Neurodevelopmental Disorders (NDD) affect 2-3% of the general population and are heterogeneous in presentation, severity, and causes. Over 2000 single gene defects responsible for NDD have been described so far and individually they qualify as ‘rare’ or ‘ultra-rare’ diseases. To resolve the diagnostic dilemma for NDD patients, we have used either a phenotype-driven approach (i.e. based on symptoms, such as brain malformations, epilepsy) or a molecular network approach (e.g. looking at families of proteins) to identify novel NDD genes. We have done this using our own genetic sequencing data from patients, as well as large datasets such the DDD study and 100,000 Genomes Project. Natural history cohort studies and genotype-phenotype correlation studies have not only enabled prognostication but also helped identify objective measures of clinical trials outcome.
With the rising diagnostic yield in rare NDD patients, research focus has turned to therapy. Severe epilepsy in NDD affects the quality of life for patients and their carer. Our recent study of patients with severe, early onset epilepsy has shown the importance of genotype in determining optimal treatment. Further work on early therapy for genetic NDD is underway.