Neurobehavioral Profiles and Clinical Consequences of MYT1L-Related Neurodevelopmental Disorder: Insights from the...

MYT1L-Related Neurodevelopmental Disorder (MYT1L-NDD) is a rare autosomal dominant syndrome characterized by intellectual disability, global developmental delay, autism, and obesity. Despite growing recognition, prospective and systematic clinical phenotyping remains limited. Here, we analyzed data from 20 individuals with MYT1L variants enrolled in the Brain Gene Registry (BGR), a national platform integrating genetic, neurobehavioral, and clinical data. Neurobehavioral assessments were conducted using the Rapid Neurobehavioral Assessment Protocol (RNAP), including virtual adaptations of the Shipley, Developmental Profile-4, ASEBA Child Behavior Checklist, and Vineland-3. Diagnostic and medication data were extracted from structured electronic health records (EHR). MYT1L participants were compared to the broader BGR cohort. Fourteen participants had pathogenic or likely pathogenic MYT1L variants. Individuals with confirmed MYT1L-NDD exhibited significant impairments in nonverbal cognition and adaptive functioning, particularly in motor tasks, communication, and daily living skills. Behavioral assessments revealed elevated rates of ADHD symptoms, behavioral conduct problems, oppositional defiance, and anxiety. EHR data showed frequent diagnoses of developmental delays, speech and language disorders, gastrointestinal problems, and obesity. Medication data indicated common prescription of alpha-2 adrenergic agonists and laxatives. This study provides the first prospective, multi-source characterization of MYT1L-NDD. Findings expand our understanding of MYT1L-NDD phenotypes in a quantitative and systematic manner and underscore the value of registry-based approaches for understanding rare neurodevelopmental disorders. Larger, longitudinal studies are needed to further define MYT1L-NDD natural history and inform clinical care.