Parkinson’s disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.
Part of the book: Challenges in Parkinson's Disease
Advances in diagnostic techniques and high-throughput biotechnologies provide a compelling opportunity to improve the diagnosis and treatment of diseases by developing a “New Taxonomy” that defines diseases on the basis of their underlying molecular and environmental factors rather than on traditional physical signs and symptoms. Oncology represents the first interesting example of how genomic medicine has changed the understanding of diseases and their therapy. However, much work remains to be completed on the molecular characterization and classification of complex and multifactorial diseases, including neurodegenerative disorders. Our research group has recently shown the genomic heterogeneity of sporadic amyotrophic lateral sclerosis (SALS), identifying two divergent subtypes associated with differentially expressed genes and pathways and providing several potential biomarkers and therapeutic targets. This chapter reviews the results emerged from our work, highlighting how molecular characterization of SALS patients may provide a framework for developing a more precise and accurate classification of diseases that could revolutionize the diagnosis, therapy, and clinical decisions of diseases, leading to more individualized treatments and improved outcomes for patients.
Part of the book: Update on Amyotrophic Lateral Sclerosis