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.