We show that the sequencing of the exomes of affected individuals from a few unrelated kindreds, with appropriate filtering against public SNP databases and a small number of HapMap exomes, is sufficient to identify a single candidate gene for a previously unsolved monogenic disorder, Miller syndrome. Several factors were important to the success of this study. First, Miller syndrome is a very rare disorder that is inherited in an autosomal recessive pattern. Therefore, the causal variants were unlikely to be found in public SNP databases or control exomes. Second, genes for recessive diseases will, in general, be easier to find than genes for dominant disorders because fewer genes in any single individual have 2 or more novel or rare nonsynonymous variants. Third, we were fortunate that there was no genetic heterogeneity in our sample of Miller cases. In the presence of heterogeneity, it is possible to relax stringency by allowing for genes common to subsets of all affected individuals to be considered candidates, although this will reduce power (Table 3). Third, all of the individuals with Miller syndrome for whom
