Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome
Authors: Maeda Ayaka , Tsuchida Naomi , Uchiyama Yuri , Horita Nobuyuki , Kobayashi Satoshi , Kishimoto Mitsumasa , Kobayashi Daisuke , Matsumoto Haruki , Asano Tomoyuki , Migita Kiyoshi , Kato Ayaka , Mori Ichiro , Morita Hiroyuki , Matsubara Akihiro , Marumo Yoshiaki , Ito Yuji , Machiyama Tomoaki , Shirai Tsuyoshi , Ishii Tomonori , Kishibe Mari , Yoshida Yusuke , Hirata Shintaro , Akao Satoshi , Higuchi Akitsu , Rokutanda Ryo , Nagahata Ken , Takahashi Hiroki , Katsuo Kosuke , Ohtani Toshio , Fujiwara Hiroshi , Nagano Hiromichi , Hosokawa Takashi , Ito Takanori , Haji Yoichiro , Yamaguchi Hiroyuki , Hagino Noboru , Shimizu Toshimasa , Koga Tomohiro , Kawakami Atsushi , Kageyama Goichi , Kobayashi Hiroshi , Aoki Akiko , Mizokami Akinari , Takeuchi Yoichi , Motohashi Rena , Hagiyama Hiroyuki , Itagane Masaki , Teruya Hiroyuki , Kato Tomohiro , Miyoshi Yuji , Kise Takayasu , Yokogawa Naoto , Ishida Takako , Umeda Naoki , Isogai Shuntaro , Naniwa Taio , Yamabe Toru , Uchino Kaori , Kanasugi Jo , Takami Akiyoshi , Kondo Yasushi , Furuhashi Kazunori , Saito Koichi , Ohno Shigeru , Kishimoto Daiga , Yamamoto Mari , Fujita Yoshiro , Fujieda Yuichiro , Araki Sachiko , Tsushima Hiroshi , Misawa Kyohei , Katagiri Akira , Kobayashi Takahiro , Hashimoto Kenichi , Sone Takehiro , Hidaka Yukiko , Ida Hiroaki , Nishikomori Ryuta , Doi Hiroshi , Fujimaki Katsumichi , Akasaka Keiichi , Amano Masako , Matsushima Hidekazu , Kashino Kaori , Ohnishi Hidenori , Miwa Yuki , Takahashi Noriyuki , Takase-Minegishi Kaoru , Yoshimi Ryusuke , Kirino Yohei , Nakajima Hideaki , Matsumoto Naomichi 
Published: August 2023

Abstract

Objectives
To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.

Methods
Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median age of onset 69.3 years (interquartile range 62.1–77.6)]. Peptide nucleic acid–clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR or targeted amplicon deep sequencing was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and -negative patients and assessed the diagnostic value of our system using receiver operating characteristics (ROC) curve analysis.

Results
Forty patients (44.9%) with reported pathogenic UBA1 variants were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering age &gt;50 years, cutaneous lesions, lung involvement, chondritis and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908).

Conclusion
Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.