Diagnostic yield of clinical exome sequencing in 868 children with neurodevelopmental disorders

Next generation sequencing has revolutionized the diagnostic approach for patients with neurodevelopmental disorders (NDDs), yields are however highly variable depending on the patient's phenotype. It is often challenging to predict which indications are likely to lead to a molecular diagnosis and which will benefit less from genetic testing.

To identify phenotypic characteristics associated with higher diagnostic yields we conducted detailed phenotyping of a cohort of 868 children with NDD, who underwent clinical exome sequencing between 2016 and 2021.

A molecular diagnosis was reached in 27 % of cases. Significantly higher yields of respectively 34 % and 32 % were observed in patients with intellectual disability (ID) or global developmental delay (GDD). Autism spectrum disorders (ASD) were less likely to result in a molecular diagnosis with a diagnostic yield of 16 %. Additional factors linked to higher yields included female gender, the presence of minor dysmorphic features — particularly involving the face, extremities, ears, eyes, and hair — and a syndromic phenotype.

Additional CNV calling in a subset of 438 patients which consented to reanalysis of sequencing data added 1.5 % to diagnostic yield.