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A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates whole-genome sequencing outperforms whole-exome sequencing.

Whole-exome (WES) or whole-genome (WGS) sequencing are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of WGS continues to be debated. This prospective randomized trial involving all Belgian Human Genetics centers compared the standard of care (SoC) - combining WES and microarray or shallow WGS - with WGS for 567 individuals with unexplained DD. The diagnostic yield of WGS was 39.8% (113/284) vs 30% for SoC (85/283) (p=0.015), mainly due to an increased detection of single nucleotide variants and indels (+8.7%). WGS also enabled the detection of three non-coding (potential) pathogenic variants. Diagnostic yield was higher for females (45.5%, 97/213) compared to males (28.5%, 101/354) (p<0.001). De novo variants were found for 23.6% of patients. Analysis of inherited variants in genes associated with autosomal dominant phenotypes contributed more to the diagnostic yield (3.9%) than X-linked variants (1.9%), and to a similar extent as autosomal recessive variants (4.1%). This nationwide study demonstrates WGS outperforms WES for the diagnosis of patients with DD in a decentralized hospital setting and well-characterized cohort. The results also highlight the importance of evaluating autosomal dominant inherited variants in genomics analyses for DD.

Type: Whole Genome Sequencing
Archive: European Genome-phenome Archive (EGA)

1 Dataset 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD50000002905	Whole-exome (WES) and whole-genome (WGS) sequencing of 567 patients with developmental disorders for which a prospective randomized trial involving all Belgian Human Genetics centers was done to compare the standard of care - combining WES and microarray or shallow WGS - with WGS.	Illumina NovaSeq 6000 Illumina NovaSeq X Plus	1166

Publications	Citations
A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care. Geysens M, Souche E, Baroni MC, Benoit V, Beyltjens T, Bossuyt W, Bours V, Crabbé M, Croes D, De Smet M, Désir J, Devriendt K, Dheedene A, Dimitrov BI, Janssens K, Kumps C, Lumaka A, Menten B, Meuwissen M, Monestier O, Mortier G, Olsen C, Palmeira L, Peeters H, Pölsler L, Revencu N, Roland D, Soblet J, Sznajer Y, Taziaux S, Van Esch H, Vandeweyer G, Vantroys E, Vilain C, Wiame E, Van Den Bogaert K, Vermeesch JR. Genome Med 18: 2026 144	0

Publications

Citations

A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.
Geysens M, Souche E, Baroni MC, Benoit V, Beyltjens T, Bossuyt W, Bours V, Crabbé M, Croes D, De Smet M, Désir J, Devriendt K, Dheedene A, Dimitrov BI, Janssens K, Kumps C, Lumaka A, Menten B, Meuwissen M, Monestier O, Mortier G, Olsen C, Palmeira L, Peeters H, Pölsler L, Revencu N, Roland D, Soblet J, Sznajer Y, Taziaux S, Van Esch H, Vandeweyer G, Vantroys E, Vilain C, Wiame E, Van Den Bogaert K, Vermeesch JR. Genome Med 18: 2026 144