BACKGROUND Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder that causes deficiency or dysfunction of the ataxia-telangiectasia mutated (ATM) protein. Not only AT patients, but also certain ATM heterozygous mutation carriers show a significantly reduced life expectancy due to cancer and ischemic heart disease; in particular, female carriers having particular alleles have an increased risk of breast cancer. The frequency of such risk heterozygotes at a population level remains to be fully determined, and evidence-based preventive medical guidelines have not yet been established. METHODS Using the 3.5KJPNv2 allele frequency panel of Japanese Multi Omics Reference Panel v201902, which shows single-nucleotide variant (SNV) and insertion/deletion (INDEL) allele frequencies from 3552 Japanese healthy individuals, we investigated the diversity of ATM gene variants. RESULTS We detected 2845 (2370 SNV and 475 INDEL) variants in the ATM gene, including 1338 (1160 SNV and 178 INDEL) novel variants. Also, we found a stop-gained SNV (NC_000008.11:g.108115650G > A (p.Trp266*)) and a disruptive-inframe-deletion (NC_000008.11:g. 108181014AAGAAAAGTATGGATGATCAAG/A (p.Ala1945_Phe1952delinsVal) and two frameshift INDELs (NC_000008.11:g.108119714CAA/C (p.Glu376fs) and NC_000008.11:g.108203577CTTATA/C (p.Ile2629fs)), which would be novel variants predicted to lead to loss of ATM functionality. CONCLUSION The combination of population-based biobanking and human genomics provided a novel insight of diversity of ATM gene variants at a population level. For the advancement of precision medicine, such approach will be useful to predict novel pathogenic/likely pathogenic variants in the ATM gene and to establish preventive medical guidelines for certain ATM heterozygotes pertaining to their risk of particular diseases.

中文翻译：

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ATM基因变体的多样性：精确医学的基于人群的基因组数据分析。

背景技术共济失调-毛细血管扩张症（AT）是一种罕见的常染色体隐性遗传疾病，其引起共济失调-毛细血管扩张突变（ATM）蛋白的缺乏或功能障碍。由于癌症和局部缺血性心脏病，不仅AT患者而且某些ATM杂合突变携带者的预期寿命也大大缩短。特别地，具有特定等位基因的女性携带者患乳腺癌的风险增加。此类风险杂合子在人群中的发生频率仍有待完全确定，并且尚未建立基于证据的预防医学指南。方法使用日本Multi Omics Reference Panel v201902的3.5KJPNv2等位基因频率面板，该面板显示了3552名日本健康个体的单核苷酸变异（SNV）和插入/删除（INDEL）等位基因频率，我们研究了ATM基因变异的多样性。结果我们在ATM基因中检测到2845个（2370 SNV和475 INDEL）变异，包括1338个（1160 SNV和178 INDEL）新变异。此外，我们发现了停止获取的SNV（NC_000008.11：g.108115650G> A（p.Trp266 *））和破坏性帧内删除（NC_000008.11：g。108181014AAGAAAAGTATGGATGATCAAG / A（p.Ala1945_Phe1952delinsVal））移码INDEL（NC_000008.11：g.108119714CAA / C（p.Glu376fs）和NC_000008.11：g.108203577CTTATA / C（p.Ile2629fs）），它们可能是会导致ATM功能丧失的新颖变体。基于人群的生物库和人类基因组学的结合为ATM基因变体在人群水平上的多样性提供了新的见解。