu Yan, Duonan Yu, Li Jin, Narla Mohandas, Shuquan Rao, Shunmin He, Xin Jin, Shuhua Xu, Xiangmin Xu
Institutions: Nanfang Hospital, Southern Medical University, Chinese Academy of Sciences, Youjiang Medical College for Nationalities, Affiliated Hospital of Youjiang Medical University for Nationalities, University of Chinese Academy of Sciences, BGI Research, Fudan University, Institute of Biophysics, University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Hematology & Blood Diseases Hospital, State Key Laboratory of Experimental Hematology, BGI Group (China), Northwest A&F University, Chinese People's Liberation Army, Huizhou Central People's Hospital, Fourth Affiliated Hospital of Guangxi Medical University, Shenzhen University, Shenzhen Second People's Hospital, Yangzhou University, Chongqing University, Jinan University, Zhuhai People's Hospital, Fujian Medical University, First Affiliated Hospital of Gannan Medical University, Chenzhou First People's Hospital, Shanghai Institute of Nutrition and Health, New York Blood Center, South China University of Technology
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Northeast Normal University, China Railway, National Natural Science Foundation of China, Ministry of Education of the People's Republic of China, Fudan University, Soochow University, Southern Medical University, Peking Union Medical College, National Key Research and Development Program of China
OpenAlex ID: W7225112869