Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis
Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis
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DOI：
10.1136/annrheumdis-2021-220089
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发表时间：
2021-08-01
影响因子：
27.4
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Tsuchida, Naomi;Kunishita, Yosuke;Matsumoto, Naomichi
目的探讨可能由泛素样修饰物激活酶1（UBA 1）致病性体细胞变异引起的复发性多囊卵巢炎（RP）患者的临床和遗传学特征。方法14例符合Damiani和Levine诊断标准的RP患者，男12例，女2例;中位发病年龄（IQR）72.1岁（67.1-78.0）。使用来自外周血白细胞或骨髓组织的基因组DNA进行UBA 1的桑格测序。采用液滴数字PCR（ddPCR）和肽核酸（PNA）夹持PCR检测低流行率的体细胞变异。回顾性分析患者的临床特点。结果14例患者中有13例检测到UBA 1，男性患者中73%（8/11）存在体细胞UBA 1变异（c.121A>C、c.121A>G或c.122T>C分别导致p.Met41Leu、p.Met41Val或p.Met41Thr）。所有变异阳性患者都有全身症状，包括皮肤病变的显著高患病率。ddPCR在1例女性患者中检测到低患病率（0.14%）的体细胞变异（c.121A>C），随后通过PNA夹持PCR证实。结论对RP患者，尤其是有皮损的男性患者，应考虑进行致病性UBA 1变异的基因筛查。女性患者UBA 1的体细胞变异是首次报道。
Objectives To determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 (UBA1). Methods Fourteen patients with RP who met the Damiani and Levine criteria were recruited (12 men, 2 women; median onset age (IQR) 72.1 years (67.1-78.0)). Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Droplet digital PCR (ddPCR) and peptide nucleic acid (PNA)-clamping PCR were used to detect low-prevalence somatic variants. Clinical features of the patients were investigated retrospectively. Results UBA1 was examined in 13 of the 14 patients; 73% (8/11) of the male patients had somatic UBA1 variants (c.121A>C, c.121A>G or c.122T>C resulting in p.Met41Leu, p.Met41Val or p.Met41Thr, respectively). All the variant-positive patients had systemic symptoms, including a significantly high prevalence of skin lesions. ddPCR detected low prevalence (0.14%) of somatic variant (c.121A>C) in one female patient, which was subsequently confirmed by PNA-clamping PCR. Conclusions Genetic screening for pathogenic UBA1 variants should be considered in patients with RP, especially male patients with skin lesions. The somatic variant in UBA1 in the female patient is the first to be reported.