Background Chromosome microarray analysis (CMA) is the current first-tier clinical investigation for paediatric patients with congenital malformations and/or neurodevelopmental disorders. Whole genome sequencing (WGS) promises to capture all classes of genetic variation in a single experiment, but the diagnostic yield of WGS compared to CMA in the clinical setting has not been established.
Objectives The purpose of the study was to compare the diagnostic yield of WGS with CMA and other targeted sequence analysis.
Methods Through the SickKids genome clinic 100 consecutive patients undergoing CMA were recruited and WGS was performed to compare diagnostic yield.
Results WGS identified variants meeting clinical diagnostic criteria in 32% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) alone and > 2-fold increase in CMA plus targeted sequence testing (15%). WGS identified all reportable rare CNVs that were detected by CMA. In an additional 27 patients, WGS revealed clinically significant SNV and indel mutations presenting in a dominant (72%) or a recessive (28%) manner. Four cases had variants in at least two genes involved in distinct genetic disorders, contributing to a more complex clinical phenotype.
Conclusions Our data indicate that WGS is highly accurate and efficient, providing a diagnosis in 32% paediatric patients that meet clinical criteria for CMA. Clinical implementation of WGS as a single and primary molecular test will provide a higher diagnostic yield than conventional testing while decreasing the number of genetic tests and ultimately the time before reaching a genetic diagnosis.
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