Clinical Characteristics Of CSMD1 Gene Mutation-related Diseases

Background and objectiveThe CSMD1 gene encodes membrane-spanning protein which contains multiple CUB(CUB C1r/C1 s,Uegf,Bmp1,CUB)and CCP(Complement control protein;CCP)domains.This gene may play an important role in the process of development of the central nervous system.A research suggests that the encoded protein may be a synapse-associated proteins.Previous studies reported that the CSMD1 gene mutations are associated with epilepsy,schizophrenia,autism,and development delay.However,the relationship between the CSMD1 gene and epilepsy is still unclear.In this study,we have screened for known and unknown gene mutations in patients with epilepsy of unknown causes by using the whole exome sequencing.We have found that six CSMD1 compound heterozygous gene missense mutations in patients with epilepsy.By summarizing the clinical characteristics,genetic characteristics and bioinformatics analysis of patients with CSMD1 gene mutation,it was found that CSMD1 gene might be a candidate pathogenic gene for epilepsy.Methods1.Case collectionAll the six patients were collected from the center of Epilepsy Clinic of the Second Affiliated Hospital of Guangzhou Medical University from Mar.2018 to Mar.2020.Epilepsy patients meeting the inclusion criteria of this study were included.The clinical characteristics of diseases caused by CSMD1 gene were summarized and the effects of missense mutations were predicted by using the software predictive protein model.2.Whole exome sequencingAfter informed consent was obtained from the probands and their parents,2ml peripheral venous whole blood samples were collected for all probands and their parents.Finally,Sanger sequencing was used to verify the selected mutation points of CSMD1 gene,and the false positive mutations were excluded.ResultsWe have found six compound heterozygous missense variants in CSMD1 gene in patients with epilepsy.These gene variants are no frequency or low frequency in the crowd.Multiple software programs predict harmful.Conservative analysis indicated that these variants are highly conservative between the vertebrate.The three-dimensional structure of most variants have changed.Changes in hydrogen bonds may reduce the stability and reduce the binding affinity.The onset age of 6 patients ranged from 1 year old to 8 years old,with clinical phenotypes ranging from mild partial epilepsy without intellectual disturbance to severe and frequent epileptic seizure attacks with intellectual disturbance.Antiepileptic drugs were effective,among which 5 patients were clinically seizure free and 1 patient was clinically seizure reduced.Conclusion1.CSMD1 gene may be a candidate pathogenic gene for epilepsy.2.The phenotypes of epileptic patients with CSMD1 gene variants range from mild to severe clinical presentations.3.Patients with CSMD1 gene variants have good antiepileptic drugs response.4.In this study,it was found that the variation of CSMD1 gene was a compound heterozygous variation,suggesting that epilepsy caused by this gene might be a recessive genetic pattern.