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.

中文翻译：

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应用全外显子组测序鉴定伊朗-阿塞拜疆土耳其族群中 ATM 基因的两种新致病变异

背景：ATM 基因编码一种多功能激酶，参与重要的细胞功能，例如检查点信号传导和细胞凋亡，以响应 DNA 损伤。该基因中的双等位基因致病变异会导致毛细血管扩张共济失调 (AT)，而 ATM 致病变异携带者患癌症的风险会增加，具体取决于他们携带的变异的致病性。识别致病变异有助于控制携带者的疾病。方法：对来自伊朗-阿塞拜疆土耳其族群的三名无关患者进行全外显子组测序（WES），这些患者被转至遗传中心进行分析。 WES 还对来自同一种族的 400 名个体进行了测定，以确定所有 ATM 变异的频率。采集患者及其家属的血样进行DNA提取，并进行PCR-Sanger测序以确认WES结果。结果：WES分析显示，第一位患有AT疾病的先证者在ATM基因中具有两个新的复合杂合子变异体（c.2639-2A>T，c.8708delC），其具有潜在/可能致病性。第二位患有双侧乳腺癌的先证者通过WES分析鉴定出ATM基因中存在纯合致病性变异(c.6067G＞A)。第三例有癌症家族史，WES分析发现ATM基因存在杂合同义致病性变异(c.7788G＞A)。桑格测序证实了 WES 结果，对突变 ATM RNA 和蛋白质结构的生物信息学分析为新变体的潜在致病性提供了证据。该队列的WES分析揭示了38种不同的变异，包括与前列腺癌相关的变异（rs1800057，ATM：c.3161C>G，p.P1054R），该变异在我们的队列中出现频率较高。结论：对三个患有 ATM 相关疾病的不相关家族进行遗传分析，发现了两种新的致病变异。在一名患有双侧乳腺癌的女性中发现了纯合错义致病性变异，并且在具有不同癌症病史的家族中发现了同义但致病性变异。