Gene mutations in a Han Chinese Alzheimer's disease cohort

Abstract

ObjectiveAlzheimer's disease (AD) is the most common form of dementia characterized by memory loss at disease onset. The gene mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the frequent causes of AD. However, the clinical and genetic features of AD overlap with other neurodegenerative diseases. The present study aimed to identify the clinical and genetic characteristics in a Han Chinese AD cohort.MethodsDetailed clinical assessment was applied to all the patients. We screened amyloid precursor protein (APP), PSEN1, PSEN2, and microtubule‐associated protein tau (MAPT) genes were assessed in 83 sporadic AD patients by Sanger sequencing. A total of 25 probands from families with AD were subjected to next‐generation sequencing on 53 dementia‐associated genes to capture the target region, and Sanger sequencing was used to detect the variants in the DNA sequence.Results PSEN1 p.L226R was found in an early‐onset AD (EOAD) family characterized by language impairment at disease onset, a novel probably pathogenetic variant (p.D534H) was identified in a frontal‐temporal dementia gene, TANK‐binding kinase 1 (TBK1) with a typical AD phenotype in a late‐onset AD (LOAD) family, and a PSEN2p.H169N mutation and two benign MAPT (p.Q230R and p.V48L) mutations were detected in three EOAD patients.ConclusionsThus, five variants were identified in a Han Chinese cohort. In the present study, a novel, probably damaging FTLD gene TBK1variant with a typical AD phenotype was detected. Also, the phenotypic characteristics of PSEN1 p.L226R, a PSEN2pathogenic mutation, and two likely benign MAPT variants were described. Hence, screening for mutations in other dementia genes could be further explored in clinically diagnosed AD patients.

Genetic study ofyoung‐onsetdementia using targeted gene panel sequencing in Taiwan

“…The mutation frequency is lower in our cohort than reported in Caucasians; 17 of 129 (13.2%) young‐onset AD patients had PSEN1 mutations in a previous study (Lanoiselee et al, 2017). However, the mutation frequency in our cohort is higher than those conducted in a previous Chinese study with 1 of 108 young‐onset and familial AD patients (0.9%) had PSEN1 mutations (Ma et al, 2019). The variant c.G438A (p.M146I) in PSEN1 is potentially a mutation hot spot, as it contributes to three‐fourths of young‐onset AD patients having a PSEN1 mutation.…”

The Genetics of Alzheimer’s Disease in the Chinese Population

“…The patient showed symptoms of cognitive decline and memory impairment, as well as atypical neurological symptoms [64]. The p.H169N mutation of PSEN2 reported by Ma et al has also been detected in both AD and FTD patients, in support of the previous finding by Shi et al [58,63]. A known PSEN2 mutation (p.V139M) which was first reported in an Italian LOAD patient, was observed in a Chinese patient with early-onset disease phenotypes [39,73].…”

“…Structural analyses indicated that these mutations might induce structural alterations in γ-secretases due to the change in interaction patterns, thereby participating in the pathogenesis of FAD [40]. The p.L226R mutation of PSEN1, which is located at the transmembrane domain of the protein, was reported in an EOAD family characterized by language impairment at disease onset [58]. In a whole-exome sequencing study on 15 Chinese FAD patients, Jiang et al identified six previously reported PSEN1 mutations in all subjects, including p.M139I, p.T147I, p.L173W, p.F177S, p.R269H, and p.R157S [39].…”

“…The p.V391G mutation in PSEN1 was found to be responsible for EOAD with extrapyramidal symptoms according to a study on a very early-onset AD proband in China [63]. Li and colleagues performed Sanger sequencing on PSEN1 in three Chinese EOAD families and discovered two novel mutations (p.Y256N and p.H214R) in AD families and a de novo mutation (p.G206V) in a patient with very early-onset sporadic AD [58]. The three mutations might contribute to the pathogenesis of EOAD [58,62,63].…”

“…Li and colleagues performed Sanger sequencing on PSEN1 in three Chinese EOAD families and discovered two novel mutations (p.Y256N and p.H214R) in AD families and a de novo mutation (p.G206V) in a patient with very early-onset sporadic AD [58]. The three mutations might contribute to the pathogenesis of EOAD [58,62,63]. A study on an FAD patient cohort in China was conducted by Gao et al recently, which showed that PSEN1 mutations account for the largest proportion of FAD patients, and three novel mutations in PSEN1, namely p.M139L, p.V103G, and p.F177V, were identified in the study [40].…”