The ability to sequence the whole genome or the whole exome of patients with a determined disease allows us to have a global look at all the genetic variants in that individual.
This approach allows us to perform a comprehensive genetic analysis without the constrains of previously established genotype-phenotype correlations. In other words: before next generation sequencing technologies were available, if a patient was diagnosed with Alzheimer’s disease and a genetic cause was suspected then only the genes known to be associated with Alzheimer’s disease (APP, PSEN1 and PSEN2) would be tested for mutations.
In most cases this screen would reveal a mutation and the genetic cause of disease in that patient/family would be established. However, this same screen would not identify a mutation in many of the other cases.
In some of these we are now showing that the genetic cause of disease does not lie in the known Alzheimer’s genes, but in genes know to be associated with other (sometimes related) diseases.
We have recently reviewed such findings in a publication in Human Molecular Genetics. More recently, we have established another of such findings when we identified a nonsense mutation in the PRNP gene in a patient diagnosed with Alzheimer’s disease.
Mutations in PRNP are known to cause prion diseases, but by reviewing the literature it became clear that specific mutations in this gene (nonsense and frameshift) predicted to cause a premature stop in the protein are usually found in patients diagnosed with Alzheimer’s disease, many times presenting with autonomic dysfunction (including chronic diarrhea in some of these cases).