Mutations in ARID2 are associated with intellectual disabilities.

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• The genetic causes of intellectual disabilities (ID) are often unidentified.
• De novo mutations are a significant factor in severe ID due to reduced reproductive fitness.
• The SWI/SNF chromatin modifier, including its ARID2 component, is implicated in neurodevelopmental disorders.

Purpose of the Study:

• To identify the genetic etiology of intellectual disability using clinical whole exome sequencing.
• To investigate the role of the ARID2 gene in neurodevelopmental disorders.

Main Methods:

• Utilized proband-parent trios in clinical whole exome sequencing (WES).
• Analyzed identified variants for loss-of-function effects and de novo status.

Main Results:

• Identified four independent, novel loss-of-function variants in the ARID2 gene in four patients with ID.
• Three of the four identified variants were confirmed as de novo.
• Patients presented with ID, ADHD, short stature, dysmorphic features, and Wormian bones.
• Variants predicted premature termination, losing conserved zinc finger motifs.

Conclusions:

• This study reports the first association of ARID2 mutations with developmental delay and intellectual disability.
• Loss-of-function variants in ARID2 are a newly identified cause of syndromic intellectual disability.