Multicenter international cohort study of haploinsufficiency of A20 reveals novel genetic architecture and phenotypic evolution

Tingyan He¹, Jun Wang², Manuel Carpio Tumba³, Shihao Wang⁴, Youyou Luo⁵, Jie Chen⁵, Guomin Li⁶, Zhou Shu⁷, Song Zhang⁸, Deborah L Stone⁹, Yanyan Huang¹⁰, Qianying Lv⁶, Wen Xiong¹⁰, Jinbo Wang¹¹, Zhongxun Yu¹², Charlotte Vera Cuff³, Elizabeth Kairis³, Akuti Kethri³, Atif Towheed³, Kyr Goyette³, Urekha Karri¹³, Jiebiao Wang¹⁴, Chen Liu¹⁴, Tina Romeo⁹, Laia Alsina¹⁵, Daniel L Rosenberg¹⁶, Daniel Clemente¹⁷, Juan Carlos López-Robledillo¹⁷, Zanhua Rong¹⁸, Xue Zhao¹⁸, Lijun Jiang¹⁸, Juan Carlos Aldave-Becerra¹⁹, Ana Beatriz Muñoz-Urribarri¹⁹, Prasad Thomas Oommen²⁰, Priscilla Campbell-Stokes²¹, Meifang Zhu²², Peng Liu²³, Li Guo²⁴, Yiping Xu²⁴, Zihua Yu²⁵, Huajuan Tong²⁵, Xiaojian Qiu²⁵, Yazhi Zhang²⁶, Hongbo Chen²⁶, Changming Zhang²⁷, Junbin Ou²⁸, Congcong Liu²⁹, Jinxiang Liu²⁹, Yunyan Shen³⁰, Jianshe Cao³¹, Xinping Zhang³¹, Kangkang Yang³², Ying Bao³³, Zhijuan Li³³, Jie Cao³⁴, Yuanhui Duan³⁴, Fujuan Liu³⁵, Buyun Shi³⁶, Min Sun³⁷, Li Ma³⁷, Yongxing Chen³⁸, Wei Yang³⁸, Xu Han², Shuangyue Ma², Jie Luo³⁹, Weiyue Gu⁴⁰, Guoliang Yu⁴⁰, Weina Shi⁴¹, Ruiqin Zhao⁴¹, Lei Sun⁴², Wenhui Li⁴³, Yunfei An⁴², Xuemei Tang⁴², Xiaodong Zhao⁴², Tongxin Han⁷, Jing Ma⁷, Yan Li⁷, Yurong Piao⁷, Fei Sun⁷, Dongfeng Zhang³⁵, Meina Yin³⁵, Shaoling Zheng⁴⁴, Tianwang Li⁴⁴, Huizhong Niu⁴⁵, Li Lin⁴⁶, Shiyue Mei⁴⁶, Fang Zhou⁴⁶, Sirui Yang²⁹, Danlu Li⁴⁷, Mei Yan⁴⁷, Huasong Zeng⁸, Ping Zeng⁸, Wenjie Zheng³², Xiaozhong Li³⁰, Xiaolin Li²⁸, Yuling Liu²⁸, Lijuan Huang²⁸, Haiguo Yu²², Zhidan Fan²², Min Shen⁴⁸, Meiping Lu²⁴, Zhihao Fang²⁴, Casey Allison Rimland⁴⁹, Hongmei Song¹², Lance W Peterson⁵⁰, Maryam Ali Yousuf Al-Nesf⁵¹, Sami Aqel⁵¹, Dalal Sideeg Mudawi⁵¹, Nikita Raje⁵², Voytek Slowik⁵², Julia G Harris⁵², Brenda Snyder⁵², Selma Scheffler-Mendoza⁵³, Marco Antonio Yamazaki-Nakashimada⁵³, Megan A Cooper⁵⁰, Yu Lung Lau⁵⁴, Kader Cetin Gedik⁵⁵, Wenjie Wang⁵⁶, Wenjing Ying⁵⁶, Jia Hou⁵⁶, Qinhua Zhou⁵⁶, Bijun Sun⁵⁶, Jinqiao Sun⁵⁶, Xiaochuan Wang⁵⁶, Amanda K Ombrello⁹, Ying Huang⁵⁷, Hai-Lin Wu⁵⁷, Li Sun⁶, Huawei Mao⁷, Xiaomin Yu², Zhihong Liu²⁷, Ivona Aksentijevich⁹, Daniel L Kastner⁹, Daniella M Schwartz⁵⁸, Jun Yang⁵⁹, Qing Zhou⁶⁰

