%0 Journal Article
%T Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases
%J -
%D 2018
%R https://doi.org/10.1038/s41525-018-0053-8
%X Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011每August 2017) and meta-analysis, following MOOSE/PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34每0.48, I2ˋ=ˋ44%) and WES (0.36, 95% CI 0.33每0.40, I2ˋ=ˋ83%) were qualitatively greater than CMA (0.10, 95% CI 0.08每0.12, I2ˋ=ˋ81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA (Pˋ<ˋ0.0001, I2ˋ=ˋ13% and I2ˋ=ˋ40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA (Pˋ<ˋ0.001, I2ˋ=ˋ36%). The diagnostic utility of WGS and WES were not significantly different. In studies featuring within-cohort comparisons of WGS/WES, the likelihood of diagnosis was significantly greater for trios than singletons (odds ratio 2.04, 95% CI 1.62每2.56, I2ˋ=ˋ12%; Pˋ<ˋ0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38每0.45, I2ˋ=ˋ48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27每0.31, I2ˋ=ˋ49%); this difference was significant among studies published in 2017 (Pˋ<ˋ.0001, I2ˋ=ˋ22% and I2ˋ=ˋ26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17每0.40, I2ˋ=ˋ54%) and WES (0.17, 95% CI 0.12每0.24, I2ˋ=ˋ76%) were higher than CMA (0.06, 95% CI 0.05每0.07, I2ˋ=ˋ42%); this difference was significant for WGS vs CMA (Pˋ<ˋ0.0001). In conclusion, in children with suspected genetic diseases, the diagnostic and clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic utility were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases
%U https://www.nature.com/articles/s41525-018-0053-8