Poster Session A

Session: (0123–0149) Miscellaneous Rheumatic and Inflammatory Diseases Poster I

0130: Three Chinese Pedigrees of A20 Haploinsufficiency

Saturday, November 12, 2022

1:00 PM – 3:00 PM Eastern Time

Location: Virtual Poster Hall

Abstract Poster Presenter(s)

MS

Min Shen

Chinese Academy of Medical Sciences & Peking Union Medical College
Beijing, Beijing, China

Yi Tian¹, Min Shen², Bingxuan Wu², linyi Peng² and Jian Wang³, ¹Rheumatology Department, The Second Affiliated Hospital of Dalian Medical University, Dalian, China, ²Department of Rheumatology, Peking Union Medical College Hospital, Beijing, China, ³Jinzhou City Center for Disease Control and Prevention, Jinzhou, China

Background/Purpose: Haploinsufficiency of A20 (HA20) is a newly described rare autoinflammatory disease caused by TNFAIP3 gene mutations. HA20 has been seldom documented in the Chinese population. Herein, we reported eight patients with HA20 from three unrelated families in China.

Methods: Eight Chinese Han patients were diagnosed with HA20 in our department from 2018 to 2021. Their clinical data and genotype were carefully documented and studied. The newly identified variants were functionally verified. We also conducted a systematic literature review about HA20, and the clinical characteristics and genotype of HA20 between the Chinese population and other populations were compared.

Results: Eight HA20 patients from three families comprised of six adults and two children. There were 1 man and 7 women. Family pedigrees, clinical manifestations, and gene sequencing of HA20 patients were shown in Fig 1. The clinical characteristics included recurrent oral ulcers (8/8, 100%), fever (5/8, 63%), perianal ulcer (3/8, 38%), skin lesions (2/8, 25%), arthritis (1/8, 13%), and uveitis (1/8, 13%). Three TNFAIP3 variants, A547T, c.1906+2T >G, and R271*, were identified. Two novel variants, A547T and c.1906+2T >G, were validated to be pathogenic in our study (Fig 2). Through literature review, a total of 126 patients with HA20 reported by 35 articles were included. The clinical phenotype of Chinese HA20 patients was similar to that of patients from other populations except for a lower frequency of genital ulcers (16.7% vs. 54.4%, p< 0.01). Autoantibodies were detectable in about one-third of the 126 patients, among which ANA and anti-thyroid antibodies were commonly seen.

Conclusion: The rarity and diversity of phenotype make the diagnosis of HA20 a huge challenge to physicians. HA20 should be considered in child-onset patients with manifestations that resemble Behçet's syndrome, especially those whose family members have similar symptoms. Gene testing is critically helpful for the diagnosis of HA20. Two novel TNFAIP3 variants, A547T and c.1906+2T >G, have been identified in this study.
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Fig 1. Family pedigrees, clinical manifestations, and gene sequencing of HA20 patients. A: Pedigree analysis of Family 1. B: Erythema nodosa of P1 (V:24). C: Whole-exome sequencing by Next Generation Sequencing of Family 1, showing the heterozygous TNFAIP3 (NM_006290.4): c.1639G>A, p.A547T variant. D: Pedigree analysis of Family 2. E: Gene sequencing of Family 2, showing TNFAIP3 c.1906+2T>G heterozygous variant in P2 (III:5) and her daughter (IV:1). F: Pedigree analysis of Family 3. P: proband; (+/-): Heterozygous variants; (-/-): Wild type; (NA): Undetected.

Fig 2. Pathogenicity validation of novel TNFAIP3 variants. A: The predicted 3D structure of wild type (WT) and A547T variant of A20 protein. B: Schematic view of Complementary DNA analysis of WT and the splice site mutation c.1906+2T>G. C: Agarose gel electrophoresis result. P2, the proband of the second family; Ctrl, healthy controls. D: Western blot analysis of A20 expression, NF-κB and NLRP3 inflammasome signaling pathway in PBMCs from P2 and controls. E: Cytokine (TNF-α, IL-6 and IL-1β) levels in plasma and culture supernatants of PBMCs from P2 and controls (mean ± SD from three independent experiments in P2 and n=3 controls, P values were determined by unpaired two-tailed Student’s t-test).

Fig 3. A: Comparison of clinical phenotypes of HA20 patients in China and other populations. *: P < 0.05. B: The locations of variants in the TNFAIP3 gene. The red arrows represent the locus of variants in the Chinese (20). The orange arrows represent the locus of variants from other populations (41). The purple boxes represent co-owned variants (4).
Disclosures: Y. Tian, None; M. Shen, None; B. Wu, None; l. Peng, None; J. Wang, None.