Presenter of 2 Presentations
NOVEL PRIMARY IMMUNODEFICIENCY ASSOCIATED WITH BIALLELIC VARIANTS IN CWF19L2
Abstract
Background and Aims
CWF19L2 is a part of the post-mRNA release spliceosomal complex and is responsible for pre-mRNA splicing into its mature form. Here we present a compound heterozygous mutations (c.2200C>T, p.Gln734Ter; c.2251T>C, p.Cys751Arg) in a family with microcephaly, autism and immunodeficiency.
Methods
WES was used to identify biallelic CW19L2 variants. Immunological assessment included immunophenotyping, functional T and B cell assessment and neutrophil assays. Knockdown experiments using HEK293 cells were used to study cell division.
Results
Affected sibling pair presented with early onset bronchiectasis and recurrent sinopulmonary infections. Immunoglobulin profile showed reduction in IgM, but normal IgG and IgA levels. Lymphocyte populations and T cell proliferation in the probands were normal with the exception of a reduction in naïve T-cells. T-cell recall response to range of viral antigens was detectable. Patient peripheral blood B cells were able to differentiate in vitro and secrete IgM, IgA and IgG in the culture, following T dependent stimulation. Neutrophil burst test was normal but neutrophil migration was severely impaired in the probands. RNA sequencing from the proband identified increased expression of genes associated with the adaptive immune response and T cell receptor signalling, and a decrease in genes associated with the inflammatory response, chemokine-mediated signalling and actin cytoskeleton. CWF19L2 knockdown in HEK293 resulted in reduced cellular proliferation, increased asymmetric cell division, increased time required to complete mitosis and increased number of cells failing to complete mitosis.
Conclusions
These results suggest that biallelic loss of function variants in CW19L2 result in a novel primary immunodeficiency characterised by cytoskeleton defects and impaired neutrophil migration.
A HIGH-THROUGHPUT AMPLICON SCREEN FOR SOMATIC UBA1 VARIANTS IN CYTOPENIC AND GIANT CELL ARTERITIS COHORTS
Abstract
Background and Aims
Somatic mutations in UBA1 exon 3 are a known cause of VEXAS syndrome, a late-onset acquired auto-inflammatory syndrome. Differential diagnoses for patients subsequently found to have VEXAS include, relapsing polychondritis (most frequent diagnosis), Sweet’s syndrome, myelodysplastic syndrome (MDS), giant cell arteritis (GCA) and undifferentiated systemic autoinflammatory disease (uSAID). We sought to investigate the frequency of VEXAS associated mutations in patients with confirmed GCA and those with unexplained cytopenia.
Methods
A one-step, PCR-based amplicon sequencing assay was developed to screen UBA1 exon 3 in high-throughput. Using the amplicon sequencing assay, 612 males diagnosed with GCA, and 1,055 cases with an undiagnosed cytopenia were sequenced by massively paralleled sequencing.
Results
No GCA cases were found to have UBA1 mutations, however 4 different mutations in the cytopenic cohort were identified in 7 individuals (1.0% of males of males screened). We identified a female with VEXAS due to a UBA1 mutation who was subsequently found not to have Monosomy X.
Conclusions
We identified 1.0% of males with a non-diagnostic cytopenia had VEXAS syndrome. The finding of a female case adds further evidence that VEXAS should not be ruled out as a differential diagnosis in females.