Dimensionality reduction of quantitative EEG and clinical profiles uncover associations with monogenic neurodevelopmental phenotypes in SNAREopathies.

Introduction: Monogenic neurodevelopmental disorders (mNDDs) such as SNAREopathies exhibit complex electrophysiological features and diversity among clinical symptoms, complicating the mapping of electro-clinical relationships, essential for improving diagnosis and treatment monitoring. Establishing robust normative electrophysiological feature distributions from typically developing populations enables precise, individualized quantification of patient-specific abnormalities. Here, we introduce a multivariate framework to reveal patient-specific electrophysiological phenotypes and clinical severity dimensions of direct relevance for individual prognosis and therapeutic tracking. Methods: We analyzed resting-state electroencephalography (EEG) data from15 SNAREopathy subjects ( Results: The normative qEEG space identified diffuse, spectro-spatial patterns for absolute power, while relative power and LRTC displayed frequency-specific distributions. Clinical PCA identified a primary dimension of clinical impairment integrating deficits in mobility, hand function, communication, and adaptive behavior, whereas the secondary component captured the severity of qualitative EEG abnormalities. Patient deviations from normative absolute and relative power correlated with the primary, while LRTC deviations aligned with the secondary severity component. Discussion: Normative qEEG deviance metrics correspond to distinct clinical severity dimensions in SNAREopathies, making them promising for tracking disorder progression and therapeutic response.