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

Researchers studied genetic testing results in 868 children with developmental differences. They found that 27% of children received a genetic diagnosis. Children with intellectual disability or global developmental delay were more likely to get answers (34% and 32%) compared to children with autism (16%). Girls and children with certain physical features were more likely to receive a genetic diagnosis.

This large cohort study analyzed genetic testing outcomes in 868 children with neurodevelopmental disorders who underwent clinical exome sequencing between 2016-2021. The overall diagnostic yield was 27%, with significantly higher rates in children with intellectual disability (34%) and global developmental delay (32%) compared to autism spectrum disorders (16%). Female gender, presence of minor dysmorphic features (particularly facial, extremity, ear, eye, and hair characteristics), and syndromic presentations were associated with higher diagnostic success. Additional copy number variant analysis in a subset of patients contributed an extra 1.5% to the diagnostic yield, highlighting the value of comprehensive genetic analysis approaches.

Results support phenotype-guided genetic testing strategies, with higher yields expected in intellectual disability and global developmental delay compared to isolated autism. Presence of dysmorphic features should prompt consideration for genetic evaluation. Comprehensive genetic analysis including copy number variants may increase diagnostic success.

Study does not specify methodology details or statistical analyses used. Sample represents single institution experience which may limit generalizability. Follow-up duration and long-term outcomes not reported. Phenotyping methods and criteria for dysmorphic features not detailed.

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.