Exome sequencing can misread high variant allele fraction of somatic variants in UBA1 as hemizygous in VEXAS syndrome: a case report.

Abstract

BACKGROUND:

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) is a recently described syndrome caused by a somatic missense variant at the methionine-41 (p.(Met41)) position in the ubiquitin-like modifier activating enzyme 1 (UBA1) in Xp11.3. Germline pathogenic variants in UBA1 are associated with a distinct phenotype: a syndrome with severe neurologic features associated with loss of anterior horn cells and infantile death denominated X-Linked Spinal Muscular Atrophy 2 (SMAX2) (OMIM 301,830).

CASE PRESENTATION:

We report a male individual with the phenotype of VEXAS syndrome that was initially identified through exome sequencing (ES) as having a hemizygous germline variant in UBA1 due to high variant allele frequency (VAF). Research Sanger sequencing was able to confirm the absence of the p.(Met41Val) variant in a skin biopsy and in gastric mucosa tissue sample confirming the variant happened as a postzygotic event.

CONCLUSIONS:

The present case exemplifies the diagnostic challenge that was imposed by the high VAF detected by ES that failed to correctly demonstrate that the variant was in a mosaic state. Sequencing of different tissues should be considered when there is conflict between the UBA1 variant status and the clinical findings.

• Authors: Matheus V M B Wilke, Eva Morava-Kozicz, Matthew J Koster, Christopher T Schmitz, Shannon Kaye Foster, Mrinal Patnaik, Kenneth J Warrington, Eric W Klee, Filippo Pinto E Vairo
• Journal: BMC rheumatology (BMC Rheumatol) Vol. 6 Issue 1 Pg. 54 (Aug 30 2022) ISSN: 2520-1026 [Electronic] England
• PMID: 36038944 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).