Diagnostic yield of genome sequencing for children with intellectual disability and developmental delay

Genome sequencing (GS) has recently been considered as a first-tier diagnostic tool for individuals with intellectual disability (ID) and developmental delay (DD). In this study, we assess the diagnostic yield of GS for a large cohort of children with ID/DD and describe variants contributing to genetic diagnoses in this cohort.

A retrospective analysis of consecutive GS results for individuals under 18 years of age with a clinical indication of ID/DD was conducted using data from a clinical diagnostic laboratory. The present analysis included 666 individuals.

In this cohort, 31.1% (207/666) of children received positive GS results. There were 186 children who received a genetic diagnosis that was at least partially associated with their history of ID/DD, leading to a phenotype-specific diagnostic yield of GS for ID/DD of 27.9%. For individuals without known prior genetic testing, 35.3% (103/292) had positive GS results. There were 259 variants that led to genetic diagnoses in this cohort. Of these, 7.7% (20/259) were variants with limited to no coverage on exome sequencing.

GS identified at least one genetic diagnosis associated with ID/DD in 27.9% of children with ID/DD as a clinical indication. An additional 3.2% of children received positive GS results associated with other features of their clinical indication. Almost 8% of variants related to the genetic diagnoses in this cohort may not have been detected through other standalone genomic technologies. These findings further support the recommendation by medical and professional societies of GS as a first-tier diagnostic test for individuals with ID/DD.