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. 2019 Jun 4;21(1):137.
doi: 10.1186/s13075-019-1928-5.

Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3 is clinically distinct from Behçet's disease

Naomi Tsuchida  1   2 , Yohei Kirino  3 , Yutaro Soejima  2 , Masafumi Onodera  4 , Katsuhiro Arai  5 , Eiichiro Tamura  4 , Takashi Ishikawa  4 , Toshinao Kawai  4 , Toru Uchiyama  4 , Shigeru Nomura  6 , Daisuke Kobayashi  7 , Masataka Taguri  8 , Satomi Mitsuhashi  1 , Takeshi Mizuguchi  1 , Atsushi Takata  1 , Noriko Miyake  1 , Hideaki Nakajima  2 , Satoko Miyatake  1   9 , Naomichi Matsumoto  10
Affiliations

Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3 is clinically distinct from Behçet's disease

Naomi Tsuchida et al. Arthritis Res Ther. .

Abstract

Background: Haploinsufficiency of A20 (HA20) is caused by loss-of-function TNFAIP3 variants. Phenotypic and genetic features of HA20 remain uncertain; therefore, the clinical distinction between HA20 and Behçet's disease (BD) requires clarification.

Methods: We have collected 12 Japanese BD-like families. Probands of these families were analyzed by whole exome sequencing (WES) and subsequent Sanger sequencing. Clinical features were compared between 54 HA20 patients (including previously reported and new cases) and 520 Japanese BD patients.

Results: We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3 containing TNFAIP3 in another family. Four HA20 patients in the two families presented with childhood-onset recurrent oral and genital ulcers and were initially diagnosed and treated as BD. Consistent with the clinical features of HA20, recurrent, refractory fever attacks (three of four patients), and digestive ulcers (two of the four patients) were observed. A comparison of clinical features between HA20 patients and cohorts of BD patients revealed several critical features specific to HA20. These were early-onset, familial occurrence, recurrent fever attacks, gastrointestinal involvement, and infrequent ocular involvement.

Conclusions: We identified a novel nonsense variant and deletion of the entire TNFAIP3 gene in two unrelated Japanese HA20 families. Genetic screening of TNFAIP3 should be considered for familial BD-like patients with early-onset recurrent fevers.

Keywords: Autoinflammatory; Behçet’s disease; Haploinsufficiency of A20; TNFAIP3; Whole exome sequencing.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
TNFAIP3 variants in two HA20 families. a Pedigree of family 1 and electropherograms of two patients with a TNFAIP3 variant and a control subject. b Pedigree of family 2 and quantitative PCR of family members with a TNFAIP3 deletion. Affected individuals and probably affected individuals are depicted using black and gray symbols, respectively. Black and red arrows indicate the probands and variants, respectively. The TNFAIP3 alleles identified in each individual are labeled as M1 and M2 for variants and WT for wild-type. M1: c.1434C>A:p.(Cys478*), M2: chr6:138192201-138428412 (GRCh37/hg19) deletion
Fig. 2
Fig. 2
RT-PCR analysis of lymphoblastoid cell lines from patients 1 and 2 in family 1. Total RNA was extracted from a patient-derived lymphoblastoid cell line treated with or without CHX. a Electrophoresis of RT-PCR products. The band intensity in cells from affected patients treated with DMSO (vehicle control) was weak compared to that of control cells and was significantly stronger after CHX treatment (an NMD inhibitor). b Electropherograms of RT-PCR products (reverse strand). The mutant allele was recovered by CHX treatment. Red square highlights the change in signal of the mutant allele. CXH cycloheximide, DMSO dimethyl sulfoxide, NMD nonsense-mediated mRNA decay, RT (−) without reverse transcriptase (negative control)
Fig. 3
Fig. 3
CNV analysis by XHMM and Nord’s method in family 2. a A 236 kb deletion at 6q23.3 involving TNFAIP3 in patients 3 and 4 detected by XHMM. The x-axis shows the genomic position, and the y-axis indicates the Z score. Red arrows represent calls for copy number losses. b A deletion involving TNFAIP3 and PERP in patients 3 and 4 detected by Nord’s method. The x-axis shows arrays of targeted genes of different colors with their proportional physical length and the y-axis shows log2 ratios for each targeted base in the genes tested. Red arrows represent calls for copy number losses. c Schematic representation and comparison of the deletions containing TNFAIP3. The thick red bar represents the 236 kb deletion in family 2, and the thick blue bar represents the 13 Mb deletion at 6q23.2-q24.3 reported by Franoco-Jarava et al. (2018). The genomic region diagrams were captured from the browser using DECIPHER (http://decipher.sanger.ac.uk). CNV copy number variation, XHMM eXome Hidden Markov Model
Fig. 4
Fig. 4
Skin and gastrointestinal lesions of patient 2. a Erythema nodosum in the bilateral lower extremities. b, c Pernio-like rash in the fingers. d, e Endoscopic findings at 29 years of age; d multiple ulcers in the gastric mucosa and e ulceration in the ileocecum. f, g CT findings at 29 and 33 years of age; f hepatosplenomegaly and g generalized lymphadenopathy. White arrows indicate swollen lymph nodes
Fig. 5
Fig. 5
Endoscopic findings of patient 3 at 10 years of age. Multiple ulcers were detected throughout the intestinal tract by endoscopy; a terminal ileum, b cecum, c transverse colon, d rectum, e duodenum, and f ileum. Most of the mucosa surrounding ulcerous lesions was normal, but there was mild inflammation in the rectal mucosa
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