Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases

Abstract

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.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Frameshift mutations; Frontotemporal dementia; Gene discovery, genetic variants of uncertain significance (VUS), functional research; Missense mutations; Neurodegenerative brain diseases; Parkinson’s disease; Rare coding variants.

Fig. 1

The figure illustrates the penetrance continuum of disease mutations at the extremes, high penetrance (left) and low penetrance (right). The missense mutations in autosomal dominant disease genes (e.g., PSEN1) are highly pathogenic (extreme left) while the role of rare PTC variants needs to be addressed (extreme right). In dosage-sensitive genes (e.g., GRN), PTC mutations are highly pathogenic (extreme left), but rare missense mutations have variable effects on protein function (right). Oligogenic inheritance might explain the reduced penetrance of some pathogenic mutations, in both dominant and dosage-sensitive genes, since one single variant is not penetrant enough to cause the disease on itself. Combinations of multiple rare variants in disease genes increase the effect on gene expression and disease penetrance (extreme left). In risk genes (e.g., ABCA7), common rare single-nucleotide polymorphisms (SNPs) result in a modest increase of disease risk (extreme right), while rare variants can be highly pathogenic and resemble autosomal dominant inheritance in families (left)