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Genetic Risk Variants for Class Switching Recombination Defects in Ataxia-Telangiectasia 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...

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Detalles Bibliográficos
Autores principales: Amirifar, Parisa, Mehrmohamadi, Mahya, Ranjouri, Mohammad Reza, Akrami, Seyed Mohammad, Rezaei, Nima, Saberi, Ali, Yazdani, Reza, Abolhassani, Hassan, Aghamohammadi, Asghar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8821084/
https://www.ncbi.nlm.nih.gov/pubmed/34628594
http://dx.doi.org/10.1007/s10875-021-01147-8
Descripción
Sumario: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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10875-021-01147-8.