Towards a Pathway Driven Clinical-Molecular Framework for Classifying Neurodevelopmental Disorders
The current clinical classification system of neurodevelopmental disorders is outdated, offering little insight into the molecular pathophysiology of disease that would guide targeted treatment. Neurodevelopmental disorders share common molecular and cellular pathways of dysregulation and recently, there has been a move toward gene-specific classification of neurodevelopmental disease, however, classification at this level of detail is not immediately clinically useful.
To propose an intermediate classification scheme based on molecular and cellular pathways and their clinical features.
We compiled a list of all OMIM genes and syndromes with the keywords ‘autism’ and ‘epilepsy or seizure’ and used gene set enrichment analysis to determine shared pathways significantly over-represented among this set of genes (with Benjamini-corrected p-value < 0.05). We manually curated all one-hundred twelve OMIM entries into molecular pathways, and then compared the clinical features of syndromes within these pathways.
Ninety-eight of one-hundred twelve OMIM entries curated enriched for one of three pathways: transcriptional regulation, molecular transport, or cellular synaptic function. Transcriptional regulation was the most commonly enriched pathway (n=50), and included 23 recognized syndromes. Syndromes enriching for the transcriptional regulation pathway had the highest incidence of systemic symptoms (n=20/23), the molecular transport group had the highest incidence of psychiatric symptoms (n=5/6), and the cellular transport pathway the highest incidence of motor symptoms (n=11/13).
A classification system such as this would allow clinicians to leverage the expanding genetic information in a clinically-actionable manner, providing information about disease pathophysiology and be used to guide treatment and influence the development of new therapies.