Study On The Genetic Etiology Of Intellectual Disability/General Developmental Delay With Epilepsy In Children

Objective: To investigate the genetic etiology of children with intellectual disability/general developmental delay with epilepsy(ID/GDD-EP),and to provide genetic information for clinical diagnosis and genetic counseling.Methods:(1)Children with ID/GDD-EP who were treated in our hospital from January 2015 to December 2018 were selected.Family history and clinical data were collected in detail.(2)The clinical data were analyzed.Chromosome karyotype analysis was performed on all patients with ID/GDD-EP.Negative cases for chromosome karyotype analysis received single nucleotide polymorphism array(SNP array)detection to search copy number variations(CNV).Data of CNV were compared with relevant databases for the pathogenicity of CNV.Correlation between the clinical phenotype of ID/GDD-EP and pathogenic CNV(pCNV)was analyzed.Whole exon sequencing(WES)was offered to those negative cases for SNP array,to seek the pathogenic gene mutation furtherly.Correlation between the clinical phenotype of ID/GDD-EP and WES detection rate was statistically analyzed.Results: Chromosome karyotype analysis was performed in 92 patients with ID/GDD-EP.Six cases were positive and the detection rate was 6.5%(6/92).SNP array was performed in 86 patients with negative karyotype analysis.Two cases had variants of unknown significance.Twenty-two pCNV were identified in 21 cases.The detection rate of pCNV was 24.4%(21/86).Nineteen of all detected pathogenic CNV were deletion form and three were duplication form.Thirteen known syndromes were diagnosed in 21 cases.Three new pCNV were identified in the research.Sixty cases without pCNV received WES.Pathogenic gene mutations were detected in 10 cases,and the detection rate was 16.7%(10/60).All gene mutations in 10 cases were de novo.The pathogenic genetic etiology of 37 cases were diagnosed in 92 patients of our research,and the detection rate was 40.2%(37/92).By comparing the clinical characteristics of pCNV,there was significant difference in the degree of intellectual disturbance between the pCNV positive group and negative(p=0.036).We conduct the more severe the degree of intellectual disturbance of ID/GDD-EP,the higher the detection rate of pCNV(p<0.05).There were significant differences in clinical phenotypic microcephaly and special face between the two groups in children with ID/GDD-EP(p=0.033,p=0.001),suggesting that the detection rate of pCNV was higher when ID/GDD-EP was accompanied with microcephaly or special face.Microcephaly(p=0.049)and special face(p=0.003)were identified as independent predictors of the detection rate of pCNV according to multivariate logistic regression analysis(p<0.05).Between WES positive and negative groups,there is a statistically significant difference in the degree of intellectual disturbance(p=0.004),indicating that the more severe the intellectual disturbance,the higher the WES detection rate(p<0.05).Conclusion: 1.There are many genetic causes of ID/GDD-EP,CNV is highly correlated.Reasonable and combined application of detection techniques can significantly improve the detection rate of genetic causes in children with ID/GDD-EP.2.The more severe the intellectual disturbance of ID/GDD-EP,the higher the detection rate of genetic causes.3.When ID/GDD-EP is associated with microcephaly or special face,the detection rate of pCNV is high,which is helpful for the selection of genetic detection methods,early diagnosis and cost reduction.