Gene Mutation Analysis In 48 Children With Unexplained Mental Retardation/ Intellectual Disabilities

Objective:Mental retardation is the most common clinical syndrome of neurological and psychiatric system in children, etiology of which is complicated. Gene mutation is the important cause of mental retardation. In this study, we used the disease target sequencing technology to investigate the pathogenic genes of MR/ID, in order to clarify the molecular diagnosis of 48 cases of children with unknown causes. Analyse pathogenic mutations and relationships of genotype- phenotype in mental retardation. Provide genetic counseling and prenatal diagnosis, evaluating prognosis of patients, at the same time, provide the direction for the research of pathogenesis and individualized treatment. Methods:Children with unexplained MR/ID were recruited from the Department of Pediatrics, Peking University First Hospital from 2005 to 2015. All patients were clinically diagnosed as having MR/ID of unknown origin. A series of filtering criteria was used to select the patients. We used targeted next-generation sequencing to detect mutations within 450 genes related to MR/ID in 48 children with unexplained MR/ID. Parental origin analyses were performed by Sanger sequencing. We reviewed the phenotypes of patients with each mutated gene. Results:We identified mutations within11 genes in 10 patients of our cohort. The detection rate was 21%(10/48), genetic diagnosis rate was 17%(8/48), in the whole group. Molecular diagnosis in 8 cases has been unequivocal.Six of the mutations were non-synonymous(LIG4 p.Glu461Gly; MAGT1 p.His270Arg; UPF3 B p.Arg358His; SETBP1 p.Glu858Lys; KIF1 A p.Arg254Trp; BCOR p.Arg104Trp), Four premature/delayed termination codon mutations(PQBP1 p.Arg214fs; ERCC8 p.Thr131fsX7; SHH p.Glu71AspfsX3; KMT2 D p.Ser4673fsX16)and one nonsense mutations(ARID1B p.Arg1062*). The detected mutations included 10 novel and 1 reported mutations. Six of them are new mutations(de novo), four mutations for x-linked, a mutation inherited from the parents. In this research group, expand the phenotypic spectrum of UPF3 B in the patient 1883 with microcephaly.The patient 2867 was currently reported the second case of Cockayne syndrome A in China, the pathogenic mutation is ERCC8, p.Thr131fsX7, expanding the mutated genes spectrum in our country. The phenotypes of the patient 484(SHH, p.Glu71AspfsX3) and The patient 534(MAGT1,p.His270Arg) are different from those of diseases caused by the mutation genes,the genetic diagnosis can not be clear. each of 9 different mutations can cause MR/ID. Genes related to transcription regulation are the most common to occur. Conclusion:In this study, the detection rate was high. We made genetic diagnosis for these 8 patients. This was critical for them to provide genetic counseling and prenatal diagnosis. We detected10 novel mutations and expanded the phenotype and mutation spectrum of the 9 genes identified in our study. A total of the mutated genes occurred only one time in our study.therefore, it seems that MR/ID are phenotypes that occur caused by highly diverse mutated genes, most of which are isolated and fit the rule of common disease rare variations. Genes related to transcription regulation were the most common to occur.This provided more information for further understanding of these disease-causing genes.The targeted next-generation sequencing(NGS) was has been proved to be a fast, economic approach for screening gene mutations in disorders with both genetic and phenotypic heterogeneity, including MR/ID, the detection rate of which was high. Gene mutation is the important cause of mental retardation.