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)