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Genetic risk variants for class switching recombination defects in ataxia-telangiectasia patients

Amirifar, P ; Sharif University of Technology | 2022

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  1. Type of Document: Article
  2. DOI: 10.1007/s10875-021-01147-8
  3. Publisher: Springer , 2022
  4. Abstract:
  5. 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)
  6. Keywords:
  7. Ataxia-telangiectasia (A-T) ; ATM ; Class switching recombination (CSR) ; DNA repair ; Inborn errors of immunity ; Modifier genes ; Primary immunodeficiency ; Whole-exome sequencing ; Golga8j protein ; Gxylt1 protein ; Killer cell immunoglobulin like receptor 3DL1 ; Mucin 4 ; Mucin 6 ; Protein ; Unclassified drug ; vwa3b protein ; XRCC3 protein ; ATM protein ; Antigen presentation ; Ataxia telangiectasia ; Bioinformatics ; Case control study ; Child ; Class switching recombination ; Clinical article ; Controlled study ; Double strand break repair ; Double stranded DNA break ; Exome ; Female ; Genetic analysis ; Genetic heterogeneity ; Genetic risk ; Genetic variability ; Human ; Male ; Missense mutation ; Mutation accumulation ; Mutational analysis ; Pathogenesis ; Signal transduction ; Whole exome sequencing ; Genetic recombination ; Genetics ; Immunoglobulin class switching ; Ataxia Telangiectasia Mutated Proteins ; Humans ; Phenotype ; Recombination, Genetic
  8. Source: Journal of Clinical Immunology ; Volume 42, Issue 1 , 2022 , Pages 72-84 ; 02719142 (ISSN)
  9. URL: https://link.springer.com/article/10.1007/s10875-021-01147-8