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Motivation and Challenges
The unmet clinical need
Characterizing the natural history of rare genetic neurodevelopmental disorders (NDDs) is a significant scientific and clinical challenge. Due to the scarcity of affected individuals, these studies require multi-lingual, multi-age samples. The complexity increases with the need to assess adaptive functions such as cognition, socialization, and language, which are central to NDDs. The extensive behavioral heterogeneity and the difficulty in assessing individuals with high support needs, such as those with intellectual disabilities or minimal verbal ability, further complicate these efforts. These individuals are often excluded from NDD studies.
The emergence of gene-targeted experimental treatments for NDDs and the need to identify gene-specific biomarkers and clinical endpoints make it urgent to tackle these challenges. Studying the natural history of ARID1B-related disorder (ARID1B‑RD) is a prime example of this effort.
ARID1B-Related Disorder (ARID1B‑RD)
ARID1B‑RD is caused by de novo loss-of-function mutations in the ARID1B gene on chromosome 6. This single-gene haploinsufficiency disorder leads to intellectual disability (ID) and often autism spectrum disorder (ASD), manifesting in early childhood as moderate to severe developmental delay. Affected individuals exhibit various clinical features, such as facial characteristics, hypoplasia of the fifth finger and toenails, microcephaly, and hirsutism. Many also experience speech delays, gastrointestinal issues, hypotonia, and motor impairments. Seizure prevalence estimates range from 7% to 30%, highlighting the need for further research. In severe cases, a diagnosis of Coffin-Siris syndrome (CSS) is established, requiring continuous care and limiting independence.
Recent large-scale exome sequencing studies have identified ARID1B as the most frequently mutated gene in monogenic de novo NDDs, with a prevalence of pathogenic ARID1B variants estimated at 1 in 9,372 individuals. Despite its high prevalence and severe impact, the understanding of ARID1B‑RD’s developmental phenotypes remains limited, hindering the development of targeted interventions.