A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care
In brief
Genome sequencing diagnosed 40% of patients, versus 30% with standard testing
In a nationwide randomized trial of 567 people with unexplained developmental disorders, genome sequencing had a 39.8% diagnostic yield, compared with 30% for standard testing, largely by finding more small genetic changes. After accounting for differences between groups, the advantage fell to 7.3 percentage points and was not statistically clear, so the size of the benefit remains uncertain.
- Journal
- Genome medicine (Q1)
- Published
- 5 October 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Mathilde Geysens, Erika Souche, Maria Chiara Baroni, Valérie Benoit, Tessi Beyltjens, Wouter Bossuyt, et al.
- PMID
- 42830293
- DOI
- 10.1186/s13073-026-01771-2
Why clinicians should know about it
- Picked for Genetics (clinical) (top studies of the week, 18 October 2026): GS outperforms standard of care for developmental disorders
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).
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.