Variants in EP400, encoding a chromatin remodeler, cause epilepsy with neurodevelopmental disorders

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• EP400 is a key component of ATP-dependent chromatin remodeling complexes.
• The role of EP400 in human diseases, particularly epilepsy and neurodevelopmental disorders (NDDs), was previously undetermined.
• Chromatin remodeling is crucial for regulating gene expression during development.

Purpose of the Study:

• To investigate the potential association between EP400 gene variants and epilepsy/NDDs.
• To elucidate the functional role of EP400 in neurodevelopment and neuronal function.
• To identify EP400 as a novel causative gene for epilepsy and NDDs.

Main Methods:

• Trio-based whole-exome sequencing in 402 families with epilepsy/NDDs.
• Recruitment of additional individuals with EP400 variants through a matching platform.
• Functional studies including gene knockdown in Drosophila and crisprants in zebrafish, alongside transcriptome analysis.

Main Results:

• Compound heterozygous and de novo heterozygous EP400 variants were identified in individuals with epilepsy and NDDs.
• EP400 is highly expressed in the developing brain, with specific expression patterns in inhibitory and excitatory neurons.
• Loss-of-function studies in model organisms demonstrated increased seizure susceptibility, abnormal neuronal activity, and developmental defects.
• EP400 deficiency led to dysregulation of numerous epilepsy/NDD-associated genes.

Conclusions:

• EP400 is a newly identified causative gene for epilepsy and neurodevelopmental disorders.
• The spatiotemporal expression pattern of EP400 is critical for normal neurodevelopment and neuronal function.
• Disruption of EP400 function leads to epilepsy and NDD phenotypes through the dysregulation of key developmental genes.