阿尔茨海默病及相关认知障碍基因检测的临床策略

Clinical strategies for genetic testing of Alzheimer’s disease and related cognitive impairments

对阿尔茨海默病(Alzheimer’s disease,AD)及认知障碍的患者进行基因检测有助于使患者得到临床确诊,帮助患者家属评估日后患病风险及必要时接受早期干预治疗。临床上需要对痴呆患者进行全面评估,明确临床诊断,选择合适的基因检测方式。对于有AD家族史的痴呆患者,或发病年龄<60岁的早发AD,推荐痴呆基因Panel检测;行为变异性额颞叶痴呆(behavioral variant frontotemporal dementia,bvFTD)、额颞叶痴呆-肌萎缩侧索硬化症(frontotemporal dementia-amyotrophic lateral sclerosis,FTD-ALS)、有家族史的原发性进行性失语症(primary progressive aphasia,PPA)或皮质基底节综合征(cortico-basal syndrome,CBS)患者,推荐痴呆基因Panel检测[如果同时合并肌萎缩侧索硬化症(amyotrophic lateral sclerosis,ALS)和额颞叶痴呆(frontotemporal dementia,FTD)则推荐加做C9orf72六核苷酸异常重复扩增检测];临床考虑亨廷顿病(Huntington disease,HD)或朊蛋白病的患者,推荐单基因检测,如果单基因检测结果是阴性但具有早发痴呆家族史的患者需要全外显子组测序(whole exome sequencing,WES)/全基因组测序(whole genome sequencing,WGS)+C9orf72六核苷酸异常重复扩增检测。二代测序识别的诸多单核苷酸多态性(single nucleotide polymorphism,SNP),推荐按照ACMG-AMP进行分类,分析SNP致病的可能性。

Clinical genetic testing in the patients with Alzheimer’s disease(AD)and related cognitive impairments offers a precise molecular diagnosis,and could help members of an affected family to determine personal risk.Patients with dementia should be offered a full diagnostic assessment to determine their likely clinical diagnosis.We recommend gene panel testing for all patients with AD and a strong family history or early-onset disease(<60 years),all patients with behavioral variant frontotemporal dementia(bvFTD)or frontotemporal dementia-amyotrophic lateral sclerosis(FTD-ALS),and patients with primary progressive aphasia(PPA)or a corticobasal syndrome(CBS)and a positive family history.Patients with amyotrophic lateral sclerosis and frontotemporal dementia are recommended to perform C9 orf72 repeat testing additionally.Patients with Huntington disease(HD)or prion disease phenotypes should undergo a single-gene test first and,if this test is negative,whole-exome sequencing(WES)or whole-genome sequencing(WGS)should be performed.WES and WGS become financially feasible but raise complex issues such as variants of uncertain significance.The American College of Medical Genetics and Genomics and the Association of Molecular Pathology(ACMGAMP)guidelines for the classification of single nucleotide polymorphisms are designed to combine several pieces of evidence to classify that a variant is pathogenic or benign.