Sequencing large cohorts of ethnically homogeneous individuals yields genetic insights with implications for the entire population rather than a single individual. In order to evaluate the genetic basis of certain diseases encountered at high frequency in the Ashkenazi Jewish population (AJP), as well as to improve variant annotation among the AJP, we examined the entire exome, focusing on specific genes with known clinical implications in 128 Ashkenazi Jews and compared these data to other non-Jewish populations (European, African, South Asian and East Asian). We targeted American College of Medical Genetics incidental finding recommended genes and the Catalogue of Somatic Mutations in Cancer (COSMIC) germline cancer-related genes. We identified previously known disease-causing variants and discovered potentially deleterious variants in known disease-causing genes that are population specific or substantially more prevalent in the AJP, such as in the ATP and HGFAC genes associated with colorectal cancer and pancreatic cancer, respectively. Additionally, we tested the advantage of utilizing the database of the AJP when assigning pathogenicity to rare variants of independent whole-exome sequencing data of 49 Ashkenazi Jew early-onset breast cancer (BC) patients. Importantly, population-based filtering using our AJP database enabled a reduction in the number of potential causal variants in the BC cohort by 36%. Taken together, population-specific sequencing of the AJP offers valuable, clinically applicable information and improves AJP filter annotation.

中文翻译：

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犹太人口突变的差异分析及其对疾病的影响。

对大批种族同质的个体进行测序可产生遗传学见解，对整个人口而不是单个个体产生影响。为了评估阿什肯纳兹犹太人口（AJP）中某些高频发生的疾病的遗传基础，并改善AJP之间的变异注释，我们检查了整个外显子组，重点研究了已知临床意义的特定基因128 Ashkenazi犹太人，并将这些数据与其他非犹太人口（欧洲，非洲，南亚和东亚）进行了比较。我们针对美国医学遗传学学院偶然发现的推荐基因和《癌症体细胞突变目录》（COSMIC）种系癌症相关基因。我们鉴定了先前已知的致病变异体，并在已知的致病基因中发现了潜在的有害变异体，这些基因在AJP中具有种群特异性或更为普遍，例如分别与大肠癌和胰腺癌相关的ATP和HGFAC基因。此外，当将致病性分配给49位Ashkenazi犹太人早期发作的乳腺癌（BC）患者的独立全外显子组测序数据的罕见变异时，我们测试了利用AJP数据库的优势。重要的是，使用我们的AJP数据库进行的基于人群的过滤使BC队列中潜在因果变体的数量减少了36％。综上所述，AJP的人群特异性测序可提供有价值的，可用于临床的信息，并改善AJP过滤器注释。