Genome sequencing as a platform for pharmacogenetic genotyping: a pediatric cohort study

Abstract

Whole-genome sequencing and whole-exome sequencing have proven valuable for diagnosing inherited diseases, particularly in children. However, usage of sequencing data as a pharmacogenetic screening tool to ensure medication safety and effectiveness remains to be explored. Sixty-seven variants in 19 genes with known effects on drug response were compared between genome sequencing and targeted genotyping data for coverage and concordance in 98 pediatric patients. We used targeted genotyping data as a benchmark to assess accuracy of variant calling, and to identify copy number variations of the CYP2D6 gene. We then predicted clinical impact of these variants on drug therapy. We find genotype concordance across those panels to be > 97%. Concordance of CYP2D6 predicted phenotype between estimates of whole-genome sequencing and targeted genotyping panel were 90%; a result from a lower coverage depth or variant calling difficulties in our whole-genome sequencing data when copy number variation and/or the CYP2D6*4 haplotype were present. Importantly, 95 children had at least one clinically actionable pharmacogenetic variant. Diagnostic genomic sequencing data can be used for pre-emptive pharmacogenetic screening. However, concordance between genome-wide sequencing and target genotyping needs to be characterized for each of the pharmacologically important genes.

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

“…Similarly, mitochondrial genomes in each cell may not all be identical, and a variant in only a subset is called heteroplasmy. 14,15 To gain further insight into the spectrum of genomic variation, we assessed the disease-causing potential of all disease-associated variants in accordance with guidelines of the American College of Medical Genetics and Genomics. Variants were sorted into categories of standard terminology: "benign," "likely benign," "variant of uncertain significance" (VUS), "likely pathogenic" or "pathogenic," 16 by applying specified information from the published literature and various disease-and populationbased databases.…”

High-performance DNA sequencing to identify genetically determined diseases in pediatric practice

“…Главной целью сбора и анализа фармакогенетической информации в настоящее время является возможность оптимизации терапии -выбор препарата, который улучшил бы соотношение риска и пользы для конкретного пациента. В одной из описанных ранее когорт 95 из 98 детей имели по крайней мере один клинически значимый фармакогеномный вариант, следовательно, превентивный фармакогенетический скрининг может способствовать безопасности пациентов [24].…”

Care and cost consequences of pediatric whole genome sequencing compared to chromosome microarray

“…While these exome cases did not meet criteria for Stavropoulos' technical comparison study, outcome data prompted by WES result disclosure remain relevant to the study reported here. As well, while pharmacogenomics variants were identified in this cohort [41], medical management implications of these variants were not captured because identified variants had not been validated or reported back to patients at the time these data were ascertained. The absence of cascade family testing is surprising, but perhaps attributable to de novo findings or the absence of documentation related to cascade family testing in the proband's medical record.…”