Journal
JOURNAL OF CLINICAL IMMUNOLOGY
Volume 42, Issue 1, Pages 72-84Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10875-021-01147-8
Keywords
Primary immunodeficiency; Inborn errors of immunity; Ataxia-telangiectasia (A-T); ATM; Class switching recombination (CSR); DNA repair; Modifier genes; Whole-exome sequencing
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Funding
- Karolinska Institute
- Tehran University of Medical Sciences [40601]
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The study identified variants associated with the antigen processing and presentation pathway, as well as variants in four genes involved in DNA double-strand breaks repair signaling in a group of A-T patients. These additional genetic influences may explain the heterogeneity in the CSR defect phenotype among A-T patients.
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.
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