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Approved Research

Associations between CXCR4 genetic variants and immunodeficiency phenotypes

Principal Investigator: Dr Katarina Zmajkovicova
Approved Research ID: 81315
Approval date: February 8th 2022

Lay summary

Primary immunodeficiencies (PIDs) are a group of inherited diseases that result in impairment of normal immune system function. The affected individuals often suffer from recurrent infections. Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome, one such PID, causes different symptoms including low immune cell counts in blood, bacterial infections or skin warts and it is caused by mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene.  Currently there is a small number of pathogenic mutations in CXCR4 that are known to cause WHIM syndrome. Novel CXCR4 mutations are sometimes identified in patients with immunodeficiency, but due to  missing information on their pathogenicity, the diagnosis of WHIM syndrome cannot be confirmed. As a result, these individuals may not be eligible for the best suitable treatment. We plan to look at a large group of people in the UK Biobank to identify individuals who have CXCR4 mutations  as well as low blood cell counts or other signs of immunodeficiency. We will analyze these mutations in laboratory tests and then combine all data to conclude which of the mutations are likely to cause decreased immune system function. This study will form the foundations for better diagnosis of WHIM syndrome or other CXCR4-related immunodeficiency. The project will last for one year.

Scope extension:

CXCR4 is a master regulator of immune cell trafficking and homeostasis. CXCR4 mutations are found in patients with WHIM syndrome, a rare immunodeficiency. WHIM syndrome patients show high variability in their clinical presentations based on the mutation type, complicating the diagnostic process. Studies addressing the CXCR4 genotype-phenotype correlations are lacking as is the information on the prevalence of CXCR4-related immunodeficiency.

We aim to get insights into population-wide variability in CXCR4 protein sequence and the associated phenotypes in order to build enhanced models of genotype-phenotype correlation for CXCR4 variants and identify potential biomarkers of WHIM syndrome. Based on these results, we also intend to estimate the prevalence of CXCR4-related immunodeficiencies.

AIM 1: Identify CXCR4 variants that occur in individuals with immune system dysfunction (cytopenias, infections) and presentations of WHIM syndrome (warts, congenital heart defects).

AIM 2: Analyze selected CXCR4 variants in in-vitro functional assays (see Methods section)

AIM 3: Merge the functional, genomic and phenotypic data. Analyze correlations between them to build a model that defines 'likely pathogenic' variants. Identify potential biomarkers of WHIM syndrome.

AIM4: Estimate prevalence for CXCR4-related immune system dysfunctions using the frequency of the likely pathogenic alleles observed in UK Biobank database and other population-based genomic databases.

NEW scope:

WHIM syndrome has also been causally linked to loss-of-function variants in CXCR2, but information is limited. We plan to extend the analysis of UK Biobank dataset to asses the genotype-phenotype correlations for the CXCR2 gene.

NEW AIM 1: Is variation in CXCR2 associated with changes in neutrophil counts and with neutropenia?

NEW AIM 2: Which CXCR2 variants are associated with a decrease in neutrophil counts?

NEW AIM 3: Do these identified variants have in vitro signature (Loss Of Function)?

NEW AIM 4: Do people carrying the identified variants of interest have increased risk of infections?

The results of this analysis will enable us to potentially uncover new disease-causing variants and make more accurate estimate of prevalence of neutropenia due to CXCR2 deficiency.