FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability

Area of Science:

• Genetics
• Neurology
• Developmental Biology

Background:

• Chromosome 1q41-q42 deletion syndrome is linked to intellectual disability and seizures.
• WDR26 and FBXO28 genes within this region are implicated in rare diseases.
• FBXO28 encephalopathy is poorly understood, with limited clinical descriptions.

Purpose of the Study:

• To investigate the role of pathogenic FBXO28 variants in causing developmental and epileptic encephalopathies (DEEs).
• To delineate the phenotypic spectrum of FBXO28 encephalopathy by analyzing new and known cases.

Main Methods:

• Clinical analysis of nine new patients with pathogenic FBXO28 variants.
• Review and integration of all 10 previously reported cases.
• Phenotypic characterization including epilepsy type, intellectual disability, and neurological features.

Main Results:

• All 10 patients presented with epilepsy, and 9/10 had DEE, including infantile spasms and progressive myoclonic epilepsy.
• Intellectual disability was present in 9/10 patients, ranging from severe to profound.
• Movement disorders, hypotonia, acquired microcephaly, and dysmorphic features were observed, with distinct characteristics compared to WDR26 encephalopathy and 1q41-q42 deletion syndrome.

Conclusions:

• Pathogenic FBXO28 variants are a significant cause of DEE.
• FBXO28 encephalopathy is characterized by severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.
• This study differentiates FBXO28 encephalopathy from WDR26 encephalopathy and 1q41-q42 deletion syndrome based on distinct clinical features.