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Developmental Trajectories in ARID1B-Related Disorder

Understanding ARID1B-Related Disorder: A Multi-Method, Multi-Site Prospective Natural History Study

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.

Our Goals

To bridge this knowledge gap, our study employs a comprehensive, longitudinal multi-method design with two primary objectives:
  1. Understanding Developmental Trajectories: We aim to create an integrative understanding of ARID1B‑RD's impact on all functional domains and physiological systems.
  2. Characterizing Clinical Endpoints: We seek to define traditional and novel clinical endpoints for future targeted ARID1B‑RD clinical trials.
Additionally, our study aims to identify biosignatures that can help predict and stratify the progression of ARID1B‑RD.

Study Design and Methods

We will monitor the development of 135 children and adolescents with ARID1B‑RD over 30 months across seven sites. Our methods include:
  • Bi-annual standardized neurodevelopmental assessments are conducted by clinicians and supplemented with caregivers' reports.
  • Evaluation of specific biomarkers, such as brain activity using EEG, l genetic, epigenetic, and protein markers, and facial phenotype analysis.
  • Ecologically Valid Data Collection: Utilizing caregivers' reports and wearable technology to track motor and language development.

Collaborative Expertise

Our project team comprises experts with state-of-the-art knowledge who collaborate closely with leading patient advocacy organizations. The data collected will help identify and validate clinical endpoints, serve as a historical control, and aid in developing effective therapies for thousands of children worldwide.

Impact and Future Directions

The methodologies used in this study will set a benchmark for future multi-national and multi-lingual natural history studies for NDDs, paving the way for more effective therapeutic developments and improved quality of life for those affected by ARID1B‑RD.

Funders

  • European Joint Programme on Rare Diseases (EJP RD)
  • Israel: Chief Scientist Office of the Ministry of Health (CSO-MOH)
  • Canada: Canadian Institutes of Health Research – Institute of Genetics (CIHR-IG)
  • Germany: German Ministry of Education and Research (BMBF)
  • Italy: Fondazione Telethon
  • Sweden: Swedish Research Council (SRC)
  • France: French National Research Agency (ANR)
  • Turkey: The Scientific and Technological Research Council of Turkey (TUBITAK)