Whole genome sequencing diagnostic yield for paediatric patients with suspected genetic disorders: systematic review, meta-analysis, and GRADE assessment

Abstract

Background: About 80% of the roughly 7,000 known rare diseases are single gene disorders, about 85% of which are ultra-rare, affecting less than one in one million individuals. NGS technologies, in particular whole genome sequencing (WGS) in paediatric patients suffering from severe disorders of likely genetic origin improve the diagnostic yield allowing targeted, effective care and management. The aim of this study is to perform a systematic review and meta-analysis to assess the effectiveness of WGS, with respect to whole exome sequencing (WES) and/or usual care, for the diagnosis of suspected genetic disorders among the paediatric population.

Methods: A systematic review of the literature was conducted querying relevant electronic databases, including MEDLINE, EMBASE, ISI Web of Science, and Scopus from January 2010 to June 2022. A random-effect meta-analysis was run to inspect the diagnostic yield of different techniques. A network meta-analysis was also performed to directly assess the comparison between WGS and WES.

Results: Of the 4,927 initially retrieved articles, thirty-nine met the inclusion criteria. Overall results highlighted a significantly higher pooled diagnostic yield for WGS, 38.6% (95% CI: [32.6 - 45.0]), in respect to WES, 37.8% (95% CI: [32.9 - 42.9]) and usual care, 7.8% (95% CI: [4.4 - 13.2]). The meta-regression output suggested a higher diagnostic yield of the WGS compared to WES after controlling for the type of disease (monogenic vs non-monogenic), with a tendency to better diagnostic performances for Mendelian diseases. The network meta-analysis showed a higher diagnostic yield for WGS compared to WES (OR = 1.54, 95%CI: [1.11 - 2.12]).

Conclusions: Although whole genome sequencing for the paediatric population with suspected genetic disorders provided an accurate and early genetic diagnosis in a high proportion of cases, further research is needed for evaluating costs, effectiveness, and cost-effectiveness of WGS and achieving an informed decision-making process.

Trial registration: This systematic review has not been registered.

Keywords: Diagnostic yield; Health policy; NGS; Paediatrics; Public health.

Fig. 1

PRISMA flow diagram related to the included studies in the meta- analysis

Fig. 2

Stacked bar charts of Quality Assessment of Diagnostic Accuracy Studies -2 (QUADAS-2) scores showing an overview of the methodological quality of included studies, expressed as a percentage of studies that met each criterion

Fig. 3

Forest plot of the diagnostic yield of usual care, WES and WGS, reported in the studies included in the systematic review and meta-analysis, 2015–2022

Fig. 4

Results of the network meta-analysis comparing different diagnostic techniques. a Forest plot. Estimates are reported in the form of odds ratios, and the WES test is taken as reference. b Diagnostic yield network diagram. Red highlighting means significant difference between techniques (i.e., all relationships are significant). Thickness is proportional to the inverse standard error of each model comparing two techniques