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

Abstract

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 sub-groups. Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years and various types of clinical manifestations, including fever (p= 0.005), lower respiratory tract infection (p= 0.033), diarrhea (p= 0.014), and hepatosplenomegaly (p= 0.032) were significantly higher amongst patients diagnosed with the severe phenotype. Our results showed a strong 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 compared to patients who were categorized in the mild genotype group (odds ratio= 7.3, p= 0.006). 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 are required for carrier detection and reducing the burden of disease in future using the patients’ families and for the public health care system. Keywords: Ataxia-telangiectasia (A-T), ATM, Whole-exome sequencing, Class switching recombination (CSR), phenotype severity.

“Inborn errors of immunity: An expanding horizon through a multitude of biological pathways”

“…The validity of the disease categories derived from this exercise relies heavily on the continuous confirmation and updating of such phenotypic features. In this context, the virtual issue on “Inborn Errors of Immunity” aims at providing the readers of PAI a collection of topical reviews on some of the major immunological pathways that can be affected by pathological genetic variants causing IEIs and a selection of original articles highlighting clinical observations from cohort studies of well‐known conditions, as well as original discoveries that extend the genetic and clinical features of less commonly observed IEIs 1–17 …”

“…In this context, the virtual issue on "Inborn Errors of Immunity" aims at providing the readers of PAI a collection of topical reviews on some of the major immunological pathways that can be affected by pathological genetic variants causing IEIs and a selection of original articles highlighting clinical observations from cohort studies of well-known conditions, as well as original discoveries that extend the genetic and clinical features of less commonly observed IEIs. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] In their review of IEIs caused by defects in the DNA damage response pathways, Fournier and Colleagues 3 Additional reviews of the areas of IEIs characterized by defects of actin cytoskeletal dynamics, the JAK-STAT pathways, and type I interferon disorders have been commissioned and will be available in the near future. These works will complement the current collection and provide the readers of PAI with additional timely updates and perspectives on the scientific and clinical aspects of some of the major disease subgroups in the field of IEIs.…”