RBFOX1 and RBFOX3 mutations in rolandic epilepsy.

Area of Science:

• Neurogenetics
• Molecular Biology

Background:

• RBFOX1 gene deletions are associated with neurodevelopmental disorders, including epilepsy.
• RBFOX1 and its homologs (RBFOX2, RBFOX3) regulate alternative splicing crucial for neuronal excitability.

Purpose of the Study:

• To investigate the role of structural microdeletions and exonic variations in RBFOX1, RBFOX2, and RBFOX3 in susceptibility to rolandic epilepsy (RE).

Main Methods:

• High-density SNP array screening of 289 RE patients.
• Exome sequencing of 242 RE patients.
• Comparison with 6503 non-RE subjects from the Exome Variant Server database.

Main Results:

• Identified hemizygous deletions in RBFOX1 and RBFOX3 in RE patients.
• Discovered novel, likely deleterious variants (frameshift, hexanucleotide deletion, nonsense mutation) in RBFOX1 and RBFOX3.
• Found no similar mutations in RBFOX1 or RBFOX3 in a large control cohort.

Conclusions:

• RBFOX3 is implicated as a novel risk factor for RE.
• Exon deletions and truncating mutations in RBFOX1 and RBFOX3 contribute to the genetic basis of idiopathic epilepsy syndromes.