Affiliations

¹ Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen University, Shenzhen, China; University of Pittsburgh, Departments of Medicine and Immunology, Division of Rheumatology, Pittsburgh, Pa.
² Liangzhu Laboratory, Zhejiang University, Hangzhou, China; Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Life Sciences Institute, Zhejiang University, Hangzhou, China.
³ University of Pittsburgh, Departments of Medicine and Immunology, Division of Rheumatology, Pittsburgh, Pa.
⁴ Liangzhu Laboratory, Zhejiang University, Hangzhou, China; Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Wenzhou, China; Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Life Sciences Institute, Zhejiang University, Hangzhou, China.
⁵ Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
⁶ National Children's Medical Center, Shanghai, China; Department of Rheumatology, Children's Hospital of Fudan University, Shanghai, China.
⁷ Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
⁸ Department of Pediatric, Allergy Immune and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Research Center for Child Health, Guangzhou, China.
⁹ Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
¹⁰ Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen University, Shenzhen, China.
¹¹ Liangzhu Laboratory, Zhejiang University, Hangzhou, China; Life Sciences Institute, Zhejiang University, Hangzhou, China.
¹² Department of Pediatrics, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
¹³ University of Pittsburgh, Departments of Medicine and Immunology, Division of Rheumatology, Pittsburgh, Pa; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, Pa.
¹⁴ Department of Biostatistics and Health Data Science, School of Public Health, University of Pittsburgh, Pittsburgh, Pa.
¹⁵ Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, and the Universitat de Barcelona, Barcelona, Spain.
¹⁶ University of Wisconsin School of Medicine and Public Health, Madison, Wis.
¹⁷ Pediatric Rheumatology Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
¹⁸ The Second Hospital of Hebei Medical University, Shijiazhuang, China.
¹⁹ Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.
²⁰ Department of Pediatric Oncology, Hematology and Clinical Immunology, Division of Pediatric Rheumatology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
²¹ Child Health Service, Hutt Hospital, National Pediatric Rheumatology Service, Te Whatu Ora, New Zealand.
²² Department of Rheumatology and Immunology, The Affiliated Children's Hospital of Nanjing Medical University, Nanjing, China.
²³ Department of Pediatric Intensive Care Unit, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
²⁴ Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
²⁵ Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, Fuzhou, China.
²⁶ Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
²⁷ National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
²⁸ Department of Pediatric Rheumatology and Immunology, Zhongshan Boai Hospital, Zhongshan, China.
²⁹ Department of Pediatric Rheumatology, Immunology & Allergy, Children's Medical Center, The First Hospital of Jilin University, Changchun, China.
³⁰ Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, China.
³¹ Department of Pediatric Intensive Care Unit of Hunan Children's Hospital, Changsha, China.
³² Department of Pediatric Rheumatology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
³³ Department of Pediatric Nephrology, Xi'an Children's Hospital, The Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, China.
³⁴ Department of General Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
³⁵ Children's Hospital of Hebei, Shijiazhuang, China.
³⁶ Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province, Wuhan, China.
³⁷ Department of Neonatology, Children's Hospital of Hebei, Shijiazhuang, China.
³⁸ Department of Pediatric Endocrinology and Genetic Metabolism, Henan Children's Hospital, Zhengzhou, China.
³⁹ Pediatric Department, The Affiliated Suzhou Hospital of Nanjing University Medical School, Suzhou, China.
⁴⁰ Chigene (Beijing) Translational Medical Research Center Co Ltd, Beijing Quanpu Medical Laboratory Co, Ltd, Beijing, China.
⁴¹ Department of Digestive Diseases, Hebei Children's Hospital, Shijiazhuang, China.
⁴² Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.
⁴³ Department of Infectious Disease, Children's Hospital of Hebei Province, Shijiazhuang, China.
⁴⁴ Department of Rheumatology and Immunology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
⁴⁵ The First Department of General Surgery, Hebei Children's Hospital, Shijiazhuang, China.
⁴⁶ Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou, China.
⁴⁷ First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.
⁴⁸ Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, PUMCH, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
⁴⁹ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, and Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
⁵⁰ Division of Rheumatology & Immunology, Department of Pediatrics, Washington University in St Louis, St Louis, Mo.
⁵¹ Adult Allergy and Immunology Division, Hamad Medical Corporation, Doha, Qatar.
⁵² Children's Mercy Kansas City, University of Missouri Kansas City, Kansas City, Mo.
⁵³ Servicio de Inmunología Clínica, Instituto Nacional de Pediatría, Mexico City, Mexico.
⁵⁴ Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
⁵⁵ University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Division of Pediatric Rheumatology, Pittsburgh, Pa.
⁵⁶ Department of Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁵⁷ Department of Gastroenterology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁵⁸ University of Pittsburgh, Departments of Medicine and Immunology, Division of Rheumatology, Pittsburgh, Pa. Electronic address: daniella.schwartz@pitt.edu.
⁵⁹ Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen University, Shenzhen, China. Electronic address: rogasansz@163.com.
⁶⁰ Liangzhu Laboratory, Zhejiang University, Hangzhou, China; Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Life Sciences Institute, Zhejiang University, Hangzhou, China. Electronic address: zhouqingnwu@gmail.com.

