Whole exome sequencing in primary lateral sclerosis

Our goal is to establish the contribution of genetics to the etiology of primary lateral sclerosis (PLS). This will be accomplished in several stages. The first step is to sequence as many PLS cases as possible. The total number of PLS cases in the US are estimated to number in the hundreds; it is therefore possible to sequence a large representative sample of the total number of PLS patients at a reasonable cost. Sequence data will be analyzed for association of gene mutations unique to PLS and to gene variants by comparing their frequency in PLS to sequence data from publically available controls. Low frequency functional mutations will also be considered as candidate genes. In addition, novel mutations exclusively present in PLS can be identified, although this is less likely. The mutation variants significantly difference between PLS and control populations can be analyzed for relevance to specific cellular and functional pathways. Eventually, additional cohorts of PLS patients will be sequenced and data can be combined for greater robustness.