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 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.

Known and potential molecules associated with altered B cell development leading to predominantly antibody deficiencies.

Predominantly antibody deficiencies (PADs) encompass a heterogeneous group of disorders characterized by low immunoglobulin serum levels in the presence or absence of peripheral B cells. Clinical presentation of affected patients may include recurrent respiratory and gastrointestinal infections, invasive infections, autoimmune manifestations, allergic reactions, lymphoproliferation, and increased susceptibility to malignant transformation. In the last decades, several genetic alterations affecting B-cell development/maturation have been identified as causative of several forms of PADs, adding important information on the genetic background of PADs, which in turn should lead to a better understanding of these disorders and precise clinical management of affected patients. This review aimed to present a comprehensive overview of the known and potentially involved molecules in the etiology of PADs to elucidate the pathogenesis of these disorders and eventually offer a better prognosis for affected patients.

Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3): A systematic review.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive immune disorder that is caused by mutations in 6 different genes related to the formation and function of secretory lysosomes within cytotoxic T lymphocytes and natural killer (NK) cells. Thus, defect in these genes is associated with the accumulation of antigens due to defective cytotoxic function. FHL type 3 (FHL3) accounts for nearly 30-40% of FHL, and its underlying reason is mutation in UNC13D gene which encodes Munc13-4 protein. METHODS: For the first time, we aimed to systematically review clinical features, immunologic data, and genetic findings of patients with FHL3. We conducted electronic searches for English-language articles in PubMed, Web of Science, EMBASE, and Scopus databases to collect comprehensive records related to patients with UNC13D mutations. RESULTS: A total of 279 abstracts were initially reviewed for inclusion. Among them, 57 articles corresponding to 322 individual FHL3 patients fulfilled our selection criteria. Finally, 73 and 249 patients were considered as severe and mild feature groups, respectively. Our results confirmed that fever, hepatosplenomegaly, and hemophagocytosis are common clinical features in the disease. Moreover, reduced fibrinogen and NK cell activity, as well as increased ferritin and triglycerides, are important markers for early diagnosis of the FHL3 disease. Investigation of genotype showed that the most prevalent type and zygosity of UNC13D are splice-site errors and compound heterozygous, respectively. CONCLUSION: FHL3 patients have a wide range of clinical manifestations, which makes it difficult to diagnose. Therefore, it seems that the sequencing of the entire UNC13D gene (coding and non-coding regions) is the most appropriate way to accurate diagnosis of FHL3 patients.

The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia.

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity. METHODS: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole-exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild subgroups. RESULTS: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years, and various types of clinical manifestations, including fever (P =.005), lower respiratory tract infection (P = .033), diarrhea (P = .014), and hepatosplenomegaly (P = .032), were significantly higher among patients diagnosed with the severe phenotype. Our results showed a correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher than in patients who were categorized in the mild genotype group (odds ratio = 7.3, P = .006). Thirty-four types of mutations including 9 novel mutations were observed in our study. CONCLUSION: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time the broad spectrum of mutations and phenotypes in Iranian A-T patients, which is required for carrier detection and reducing the burden of disease in the future using the patients' families and for the public healthcare system.

Ataxia-telangiectasia: A review of clinical features and molecular pathology.

Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia-telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase. A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. This congenital disorder has phenotypic heterogeneity, and the severity of symptoms varies in different patients based on severity of mutations and disease progression. The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoint. The pathogenesis of A-T is not limited to the role of ATM in the DNA damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms. However, ATM has other functions in the cells (especially cell viability) that need further investigations. In this review, we described functions of ATM in the nucleus and cytoplasm, and also its association with some disorder formation such as neurologic, immunologic, vascular, pulmonary, metabolic, and dermatologic complications.

Ataxia-telangiectasia: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management.

INTRODUCTION: Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, and cancer predisposition. Mutations cause A-T in the ataxia telangiectasia mutated (ATM) gene encoding a serine/threonine-protein kinase. AREAS COVERED: The authors reviewed the literature on PubMed, Web of Science, and Scopus databases to collect comprehensive data related to A-T. This review aims to discuss various update aspects of A-T, including epidemiology, pathogenesis, clinical manifestations, diagnosis, prognosis, and management. EXPERT OPINION: A-T as a congenital disorder has phenotypic heterogeneity, and the severity of symptoms in different patients depends on the severity of mutations. This review provides a comprehensive overview of A-T, although some relevant questions about pathogenesis remain unanswered, probably owing to the phenotypic heterogeneity of this monogenic disorder. The presence of various clinical and immunologic manifestations in A-T indicates that the identification of the role of defective ATM in phenotype can be helpful in the better management and treatment of patients in the future.

Association study of IL2RA and CTLA4 Gene Variants with Type I Diabetes Mellitus in children in the northwest of Iran.

Introduction: A variety of genetic predisposing factors and environmental factors are known to influence the pathogenesis of type-1 diabetes (T1D). This study intended to investigate the association of cytotoxic T-lymphocyte associated protein 4 (CTLA4) and interleukin 2 receptor subunit alpha (IL2RA) gene polymorphisms with type 1 diabetes in children of northwest of Iran. Methods: Genomic DNA was extracted by salting-out method. PCR amplification and direct sequencing methods were used for genotyping of CTLA4 (exon 1) and IL2RA (intron 1) genes in all patients and controls. SNPStats was used to calculate odds ratios (ORs), 95% confidence intervals (CIs), and p values. Results: In this study, the frequency of G allele and GG genotype of CTLA-4 (+49A/G) polymorphism in T1D patients were significantly different from those in the controls (26% vs. 11%, p = 0.006). Moreover, a significant difference was observed between patients and control group in the allele frequencies of the new SNP (chr2:203868145) that was identified in exon one of CTLA4 (14% vs. 3%, p = 0.006). The results showed that the GG homozygous genotype of +49 A>G was associated with increased glycemic level in T1D patients in the study population (95% CI = 10.47, p = 0.0067). However, no significant association was found between IL2RA (ss52580101C>A) polymorphism and T1D patients (2% vs. 4%, p = 0.41). Conclusion: The results further support the association of T1D with +49A>G SNP in the CTLA4 gene in the population of northwest of Iran. However, no significant relationship was observed between ss52580101C>A polymorphism of IL2RA gene and T1D in this study.