PMID: 41692116
DOI: 10.1016/j.jaci.2026.02.002

Multicenter international cohort study of haploinsufficiency of A20 reveals novel genetic architecture and phenotypic evolution

Tingyan He et al. J Allergy Clin Immunol. 2026.

. 2026 Feb 13:S0091-6749(26)00083-7.

doi: 10.1016/j.jaci.2026.02.002. Online ahead of print.

Authors

Affiliations

¹ Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen University, Shenzhen, China; University of Pittsburgh, Departments of Medicine and Immunology, Division of Rheumatology, Pittsburgh, Pa.
² Liangzhu Laboratory, Zhejiang University, Hangzhou, China; Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Life Sciences Institute, Zhejiang University, Hangzhou, China.
³ University of Pittsburgh, Departments of Medicine and Immunology, Division of Rheumatology, Pittsburgh, Pa.
⁴ Liangzhu Laboratory, Zhejiang University, Hangzhou, China; Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Wenzhou, China; Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Life Sciences Institute, Zhejiang University, Hangzhou, China.
⁵ Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
⁶ National Children's Medical Center, Shanghai, China; Department of Rheumatology, Children's Hospital of Fudan University, Shanghai, China.
⁷ Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
⁸ Department of Pediatric, Allergy Immune and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Research Center for Child Health, Guangzhou, China.
⁹ Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
¹⁰ Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen University, Shenzhen, China.
¹¹ Liangzhu Laboratory, Zhejiang University, Hangzhou, China; Life Sciences Institute, Zhejiang University, Hangzhou, China.
¹² Department of Pediatrics, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
¹³ University of Pittsburgh, Departments of Medicine and Immunology, Division of Rheumatology, Pittsburgh, Pa; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, Pa.
¹⁴ Department of Biostatistics and Health Data Science, School of Public Health, University of Pittsburgh, Pittsburgh, Pa.
¹⁵ Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, and the Universitat de Barcelona, Barcelona, Spain.
¹⁶ University of Wisconsin School of Medicine and Public Health, Madison, Wis.
¹⁷ Pediatric Rheumatology Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
¹⁸ The Second Hospital of Hebei Medical University, Shijiazhuang, China.
¹⁹ Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.
²⁰ Department of Pediatric Oncology, Hematology and Clinical Immunology, Division of Pediatric Rheumatology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
²¹ Child Health Service, Hutt Hospital, National Pediatric Rheumatology Service, Te Whatu Ora, New Zealand.
²² Department of Rheumatology and Immunology, The Affiliated Children's Hospital of Nanjing Medical University, Nanjing, China.
²³ Department of Pediatric Intensive Care Unit, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
²⁴ Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
²⁵ Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, Fuzhou, China.
²⁶ Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
²⁷ National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
²⁸ Department of Pediatric Rheumatology and Immunology, Zhongshan Boai Hospital, Zhongshan, China.
²⁹ Department of Pediatric Rheumatology, Immunology & Allergy, Children's Medical Center, The First Hospital of Jilin University, Changchun, China.
³⁰ Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, China.
