Abstract
Purpose The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered “disease causing.” In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.
Highlights
Dementia comprises a group of degenerative disorders leading to a progressive decline in cognitive function and, in some cases, to changes in behavior and motor impairment, ranging from a slowness in some motor activities to an overt parkinsonism
It is likely that evaluating the incidence of familial cases based only on clinical observation leads to an underestimation of the real number of cases, since other medical conditions may be the cause of death for presymptomatic individuals before the onset of neurodegeneration
The genetic panel was tested in 8 patients (4 females) with one of the following clinical diagnosis: Alzheimer’s disease (AD) (n = 2), mild cognitive impairment (MCI) (n = 2), frontotemporal dementia (FTD) (n = 2), and Parkinson’s disease (PD)-associated dementia (n = 2)
Summary
Dementia comprises a group of degenerative disorders leading to a progressive decline in cognitive function and, in some cases, to changes in behavior and motor impairment, ranging from a slowness in some motor activities to an overt parkinsonism. Clinicians who choose to use genetic testing often engage in the screening of a small subset of genes, with a focus on the genotype of patients with known variants with high penetrance, rather than on the sequencing of all genes of the disease. These clinical considerations and the high cost of the testing lead to a significant bias in the estimation of the incidence rates, which cannot be considered epidemiologically accurate
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