Abstract: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 C9orf72 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.
