Exome sequencing identifies additional pathogenic variants in neurodevelopmental genes in 3.6% of individuals with...

To determine the frequency of pathogenic gene or copy-number variants associated with epilepsy or neurodevelopmental disorders in individuals with tuberous sclerosis complex (TSC).

Exome sequencing and single-nucleotide polymorphism array analysis were performed on 224 individuals with TSC. Variant interpretation followed American College of Medical Genetics guidelines and variants were confirmed with Sanger sequencing. Copy-number variants were assessed through PennCNV and visual inspection and considered confirmed when present on both single-nucleotide polymorphism array and exome data.

Six pathogenic variants were found in epilepsy-associated genes, and 3 pathogenic copy-number variants associated with neurodevelopmental disorders were detected. Altogether, 8 of 224 (3.6%) participants with TSC had at least 1 additional pathogenic variant that increases risk for epilepsy, intellectual disability, and other neurodevelopmental disorders. All pathogenic variants had clinical implications for surveillance, prognosis, and recurrence risk. In addition, 44% had direct targeted therapy, such as gene therapy or specific antiseizure medications.

Pathogenic variants in additional epileptic/neurodevelopmental disorders were present in 3.6% of our TSC cohort. Broader testing beyond TSC1/TSC2 may be warranted, especially as the diagnosis of TSC could mask these second neurodevelopmental disorders and knowledge of having these conditions would inform care.