A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.

BACKGROUND

Exome (ES) or genome (GS) sequencing are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of GS continues to be debated.

METHODS

This prospective randomized trial involving all Belgian human genetics centers compared the standard of care (SoC) - combining ES and chromosomal microarray analysis or shallow GS - with GS for 567 individuals with unexplained DD. The study was retrospectively registered.

RESULTS

The diagnostic yield of GS 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%). GS also enabled the detection of three non-coding (potential) pathogenic variants. Across both study arms, the diagnostic yield was higher for females (45.5%, 97/213) compared to males (28.5%, 101/354) (p < 0.001). Upon correction for the sex distribution and analytical differences between the study arms, the diagnostic yield difference between GS and SoC was reduced to 7.3% (p = 0.069). 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%).

CONCLUSIONS

This nationwide study indicates GS outperforms SoC 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.

TRIAL REGISTRATION: ClinicalTrials.gov (NCT07051213, 03-07-2025).