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 perfo...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 pa-tients 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 be-tween gene expression and phenotype were studied to validate the geneedisease association.CSMD1 compound heterozygous variants were identified in four unrelated cases with IGE.Addi-tional 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-asso-ciated 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-pheno-type severity correlation.Gene expression analysis showed that CSMD1 was extensively ex-pressed 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 asso-ciated with epilepsy and is a novel causative gene of DEE and generalized epilepsies.展开更多
基金supported by the National Natural Science Foundation of China(No.82271505 to W.P.L.)the Multi-center Clinical Research Fund Project of the Second Affiliated Hospital of Guangzhou Medical University(No.010G271099,2020-LCYJ-DZX-03 to W.P.L.)the Science and Technology Project of Guangzhou,Guangdong,China(No.201904020028 to W.P.L.).
文摘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 pa-tients 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 be-tween gene expression and phenotype were studied to validate the geneedisease association.CSMD1 compound heterozygous variants were identified in four unrelated cases with IGE.Addi-tional 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-asso-ciated 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-pheno-type severity correlation.Gene expression analysis showed that CSMD1 was extensively ex-pressed 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 asso-ciated with epilepsy and is a novel causative gene of DEE and generalized epilepsies.
