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Abstract
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–August 2017) and meta-analysis, following MOOSE/PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34–0.48, I2 = 44%) and WES (0.36, 95% CI 0.33–0.40, I2 = 83%) were qualitatively greater than CMA (0.10, 95% CI 0.08–0.12, I2 = 81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA (P < 0.0001, I2 = 13% and I2 = 40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA (P < 0.001, I2 = 36%). 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 1.62–2.56, I2 = 12%; P < 0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38–0.45, I2 = 48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27–0.31, I2 = 49%); this difference was significant among studies published in 2017 (P < .0001, I2 = 22% and I2 = 26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17–0.40, I2 = 54%) and WES (0.17, 95% CI 0.12–0.24, I2 = 76%) were higher than CMA (0.06, 95% CI 0.05–0.07, I2 = 42%); this difference was significant for WGS vs CMA (P < 0.0001). 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.
Highlights
Genetic diseases are a leading cause of death in children less than ten years of age.[1,2,3,4,5,6,7,8] Establishing an etiologic diagnosis in children with suspected genetic diseases is important for timely implementation of precision medicine and optimal outcomes, to guide weighty clinical decisions such as surgeries, extracorporeal membrane oxygenation, therapeutic selection, and palliative care.[9]
We compared the diagnostic utility of Whole-genome sequencing (WGS) and whole-exome sequencing (WES) with that of chromosomal microarray (CMA), the recommended first-line genomic test for genetic diseases in children with intellectual disability, developmental delay, autism spectrum disorder, and multiple congenital anomalies.[15,16]
A total of 2093 records were identified by searches for studies of the diagnostic utility of WGS, WES, and CMA in affected children with a broad range of suspected genetic diseases (Figure S1)
Summary
Genetic diseases (single-gene disorders, genomic structural defects, and copy number variants) are a leading cause of death in children less than ten years of age.[1,2,3,4,5,6,7,8] Establishing an etiologic diagnosis in children with suspected genetic diseases is important for timely implementation of precision medicine and optimal outcomes, to guide weighty clinical decisions such as surgeries, extracorporeal membrane oxygenation, therapeutic selection, and palliative care.[9] With the exception of a few genetic diseases with pathognomonic findings at birth, such as chromosomal aneuploidies, etiologic diagnosis requires identification of the causative molecular basis This is remarkably difficult for several reasons: firstly, genetic heterogeneity—there are over 5200 genetic disorders for which the molecular basis has been established.[10] Secondly, clinical heterogeneity—genetic disease presentations in infants are frequently formes frustes of classic descriptions in older children (see, for example Inoue et al.[11]). Approximately four percent of children have more than one genetic diagnosis.[12]
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