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

This prospective randomized trial, run across all Belgian human genetics centres, compared genome sequencing (GS) with standard of care (exome combined with chromosomal microarray or shallow GS) in 567 individuals with unexplained developmental disorders. Diagnostic yield was 39.8% (113/284) for GS versus 30% (85/283) for standard of care (p = 0.015), mainly owing to better detection of SNVs and indels (+8.7%); three (potentially) pathogenic non-coding variants were identified. Yield was higher in females (45.5%) than in males (28.5%) (p < 0.001), and after correction for sex distribution and analytical differences between arms the GS versus standard-of-care gap fell to 7.3% (p = 0.069). De novo variants were found in 23.6% of patients, and inherited variants in genes with autosomal dominant phenotypes contributed more (3.9%) than X-linked variants (1.9%).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is one of the few randomized trials on the question, but the GS advantage shrinks to 7.3% and loses statistical significance once sex and analytical imbalances are corrected, so the claim that GS outperforms standard of care is more fragile than the title suggests. The trial was also registered retrospectively. The most useful lesson for exome/genome interpretation is the non-negligible contribution of inherited dominant variants, which should not be dismissed upfront.

Analysis by Dr Thibaut Benquey