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The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia
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  • Parisa Amirifar,
  • Mohammad Reza Ranjouri,
  • salar Pashangzadeh ,
  • Martin Lavin,
  • Reza Yazdani,
  • Tannaz Moeini Shad,
  • Mahya Mehrmohamadi,
  • Fereshte Salami ,
  • Samaneh Delavari,
  • Soraya Moamer,
  • Asghar Aghamohammadi,
  • Seyed Mohammad Akrami,
  • Hassan Abolhassani
Parisa Amirifar
Tehran University of Medical Sciences
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Mohammad Reza Ranjouri
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
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salar Pashangzadeh
Iranian Primary Immunodeficiencies Network (IPIN), Tehran University of Medical Sciences, Tehran, Iran
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Martin Lavin
University of Queensland Centre for Clinical Research (UQCCR), University of Queensland, Herston, Brisbane, QLD, Australia
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Reza Yazdani
Research Center for Immunodeficiencies
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Tannaz Moeini Shad
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science
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Mahya Mehrmohamadi
Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
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Fereshte Salami
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
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Samaneh Delavari
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science
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Soraya Moamer
School of Public Health, Student Research Committee, Hamadan University of Medical Sciences
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Asghar Aghamohammadi
RCID
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Seyed Mohammad Akrami
Tehran University of Medical Sciences
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Hassan Abolhassani
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science
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Abstract

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.

Peer review status:ACCEPTED

29 Nov 2020Submitted to Pediatric Allergy and Immunology
03 Dec 2020Reviewer(s) Assigned
28 Dec 2020Review(s) Completed, Editorial Evaluation Pending
31 Dec 2020Editorial Decision: Revise Minor
19 Jan 20211st Revision Received
20 Jan 2021Review(s) Completed, Editorial Evaluation Pending
24 Jan 2021Reviewer(s) Assigned
26 Jan 2021Editorial Decision: Accept