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. <i>CSMD1</i> compound heterozygous variants were identified in four unrelated cases with IGE. Additional <i>CSMD1</i> variants were identified in five cases with DEE featured by generalized seizures from the matching platform, including two with <i>de novo</i> and three with compound heterozygous variants. Two patients were refractory to antiseizure medications and all patients were on long-term therapy. The <i>CSMD1</i> variants presented a significantly high excess of variants in the case-cohort. Besides <i>de novo</i> 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 <i>CSMD1</i> was extensively expressed throughout the brain, particularly in the cortex. The <i>CSMD1</i> temporal expression pattern correlated with the disease onset and outcomes. This study suggests that <i>CSMD1</i> is associated with epilepsy and is a novel causative gene of DEE and generalized epilepsies.