Genome Med. 2026 Oct 5;18(1):144. doi: 10.1186/s13073-026-01771-2.
ABSTRACT
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).
PMID:42830293 | DOI:10.1186/s13073-026-01771-2
