Genomic Reanalysis of Neurodevelopmental Disorders With and Without Epilepsy: Diagnostic Yield and Mechanisms of Newly Established Diagnoses.

Abstract

Background/objectives: Genomic reanalysis may provide additional molecular diagnoses in patients with neurodevelopmental disorders (NDDs) whose initial genetic testing was nondiagnostic. We evaluated the diagnostic yield and mechanisms of newly established diagnoses in NDDs with and without epilepsy.

Methods: We retrospectively reviewed 175 patients with previously unresolved NDDs who underwent whole-exome sequencing between 2015 and 2024. Archived WES variant call format (VCF) files were reannotated using updated databases and variant prioritization criteria, followed by phenotype- and inheritance-informed clinical interpretation. Patients were classified as NDD without epilepsy (n = 133) or NDD with epilepsy (NDD+E; n = 42).

Results: Five new molecular diagnoses were established, yielding an incremental diagnostic yield of 3% (5/175). The yield was numerically higher in the NDD+E group than in the NDD group (7% [3/42] vs. 2% [2/133]), although the difference was not statistically significant (p = 0.090). Newly established diagnoses involved NPRL3, RYR1, SYNGAP1, CSNK2B, and SETD5 and arose through distinct mechanisms, including complementary CNV testing with retrospective sequencing review, phenotype- and inheritance-informed reinterpretation, recognition of insufficient initial sequencing coverage, and updated variant interpretation incorporating new evidence.

Conclusions: Genomic re-evaluation provided additional diagnoses in a modest but clinically relevant proportion of previously unresolved pediatric NDD cases. Periodic, phenotype-informed reassessment of existing genomic data, together with complementary testing when indicated, may resolve diagnoses missed or uninterpretable at the initial evaluation.