³¹ Department of Pediatric Intensive Care Unit of Hunan Children's Hospital, Changsha, China.
³² Department of Pediatric Rheumatology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
³³ Department of Pediatric Nephrology, Xi'an Children's Hospital, The Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, China.
³⁴ Department of General Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
³⁵ Children's Hospital of Hebei, Shijiazhuang, China.
³⁶ Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province, Wuhan, China.
³⁷ Department of Neonatology, Children's Hospital of Hebei, Shijiazhuang, China.
³⁸ Department of Pediatric Endocrinology and Genetic Metabolism, Henan Children's Hospital, Zhengzhou, China.
³⁹ Pediatric Department, The Affiliated Suzhou Hospital of Nanjing University Medical School, Suzhou, China.
⁴⁰ Chigene (Beijing) Translational Medical Research Center Co Ltd, Beijing Quanpu Medical Laboratory Co, Ltd, Beijing, China.
⁴¹ Department of Digestive Diseases, Hebei Children's Hospital, Shijiazhuang, China.
⁴² Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.
⁴³ Department of Infectious Disease, Children's Hospital of Hebei Province, Shijiazhuang, China.
⁴⁴ Department of Rheumatology and Immunology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
⁴⁵ The First Department of General Surgery, Hebei Children's Hospital, Shijiazhuang, China.
⁴⁶ Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou, China.
⁴⁷ First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China.
⁴⁸ Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, PUMCH, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
⁴⁹ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, and Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
⁵⁰ Division of Rheumatology & Immunology, Department of Pediatrics, Washington University in St Louis, St Louis, Mo.
⁵¹ Adult Allergy and Immunology Division, Hamad Medical Corporation, Doha, Qatar.
⁵² Children's Mercy Kansas City, University of Missouri Kansas City, Kansas City, Mo.
⁵³ Servicio de Inmunología Clínica, Instituto Nacional de Pediatría, Mexico City, Mexico.
⁵⁴ Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
⁵⁵ University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Division of Pediatric Rheumatology, Pittsburgh, Pa.
⁵⁶ Department of Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁵⁷ Department of Gastroenterology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁵⁸ University of Pittsburgh, Departments of Medicine and Immunology, Division of Rheumatology, Pittsburgh, Pa. Electronic address: daniella.schwartz@pitt.edu.
⁵⁹ Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen University, Shenzhen, China. Electronic address: rogasansz@163.com.
⁶⁰ Liangzhu Laboratory, Zhejiang University, Hangzhou, China; Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Life Sciences Institute, Zhejiang University, Hangzhou, China. Electronic address: zhouqingnwu@gmail.com.

PMID: 41692116
DOI: 10.1016/j.jaci.2026.02.002

Abstract

Background: Haploinsufficiency of A20 (HA20) is an immune dysregulation disorder caused by loss-of-function TNFAIP3 mutations. This international multicenter study aimed to delineate its clinical spectrum, genetic basis, and natural history.

Methods: A cross-sectional retrospective analysis was conducted in HA20 patients with pathogenic or likely pathogenic TNFAIP3 variants. Clinical, laboratory, and treatment data were assessed. Clustering analysis was applied to evaluate clinical features and disease phenotypes. Patients were stratified by age (<16 years vs ≥16 years), country of origin (China vs United States), and sex.

