Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches

Abstract

Genetic abnormalities play a crucial role in the development of neurodegenerative disorders (NDDs). Genetic exploration has indeed contributed to unraveling the molecular complexities responsible for the etiology and progression of various NDDs. The intricate nature of rare and common variants in NDDs contributes to a limited understanding of the genetic risk factors associated with them. Advancements in next-generation sequencing have made whole-genome sequencing and whole-exome sequencing possible, allowing the identification of rare variants with substantial effects, and improving the understanding of both Mendelian and complex neurological conditions. The resurgence of gene therapy holds the promise of targeting the etiology of diseases and ensuring a sustained correction. This approach is particularly enticing for neurodegenerative diseases, where traditional pharmacological methods have fallen short. In the context of our exploration of the genetic epidemiology of the three most prevalent NDDs—amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease, our primary goal is to underscore the progress made in the development of next-generation sequencing. This progress aims to enhance our understanding of the disease mechanisms and explore gene-based therapies for NDDs. Throughout this review, we focus on genetic variations, methodologies for their identification, the associated pathophysiology, and the promising potential of gene therapy. Ultimately, our objective is to provide a comprehensive and forward-looking perspective on the emerging research arena of NDDs.

Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders

“…On the other hand, the functional significance of CNVs affecting individual genes and/or genomic regions is still notably incomplete, making diagnostic processes and genetic counselling difficult [67]. Consequently, the discovery of significant genes that can be considered causative or associated with neurodevelopmental disorders represents a necessary step in the diagnostic procedure, for a better understanding the pathophysiology of NDDs [68,69]. A deeper knowledge will indeed help to better classify the clinical features of the patients and the mechanisms that underlie their clinical manifestations.…”