CARE4ARID1B

ARID1B is the most frequently mutated gene in monogenic de novo neurodevelopmental disorders (NDDs), with an approximated prevalence of one in 9,500 individuals. ARID1B-related disorder (ARID1B-RD) manifests in early childhood as moderate to severe developmental delay, and affected children and adults have intellectual disability (ID) and are often diagnosed with autism spectrum disorder alongside many other clinical signs. Despite ARID1B-RD’s high prevalence and extensive debilitating effects, the current understanding of the disorder’s developmental trajectories is strikingly limited. 
The proposed project will address this gap by employing a prospective longitudinal multi-method design. Its primary objectives are twofold: firstly, to establish a comprehensive, integrative understanding of the development of ARID1B-RD encompassing all relevant functional domains and physiological systems and; and secondly, to characterize multiple traditional and novel clinical endpoints for upcoming targeted ARID1B-RD clinical trials. Additionally, the project seeks to identify biosignatures of ARID1B-RD that may be utilized for stratification and prediction of the disorder’s progression. To attain these objectives, we will monitor the development of 135 children and adolescents with ARID1B-RD in seven sites, for 30 months. Monitoring will involve (a) bi-annual standardized NDD assessments conducted by clinicians, supplemented by caregivers’ reports; (b) evaluation of ARID1B-RD-specific biomarkers, including EEG, episignatures, proteomics and facial phenotype; and (c) collection of ecologically valid data based on caregivers’ reports and wearables tapping into motor and language development. 
The project team brings a diverse set of complementary state-of-the-art expertise and collaborates with leading patient advocacy organizations. The collected data will allow identifying and cross-validating clinical endpoints, and serve as an external historical control, thus facilitating the development of effective therapeutics for thousands of children worldwide. Moreover, the methods implemented as part of the project will serve as an exemplar for future multi-national/lingual natural history studies for NDDs.