The Application Of The Whole Exome Sequencing Technology In The Genetics Of Early-onset Dementia

Objectives: Our study aimed to analyze the features of clinical manifestations and genetics in patients with early onset dementia,and further to explore correlations between the phenotype and genotype.Methods: We recruited a group of 38 patients with early onset dementia.Firstly,hexanucleotide repeat expansions in C9ORF72 gene were screened in all subjects to exclude the possibility of copy number variation.Then,the whole exome sequencing(WES)was conducted,and the data was analyzed focusing on 89 dementia-related causing and susceptible genes.The effects of identified variants were classified according to the American College of Medical Genetics and Genomics(ACMG)standards and guidelines.Furthermore,we summarize the features of clinical manifestations and genetics of patients with early onset dementia.Results: There was no pathogenic expansions in C9ORF72 detected.In 19 patients with frontotemporal dementia,we found the MAPT(c.1165G>A/p.G389R)pathogenic mutation in a 27-year old patient diagnosed of behavior variant frontotemporal dementia.In 9 patients with diagnosis of uncertainty,we identified four PSEN1 pathogenic mutations,PSEN1(c.851C>T/ p.P284L;c.857-1G>A;c.G626A/p.G209E;c.428T>C/p.I143T),and one novel pathogenic mutation APP(c.2061A﹥C/p.K687N).The patients with these mutations all presented with atypical cognitive decline.Additionally,eleven variants with uncertain significance were also detected and needed further verification.Conclusions: Our study indicates that mutations in PSEN1,APP and MAPT are common causes of early onset dementia.WES and bioinformatics analysis can serve as efficient diagnostic tools for different heterogeneous dementia,and play an important role in accurate diagnosis and genetic counseling.