A comparative analysis of allele frequencies for incidental findings among five populations based on the analyses of 11K whole exome sequences. T. Gambin1, S. Jhangiani2, J. E. Below3, J. Staples6, A. Morrison3, A. Li3, I. Campbell1, W. Wiszniewski1, D. M. Muzny2, M. N. Bainbridge2, R. A. Gibbs2, J. R. Lupski1,2,4,5, E. Boerwinkle2,3 1) Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 2) The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; 3) Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX; 4) Department of Pediatrics, Baylor College of Medicine, Houston, TX; 5) Texas Children's Hospital, Houston, TX; 6) Department of genome sciences, University of Washington, Seattle,WA.
Whole exome sequencing is growing to become a routine diagnostic test in many settings, and some predict that an individuals sequence will be a routine element in the electronic medical record. Incidental findings are potential medically actionable variants detected in the results of the exome or genome sequencing that are not etiologically related to a diagnostic indication for which the genome sequencing test was ordered. Such sequence information also provides an easily accessible carrier test for autosomal recessive diseases and can reveal potential pharmacogenetic risk variant alleles. The American College of Medical Genetics and Genomics (ACMG) has identified a list of 56 genes for which pathogenic or likely pathogenic variants should be identified as incidental findings. We identified non-synonymous rare variants within the ACMG genes in 2,347 individual whole exomes sequenced in Houston at the Baylor-Johns Hopkins Center for Mendelian Genomics and in 8,602 exomes from the Atherosclerosis Risk In Communities (ARIC) study. Common variants were excluded if MAF was 1% in 1KG or EVS databases. We identified a total of 23,092 mutations (6,135 distinct) in 56 genes. The number of mutations in an individual ranged from 0 to 11 with an average of 2.1 for any given individual. Approximately 22% of all mutations were previously reported in HGMD as disease-causing mutations (DM;4702) or disease-associated polymorphisms (DP/DFP;461). Moreover, we determined the average number of HGMD non-synonymous (NS) and stop-gains (SG) among the following ethnic groups: Europeans (NS=0.46;SG=0.018), Africans (NS=0.51;SG=0.027), Mexicans (NS=0.45;SG=0.003), Turkish (NS=0.42;SG=0.021) and Asians (NS=0.45;SG=0). In addition to the analysis of incidental findings, we used the ARIC cohort to evaluate the frequency of 8 pharmacogenetic risk alleles that are being currently screened at the Whole Genome Laboratory at Baylor as a part of routine WES data analysis. We found an average of 0.5 mutations per individual in Europeans vs. 0.38 in Africans. Last but not least, we investigated the carrier frequency for 1602 known recessive genes. We determined that every individual is a carrier of 0-14 (mean=4.38) likely pathogenic variants. Our results reaffirms that analysis of WES data not only helps in the clinical diagnosis and facilitates discoveries of novel genes but also provides multifaceted insight into clinically relevant genetic information for individuals and populations.
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