In the past, researchers had to rely on linkage studies to find disease-causing genes. The linkage study method was useful, but it was like trying to find a needle in a haystack. Also, linkage studies were more difficult to perform when a condition was rare, like the NBIA disorders. Still, we and our collaborators successfully used linkage studies to discover both the PANK2 and the PLA2G6 genes, which are associated with PKAN and PLAN, respectively.
Now, with the advent of whole exome sequencing, the process of gene discovery can be much faster and easier. This technology was used to identify the gene that causes the NBIA disorder called BPAN (beta-propellar protein-associated neurodegeneration). For many years we had followed a collection of patients with very similar phenotypes, striking because they had early-onset developmental delay with a later-onset movement disorder and brain iron accumulation. By doing whole exome sequencing on this cohort, we and our collaborators were able to quickly drill down to the causative gene and learn that it works in an x-linked dominant fashion with mainly de novo mutations. Unlike a linkage study, exome sequencing allows rare conditions to be studied because fewer DNA samples are needed, individuals from different families can be analyzed more easily together, and conditions caused by a de novo mutation can be used as part of the sample.