Genome sequencing increases diagnostic yield to 39.8% compared to 30% in developmental disordersGenome sequencing improves diagnosis for children with developmental disorders

Genome medicine Published October 6, 2026 Study authors: Geysens Mathilde, Souche Erika, Baroni Maria Chiara, Benoit Valérie, Beyltjens Tessi, Bossuyt Wouter… PubMed ↗ NCT07051213 ↗ DOI ↗ Editorial oversight: Dr. Sofia Müller, MD · Lifespan & Whole-Person Care

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Key Takeaway

Consider genome sequencing as a superior diagnostic tool over standard of care for patients with unexplained developmental disorders.

This randomized trial evaluated the diagnostic yield of genome sequencing (GS) compared to standard of care (SoC) in 567 individuals with unexplained developmental disorders. The study was conducted in a decentralized hospital setting across Belgian human genetics centers.

Genome sequencing achieved a diagnostic yield of 39.8% (113/284) compared to 30% (85/283) for the SoC group (p = 0.015). GS also showed an increased detection of single nucleotide variants and indels by 8.7%. When adjusted for sex and analytical differences, the diagnostic yield difference was 7.3% (p = 0.069), which was not statistically significant. The study identified de novo variants in 23.6% of cases, with inherited variants contributing 3.9% for autosomal dominant, 1.9% for X-linked, and 4.1% for autosomal recessive conditions.

Sex-specific analysis showed a higher yield for females (45.5%) compared to males (28.5%, p < 0.001). No safety or tolerability data were reported. A limitation of the study is that it was retrospectively registered. These findings suggest that GS outperforms SoC for diagnosing patients with developmental disorders in well-characterized cohorts, though the clinical impact of sex-adjusted differences remains uncertain.

How this fits prior evidence

How this fits prior evidence: This study addresses a gap in the diagnostic pathway for children with developmental disorders. While prior coverage noted that sperm mutation burden in fathers of children with developmental disorders is indistinguishable from controls, this study focuses on the diagnostic yield of genome sequencing in the patients themselves. It provides a specific comparison between GS and standard of care in a decentralized setting.

Families of children with unexplained developmental disorders often face a long, difficult road to find answers. This study looked at how different types of genetic testing help doctors reach a diagnosis. Researchers compared a broad method called genome sequencing against the current standard of care, which usually involves more limited tests.

In a study of 567 people, genome sequencing found a diagnosis in about 40% of cases, while the standard method found a diagnosis in 30% of cases. The study also found that genome sequencing was better at spotting specific types of genetic changes, such as single nucleotide variants and indels. Interestingly, the higher success rate for females was less pronounced when researchers adjusted the data for sex and other technical differences.

While the results show that genome sequencing is a powerful tool for finding answers, the study was registered retrospectively. This means the data was collected after the fact, which is an important detail to keep in mind when looking at the results. Overall, the findings suggest that genome sequencing can offer a more complete picture for families seeking answers.

What this means for you:

Genome sequencing identifies more diagnoses in children with developmental disorders than standard testing methods.

Study Details

Study typeRct

EvidenceLevel 2

PublishedOct 2026

PMID42830293

TrialNCT07051213

View Original 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).

Genome sequencing increases diagnostic yield to 39.8% compared to 30% in developmental disordersGenome sequencing improves diagnosis for children with developmental disorders

How this fits prior evidence

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Genome sequencing increases diagnostic yield to 39.8% compared to 30% in developmental disordersGenome sequencing improves diagnosis for children with developmental disorders

How this fits prior evidence

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