Genetic Risk Variants for Class Switching Recombination Defects in Ataxia-Telangiectasia Patients Publisher Pubmed



Amirifar P^{1, 2} ; Mehrmohamadi M³ ; Ranjouri MR² ; Akrami SM¹ ; Rezaei N^{2, 4} ; Saberi A⁵ ; Yazdani R^{2, 4} ; Abolhassani H^{2, 6, 7} ; Aghamohammadi A^{2, 8} Show Affiliations
Source: Journal of Clinical Immunology Published:2022

Abstract

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. A-T patients manifest considerable variability in clinical and immunological features, suggesting the presence of genetic modifying factors. A striking heterogeneity has been observed in class switching recombination (CSR) in A-T patients which cannot be explained by the severity of ATM mutations. Methods: To investigate the cause of variable CSR in A-T patients, we applied whole-exome sequencing (WES) in 20 A-T patients consisting of 10 cases with CSR defect (CSR-D) and 10 controls with normal CSR (CSR-N). Comparative analyses on modifier variants found in the exomes of these two groups of patients were performed. Results: For the first time, we identified some variants in the exomes of the CSR-D group that were significantly associated with antigen processing and presentation pathway. Moreover, in this group of patients, the variants in four genes involved in DNA double-strand breaks (DSB) repair signaling, in particular, XRCC3 were observed, suggesting an association with CSR defect. Conclusion: Additional impact of certain variants, along with ATM mutations, may explain the heterogeneity in CSR defect phenotype among A-T patients. It can be concluded that genetic modulators play an important role in the course of A-T disease and its clinical severity. © 2021, The Author(s).