De novo SRCAP variants cause developmental and epileptic encephalopathy and the phenotypic spectrum

The SRCAP gene encodes a core catalytic subunit of adenosine triphosphate-dependent chromatin remodeling complexes that play an essential role in chromatin regulation and neurodevelopment. Our recent study showed that the EP400 gene, the paralog of SRCAP, is associated with neurodevelopmental disorders and epilepsy. This study aims to explore the relationship between SRCAP and developmental and epileptic encephalopathy (DEE) and the phenotypic spectrum of SRCAP variants.

Trio-based whole-exome sequencing was performed on patients with DEE from the China Epilepsy Gene 1.0 Project Cohort. Additional cases were screened from other subcohorts. The gene-disease association was validated by minor allele frequency (MAF), damaging effect of variants, genotype-phenotype correlation, and studies on spatial-temporal and single-cell expression.

De novo heterozygous SRCAP variants were identified in five patients with DEE. These variants were truncations or missense variants of severe damage characterized by significant changes in hydrophobicity and protein stability/hydrogen bonding. Additional SRCAP variants were identified in six patients with focal epilepsy (FE), including refractory FE. These variants were characterized by biallelic variants of mild damage, such as in-frame indel or missense with fewer changes in hydrophobicity and protein stability/hydrogen bonding, which were correlated with the severity of phenotype and outcomes. The epilepsy-associated variants presented statistically lower MAF than benign variants, with the lowest MAF in DEE-associated variants. Compared to EP400, SRCAP presented higher expression in the brain throughout the lifespan. In the late developmental brain, EP400 is predominantly expressed in excitatory neurons, in contrast to the higher proportion of SRCAP expression in inhibitory neurons, explaining the association of SRCAP variants with DEE and refractory FE.

SRCAP is associated with epilepsy and DEE. The phenotypic spectrum ranges from DEE/multisystem developmental disorders to FE of varied severity, depending on the damage of variants. The development-dependent expression pattern of neuron specificity explains the underlying mechanism of epilepsy outcomes.