The Belgian Genome Resource to Resolve Rare Diseases

The Belgian Genome Resource to Resolve Rare Diseases

Whole-exome (WES) or whole-genome sequencing (WGS) are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of WGS continues to be debated. This prospective randomized trial involving all Belgian Human Genetics centers compares the standard of care (SoC) - combining WES and microarray or shallow WGS - with WGS for 567 individuals with unexplained DD. The aim of the project is to pave the way towards diagnostic implementation of WGS for rare DD in Belgium. To reach this aim, (1) technical validation is performed at different genetic centres in Belgium, (2) clinical utility of WGS is explored and (3) the health economic impact is mapped.

Inclusion Criteria:

• Intellectual disability/Developmental delay (moderate to profound)
• Intellectual disability/Developmental delay (mild to moderate) AND family recurrence AND normal parents
• Intellectual disability/Developmental delay (mild to moderate) AND dysmorphism (≥3 well documented minor signs)
• One major malformation AND dysmorphism (≥3 well documented minor signs)
• Multiple major malformations in 2 or more different organ systems.

Exclusion Criteria:

• Suspicion of an acquired cause, e.g. congenital infection and prenatal toxic exposure
• Prior next-generation sequencing of a gene panel targeting multiple conditions or prior exome analyses