Title:Identification of Two Novel Pathogenic Variants of the ATM Gene in
the Iranian-Azeri Turkish Ethnic Group by Applying Whole Exome
Sequencing
Volume: 24
Issue: 6
Author(s): Amir-Reza Dalal Amandi, Neda Jabbarpour, Shadi Shiva and Mortaza Bonyadi*
Affiliation:
- Animal Biology Department, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
- Center of Excellence for Biodiversity, Faculty of
Natural Sciences, University of Tabriz, Tabriz, Iran
Keywords:
ATM gene, breast cancer, whole exome sequencing, c.2639-2A>T, c.8708delC, c.6067G>A, c.7788G>A.
Abstract:
Background: The ATM gene encodes a multifunctional kinase involved in important
cellular functions, such as checkpoint signaling and apoptosis, in response to DNA damage. Bi-allelic
pathogenic variants in this gene cause Ataxia Telangiectasia (AT), while carriers of ATM
pathogenic variants are at increased risk of cancer depending on the pathogenicity of the variant
they carry. Identifying pathogenic variants can aid in the management of the disease in carriers.
Methods: Whole-exome sequencing (WES) was performed on three unrelated patients from the
Iranian-Azeri Turkish ethnic group referred to a genetic center for analysis. WES was also conducted
on 400 individuals from the same ethnic group to determine the frequencies of all ATM
variants. Blood samples were collected from the patients and their family members for DNA extraction,
and PCR-Sanger sequencing was performed to confirm the WES results.
Results: The first proband with AT disease had two novel compound heterozygote variants
(c.2639-2A>T, c.8708delC) in the ATM gene revealed by WES analysis, which was potentially/-
likely pathogenic. The second proband with bi-lateral breast cancer had a homozygous pathogenic
variant (c.6067G>A) in the ATM gene identified by WES analysis. The third case with a family
history of cancer had a heterozygous synonymous pathogenic variant (c.7788G>A) in the ATM
gene found by WES analysis. Sanger sequencing confirmed the WES results, and bioinformatics
analysis of the mutated ATM RNA and protein structure added evidence for the potential pathogenicity
of the novel variants. WES analysis of the cohort revealed 38 different variants, including
a variant (rs1800057, ATM:c.3161C>G, p.P1054R) associated with prostate cancer that had a higher
frequency in our cohort.
Conclusion: Genetic analysis of three unrelated families with ATM-related disorders discovered
two novel pathogenic variants. A homozygous missense pathogenic variant was identified in a woman
with bi-lateral breast cancer, and a synonymous but pathogenic variant was found in a family
with a history of different cancers.
