Analysis Of Mutation Characteristics And Clinical Manifestations Of Two Family Alzheimer's Disease Families With Gene Mutation

BackgroundAlzheimer's disease(AD)paints a brilliant picture on the central nervous system degenerative disease chapter,it is genetically highly heterogeneous,and the pathogenesis involves multiple genes.It is artificially divided into sporadic Alzheimer's disease(SAD)and familial Alzheimer's disease(FAD).It is clinically manifested by memory impairment,aphasia,personality and behavior changes.As a feature,it seriously affects the patient's quality of life and brings a heavy burden on the family and society.Research indicates that APP gene on chromosome 21,presenilin 2 gene on chromosome 1 and presenilin 1 gene on chromosome 14 were recognized as the pathogenic gene of FAD.Apolipoprotein E(ApoE)gene is the gene that increases the risk of AD,especially in SAD.According to the latest database results,nearly 400 FAD caused by mutations in the above-mentioned pathogenic genes have been reported.The families that have had early-onset AD for three consecutive generations,the detection rate of the above-mentioned gene mutations is as high as 86%,of which PSEN1 accounts for 60%,APP accounts for 15%,and PSEN2 is rare.Considering that the age of onset of FAD is early and the consequence is severe,genetic testing of Alzheimer's disease patients and their families with a positive family history is necessary.ObjecttiveThis study clarified the clinical data of two familial Alzheimer's disease(FAD)families caused by APP and PSEN1 mutations,respectively,and analyzed the two gene mutations.MethodsThe clinical data of 2 probands and their family members who were diagnosed with Early onset Familial Alzheimer's disease(EOFAD)in the department of Neurology,people's Hospital of Zhengzhou University in October 2018 were collected.Blood samples were collected from probands and given to Whole Exome Sequencing(WES).The pathogenicity of genetic variants was evaluated according to the Sequence Variation Interpretation Standards and Guidelines(2015).Some members of the family and 100 Out-of-family individuals were given one-generation verification.Among the 100 subjects,50 were normal checkups and 50 were patients with sporadic Alzheimer's disease(SAD).Apolipoprotein E(ApoE)typing was carried out in 10 families with amyloid protein precursor(APP)gene mutation including proband.Resuts1.The family probands caused by amyloid protein precursor(APP)gene mutations show decreased memory,language repetition,personality changes,mental and behavioral abnormalities,and visual space disorders.Whole Exome Sequencing(WES)revealed a p.V717I mutation at codon 717 of exon 17 of the APP gene of the proband,it resulted in the substitution of valine(V)by isoleucine(L),and the mutation was also found in the other 5 members of the family,which was confirmed by Sanger sequencing.The 10 pedigree members of APOE typing were all ?3/?3 homozygous.This mutation was not detected in 100 individuals outside the pedigree.A plain magnetic resonance imaging(MRI)scan of the proband showed bilateral hippocampal atrophy,especially on the left side,and no obvious abnormalities were found on the skull magnetic resonance angiography(MRA).2.Presenilin1(PSEN1)gene mutation pedigrees show progressive memory loss,apraxia,mental and behavioral abnormalities,visual space disorders and temperament personality changes.Whole Exome Sequencing(WES)detected that two members of the family had c.665A>T(pQ222L)heterozygous mutation in exon 5 of the PSENI gene,resulting in glutamine(Q)replaced by Leucine(L),one of the family members carried the mutation with Sanger verification,but the mutation was not detected in the other 7 unaffected family members and 100 individuals outside the family.The proband's thin hippocampal scan showed atrophy of the right hippocampus,and laboratory tests showed no obvious abnormalities.ConclusionsWe detected two pathogenic mutations in patients with family positive history Alzheimer's disease,of which APPp.V717I mutation is the earliest APP-caused mutation found in the world,and PSEN1p.Q222L mutation may be a new familial Alzheimer's diseaset mutation sites.Up to now,there is no reports at home and abroad.