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