Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases

• Published in: Genome medicine Vol. 13; no. 1; p. 59
• Main Authors: Perrone, Federica, Cacace, Rita, van der Zee, Julie, Van Broeckhoven, Christine
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.04.2021; BioMed Central; BMC
• Subjects: Alzheimer's disease; Amyotrophic lateral sclerosis; Brain Diseases - genetics; Development and progression; Etiology; Frontotemporal dementia; Genes; Genetic aspects; Genetic diversity; Genetic research; Genetic Variation; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Humans; Inheritance Patterns - genetics; Kinases; Mutation; Neural coding; Neurodegeneration; Neurodegenerative brain diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; Next-generation sequencing; Parkinson's disease; Pathogenesis; Pathology; Rare coding variants; Review; Risk Factors; Whole Exome Sequencing; Frameshift mutations; Missense mutations; Alzheimer’s disease; Neurodegenerative brain diseases; Rare coding variants; Amyotrophic lateral sclerosis; Gene discovery, genetic variants of uncertain significance (VUS), functional research; Frontotemporal dementia; Parkinson’s disease
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-021-00878-y

Knowledge of the molecular etiology of neurodegenerative brain diseases (NBD) has substantially increased over the past three decades. Early genetic studies of NBD families identified rare and highly penetrant deleterious mutations in causal genes that segregate with disease. Large genome-wide association studies uncovered common genetic variants that influenced disease risk. Major developments in next-generation sequencing (NGS) technologies accelerated gene discoveries at an unprecedented rate and revealed novel pathways underlying NBD pathogenesis. NGS technology exposed large numbers of rare genetic variants of uncertain significance (VUS) in coding regions, highlighting the genetic complexity of NBD. Since experimental studies of these coding rare VUS are largely lacking, the potential contributions of VUS to NBD etiology remain unknown. In this review, we summarize novel findings in NBD genetic etiology driven by NGS and the impact of rare VUS on NBD etiology. We consider different mechanisms by which rare VUS can act and influence NBD pathophysiology and discuss why a better understanding of rare VUS is instrumental for deriving novel insights into the molecular complexity and heterogeneity of NBD. New knowledge might open avenues for effective personalized therapies.