CSMD1 as a causative gene of developmental and epileptic encephalopathy and generalized epilepsies

Genetic factors are the major causes of epilepsies, such as developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). However, the etiology of most patients remains elusive. This study performed exon sequencing in a cohort of 173 patients with IGE. Additional cases were recruited from the matching platform in China. The excess and damaging effect of variants, the genotype-phenotype correlation, and the correlation between gene expression and phenotype were studied to validate the gene–disease association. CSMD1 compound heterozygous variants were identified in four unrelated cases with IGE. Additional CSMD1 variants were identified in five cases with DEE featured by generalized seizures from the matching platform, including two with de novo and three with compound heterozygous variants. Two patients were refractory to antiseizure medications and all patients were on long-term therapy. The CSMD1 variants presented a significantly high excess of variants in the case-cohort. Besides de novo origination, the DEE cases had each of the paired variants located closer to each other than the IGE cases or more significant alterations in hydrophobicity. The DEE-associated variants were all absent in the normal population and presented significantly lower minor allele frequency than the IGE-associated variants, suggesting a minor allele frequency-phenotype severity correlation. Gene expression analysis showed that CSMD1 was extensively expressed throughout the brain, particularly in the cortex. The CSMD1 temporal expression pattern correlated with the disease onset and outcomes. This study suggests that CSMD1 is associated with epilepsy and is a novel causative gene of DEE and generalized epilepsies.