2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-A Case Series of 17 Patients with VEXAS Syndrome due to <em>UBA1</em> Met41 Variants

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A case series of 17 patients with VEXAS syndrome due to UBA1 p.Met41 variants is summarized in this study. VEXAS syndrome is an adult-onset inflammatory condition primarily affecting males and is characterized by rheumatologic and hematologic symptoms. The disease is confirmed when a disease-associated somatic variant in the UBA1 gene is identified in a DNA specimen containing myeloid tissue.<br /><br />The most common UBA1 variants associated with VEXAS affect the Met41 residue. In this study, the UBA1 Met41Thr variant was found in 76% of patients, followed by Met41Val in 18% and Met41Leu in 6%. All three variants were classified as pathogenic.<br /><br />NGS-based genetic testing was performed on specimens including peripheral blood, saliva, and DNA extracted from other tissue sources. The median variant allele fraction (VAF) of the UBA1 Met41 variants in blood or bone marrow specimens was 62%, consistent with previous findings. However, the two saliva specimens showed the lowest VAFs at 4% and 28%.<br /><br />There was a significant difference in mean VAF between specimens extracted from blood or bone marrow and saliva. It is suggested that caution may be warranted in using saliva specimens for molecular confirmation of VEXAS, as the VAFs reported in this study are below the level of detection for many NGS assays.<br /><br />In conclusion, NGS-based genetic testing can identify UBA1 p.Met41 somatic variants associated with VEXAS syndrome. However, further studies are needed to confirm if VAFs of UBA1 Met41 variants are consistently lower in saliva samples compared to blood or bone marrow samples.

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Co-Author - Alicia Scocchia, MS, CGC; Co-Author - Allison Sluyters, MSc, CGC, CCGC; Co-Author - Margarita Andreevskaya, PhD; Co-Author - Kirsi Alakurtti, PhD, CLG; Co-Author - Paivi Kokkonen, PhD; Co-Author - Kimberly Gall, MSc., CGC; Co-Author - Julie Hathaway, MSc., CGC, CCGC; Presenting Author - Victoria Howell, MS, CGC; Co-Author - Lotta Koskinen, PhD; Co-Author - Janica Djupsjöbacka, MSc; Co-Author - Massimiliano Gentile, PhD; Co-Author - Pertteli Salmenperä, PhD; Co-Author - Jussi Paananen, PhD; Co-Author - Samuel Myllykangas, PhD; Co-Author - Juha W. Koskenvuo, MD, PhD;

Meta Tag

Genetic Testing

Genomic Methodologies

NextGen Sequencing

Sequencing

Variant Detection

Co-Author Alicia Scocchia, MS, CGC

Co-Author Allison Sluyters, MSc, CGC, CCGC

Co-Author Margarita Andreevskaya, PhD

Co-Author Kirsi Alakurtti, PhD, CLG

Co-Author Paivi Kokkonen, PhD

Co-Author Kimberly Gall, MSc., CGC

Co-Author Julie Hathaway, MSc., CGC, CCGC

Co-Author Lotta Koskinen, PhD

Co-Author Janica Djupsjöbacka, MSc

Co-Author Massimiliano Gentile, PhD

Co-Author Pertteli Salmenperä, PhD

Co-Author Jussi Paananen, PhD

Co-Author Samuel Myllykangas, PhD

Co-Author Juha W. Koskenvuo, MD, PhD

Presenting Author Victoria Howell, MS, CGC

Keywords

VEXAS syndrome

UBA1 p.Met41 variants

adult-onset inflammatory condition

rheumatologic symptoms

hematologic symptoms

disease-associated somatic variant

DNA specimen

NGS-based genetic testing

variant allele fraction (VAF)

saliva specimens