O'Neill, Helen; Tirrell, Kimberley; (2023) Comparing the diagnostic and clinical utility of WGS and WES with standard genetic testing (SGT) in children with suspected genetic diseases: A systematic review and meta-analysis. medRxiv

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Text 2023.07.17.23292722v1.full.pdf - Published Version Download (1MB) | Preview

Abstract

Rare genetic diseases remain a significant cause of infant mortality worldwide. Despite the established use of classic newborn screening (NBS) methodologies, many genetic diseases escape detection, necessitating the exploration of alternative diagnostic approaches. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) have emerged as promising techniques for diagnosing genetic diseases in children. This study aimed to systematically evaluate the diagnostic and clinical utility of WGS and WES compared to standard genetic testing (SGT) in children suspected of having genetic diseases and discuss their potential impact on the expansion of NBS. A thorough search of EMBASE, MEDLINE, PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, and references of included full-text articles was conducted until October 21, 2021. Studies reporting the diagnostic yield or rate of change in management using WGS and/or WES were included for analysis. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed for data extraction, and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to assess study quality. Meta-analysis was performed using a random-effects model to calculate pooled proportions and odds ratios. The main outcomes of interest were the diagnostic utility and clinical utility of WGS, WES, and SGT. Diagnostic utility was defined as the identification of pathogenic or likely pathogenic variants strongly or moderately associated with the patient's clinical phenotype, which were subsequently reported to the clinician. Clinical utility encompassed any changes observed in medical or surgical management, as assessed through clinician questionnaires or Electronic Health Record reviews. The analysis included 43 studies involving 6,168 children. The pooled diagnostic utility of WES (0.40, 95% CI 0.34-0.45, I2=90%) exhibited a qualitative superiority over WGS (0.34, 95% CI 0.29-0.39, I2=79%) and SGT (0.19, 95% CI 0.13-0.25, I2=64%). Regarding clinical utility, WGS (0.74, 95% CI 0.56-0.89, I2=93%) demonstrated a qualitative advantage over WES (0.72, 95% CI 0.61-0.81, I2=86%), while both outperformed SGT (0.69, 95% CI 0.38-0.94). In conclusion, our findings suggest that WGS and WES should be considered as primary diagnostic tools for identifying genetic diseases in children. Furthermore, the integration of WGS and WES into NBS holds promise; however, additional investigations are warranted to assess the cost-effectiveness of this approach. This study sheds light on the potential of advanced sequencing methods to revolutionize the diagnosis and management of genetic diseases, thus impacting the field of human genetics significantly.

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