Distinct Epileptogenic Mechanisms Associated with Seizures in Wolf-Hirschhorn Syndrome

Seizures are one of the clinical hallmarks of Wolf-Hirschhorn syndrome (WHS), causing a significant impact on the life quality, still in the first years of life. Even that the knowledge about WHS-related seizure candidate genes has grown, cumulative evidence suggests synergic haploinsufficiency of distinct genes within cellular networks that should be better elucidated. Herein, we evaluated common mechanisms between candidate genes from WHS seizure-susceptibility regions (SSR) and genes globally associated with epilepsy. For this purpose, data from 94 WHS patients delineated by chromosomal microarray analysis were integrated into a tissue-specific gene network with gene expression, drugs, and biological processes. We found functional modules and signaling pathways involving candidate and new genes with potential involvement in the WHS-related seizure phenotype. The proximity among the previous reported haploinsufficient candidate genes (PIGG, CPLX1, CTBP1, LETM1) and disease genes associated with epilepsy suggests not just one, but different impaired mechanisms in cellular networks responsible for the balance of neuronal activity in WHS patients, from which neuron communication is the most impaired in WHS-related seizures. Furthermore, CTBP1 obtained the largest number of drug associations, reinforcing its importance for adaptations of brain circuits and its putative use as a pharmacological target for treating seizures/epilepsy in patients with WHS.