Dataset Information

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.

SUBMITTER: Wilke MVMB

PROVIDER: S-EPMC9426024 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Wilke Matheus V M B MVMB Morava-Kozicz Eva E Koster Matthew J MJ Schmitz Christopher T CT Foster Shannon Kaye SK Patnaik Mrinal M Warrington Kenneth J KJ Klee Eric W EW Pinto E Vairo Filippo F

BMC rheumatology 20220830 1

<h4>Background</h4>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 Mus ...[more]

PMID: 36038944

Similar Datasets

Project description:ImportanceVEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes.ObjectiveTo determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.Design, setting, and participantsThis retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022.ExposuresExome sequencing was performed.Main outcomes and measuresOutcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays.ResultsIn 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669).Conclusions and relevanceThis study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.

Project description:ImportanceVEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described.ObjectiveTo better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome.Design, setting, and participantsThis multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies.ResultsAll 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients.Conclusions and relevanceThis case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.

Dataset Information

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

Background

Case presentation

Conclusions

Publications

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

Similar Datasets

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