Abstract
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.
Highlights
High-throughput sequencing, known as nextgeneration sequencing (NGS), reduced the cost and increased the yield of DNA sequencing
We focused on the clinical utility and practical implications resulting from WES analysis of 128 Ashkenazi Jews, of whom 74 individuals had no discernible disease and 54 were controls in a Parkinson’s disease (PD) study
We examined the genetic differences between the Ashkenazi Jewish population (AJP) and other non-Jewish populations (NJPs) and searched for genes that are more likely to carry pathogenic variants among the AJP than in NJPs
Summary
High-throughput sequencing, known as nextgeneration sequencing (NGS), reduced the cost and increased the yield of DNA sequencing. The Ashkenazi Jewish population (AJP) is known to have a high rate of several diseases affecting individuals of that ethnic origin compared with other world ethnicities (Rosner et al, 2009) These include both autosomal recessive disorders due to the founder effect (Slatkin, 2004; Bray et al, 2010; Carmi et al, 2014), such as Gaucher disease (Beutler et al, 1993), cystic fibrosis (Abeliovich et al, 1992) and Tay–Sachs disease (Myerowitz & Costigan, 1988), as well as more common, adult-onset autosomal dominant diseases such as Parkinson’s disease (PD) (Ozelius et al, 2006) and hereditary BC and ovarian cancer (Struewing et al, 1997). Further research is warranted in order to elucidate the possible clinical implications of the AJP allelic architecture and to improve the curation and accuracy of pathogenic variant screening in current and future AJP studies
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