Epilepsy and developmental disorders: Next generation sequencing in the clinic

Area of Science:

• Epigenetics and Genomics
• Neuroscience
• Medical Genetics

Background:

• Next Generation Sequencing (NGS) has revolutionized the understanding of epilepsy genetics.
• Hundreds of single-gene epilepsies have been identified, involving diverse biological processes.
• Molecular genetic diagnosis is now achievable for a significant portion of epilepsy patients.

Purpose of the Study:

• To update the genetic landscape of epilepsies.
• To categorize epilepsy-associated genes by function.
• To review genetic testing approaches and their utility.

Main Methods:

• Literature review of Next Generation Sequencing (NGS) studies.
• Categorization of epilepsy-associated genes into functional groups.
• Analysis of factors influencing diagnostic yield and utility of genetic testing.

Main Results:

• Epilepsy genes are grouped into five functional categories: ion transport, cell growth, synaptic regulation, small molecule transport/metabolism, and gene transcription/translation.
• Early seizure onset, drug resistance, and developmental comorbidities correlate with higher diagnostic yield.
• Commonly implicated genes include SCN1A, KCNQ2, CDKL5, SCN2A, and STXBP1; PRRT2 is frequent in infantile cohorts.

Conclusions:

• Genetic testing is a first-line diagnostic tool in epilepsy, with increasing utility.
• Genetic diagnosis significantly impacts treatment choices, especially in early-onset epilepsies.
• Advances in genetic testing and the potential for gene therapy offer optimism for epilepsy management.