Results Analysis Of Targeted Next Generation Sequencing In Patients With Unknown Intellectual/Developmental Disabilities

Objective:Intellectual/developmental disabilities are common diseases happened during the development of children,with complex etiologies,a varity of clinical manifestaions and high morbidity,bringing heavy burden to children and families.Besides,they always have a high rate of co-occurence with another neurological disease-epilepsy.It is well known that the two diseases may share a common genetic etiology.Therefore,we selected 50 children with unknown ID/DD to detect the genes associated with ID/DD and epilepsy by targeted Next-Generation Sequencing,in order to find pathogenic mutations and definite the relationships between genotype and phenotype.What’s more,it is important to verify the possible relations between the etiology of ID/DD and epilepsy on gene level, and provide evidences for further functional study and targets for drug therapy.Methods:A total of 50 patients with unknown ID/DD were recruited from the children who visited the Peking University First Hospital Pediatric neurology clinics between 2005 to2014. Targeted Next Generation Sequencing was used to detect mutations in 485 genes assossiated with ID/DD and epilepsy.Making screening standards,selected all the possible pathogenic mutaions.We used Sanger sequencing to identify the probably pathogenic variations by examing parental origin of mutations.Results:We identified 597 mutations from 485 genes associatied with ID/DD and epilepsy in50 children and definited two pathogenic variations. In patient 3490,we detected a mutation c.2030C>G p.Ser677* in ZEB2（NM₀01171653）,as a result,the 677 thamino acid was replaced by a stop codon, which resulted in a premature coding protein.In patient3934,we identified a mutation c.2444G>C p.Arg815 Pro in GRIN1（NM₀01185091）,which leading to the 815 thamino acid replaced by proline. The function of the mutational protein was probably damaged predicted by Polyphen2.Both mutations were de nove and autosomal dominant.According to UCSC and Human Gene Mutation Database（HGMD）,both mutations were located in a extremely conserved positions and unreported.Conclusions:This study identified two disease causing mutations in total.It was important for us to provide antenatal diagnosis and genetic counselling for the families.What’s more,the two mutations expand the genotypes and phenotypes of ZEB2 and GRIN1,and offered a evidence for us to confirm the genetic etiology relations between ID/DD and epilepsy.Besides,Next-Gneration Sequencing is a new high throughput gene detection technology,it has been improved in the aspects of cost,sequencing time and efficiency,compared with Sanger sequencing, should be popularized in aetiological screening of unexplained ID/DD and epilepsy.