Results: A total of 185 patients from 41 clinics across 7 countries were included (median age at onset, 3.3 years). Common clinical features were mucocutaneous involvement (80.5%), recurrent fever (63.3%), gastrointestinal symptoms (58.6%), cytopenia (56.6%), arthritis/arthralgia (46.7%), and recurrent infections (35.5%). Compared with adults and patients from the US cohort, intestinal ulcers were significantly more frequent in children and patients from the Chinese cohort (P = .002 and P < .0001, respectively), whereas uveitis was less common in these groups (P = .001 and P < .0001, respectively). Hierarchical clustering of clinical disease phenotypes based on Pearson distance identified two major clusters, an autoinflammation-predominant phenotype and an autoimmune-predominant phenotype. The autoinflammation-predominant phenotype was more common in children and patients from the Chinese cohort (P = .033 and .003, respectively). A total of 89 pathogenic TNFAIP3 mutations were identified, including 46 novel variants. Large deletions were associated with neurologic disease and developmental delay (P = .0054 and .0245, respectively); however, there were no clear associations between disruptions of specific functional A20 domains and age at onset or phenotype. Therapeutically, TNF and IL-1 inhibitors were effective in most patients, with thalidomide and JAK inhibitors provided in refractory cases; 51.5% had obtained minimal disease activity at most recent follow-up.

Conclusions: HA20 is a common dominantly inherited immune dysregulation disorder with phenotypic heterogeneity and potential age-dependent evolution. This large international cohort highlights diagnostic and therapeutic strategies to advance evaluation and management of HA20.

Keywords: Haploinsufficiency of A20; TNFAIP3; autoimmunity; autoinflammation.

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Conflict of interest statement

Disclosure statement T.H. received grant SZTP05202501005 from Special Support Program for High-level Talents in Shenzhen Health System and grant 82302056 from the National Natural Science Foundation of China. Q.Z. received grants 82225022, 32141004 and 32321002 from the National Natural Science Foundation of China, the XPLORER PRIZE from the New Cornerstone Science Foundation, grant 2024YFC2511002 from the National Key Research and Development Program of China, and grant CHCMU-2024-XKDF-1001 from Clinical Research Project for the Summit Program of Children’s Hospital of Chongqing Medical University. J.Y. received grant SZSM202411012 supported by Sanming Project of Medicine in Shenzhen. D.M.S. received grants by Jeffrey Modell Foundation, Eli Lilly, Sobi, and the Samuel and Emma Winters Foundation, and Rheumatology Research Foundation. J.W received grants 82394420, 82394423, and 82402121 from the National Natural Science Foundation of China and grant 2023M733104 from China Postdoctoral Science Foundation. S.W. received grant 82402118 from the National Natural Science Foundation of China. L.G. received the grant LHDMY23H100005 from Joint Funds of the Zhejiang Provincial Natural Science Foundation of China. X.Y. received grants 82394420, 82394424, and 82471844 from the National Natural Science Foundation of China, the Hundred-Talent Program of Zhejiang University, grant 2021R01012 from the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang and grant 2024Z221 from the Key Technology Breakthrough Program of Ningbo Sci-Tech Innovation YONGJIANG 2035. Y.L.L. received a grant from the Hong Kong Society for Relief of Disabled Children. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the US Department of Health and Human Services. Disclosure of potential conflict of interest: W. Gu and G. Yu are employees of Chigene (Beijing) Translational Medical Research Center Co Ltd and Beijing Quanpu Medical Laboratory Co Ltd. D. M. Schwartz has received consulting fees from Sobi and grant support from Sobi and Eli Lilly. The rest of the authors declare that they have no relevant conflicts of interest.

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Multicenter international cohort study of haploinsufficiency of A20 reveals novel genetic architecture and phenotypic evolution

Affiliations

Multicenter international cohort study of haploinsufficiency of A20 reveals novel genetic architecture and phenotypic evolution

Authors

Affiliations

Abstract

Conflict of interest statement

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