To further exclude candidate genes containing non-pathogenic variants, we next compared the NS/SS/I variants from both siblings in kindred 1 to the novel variants in two unrelated individuals with Miller syndrome (kindreds 2 and 3). Using both dbSNP129 and the 8 HapMap exomes as filters, comparison between the siblings in kindred 1 and the unrelated simplex case in kindred 2 reduced the number of candidate genes to 26 under our dominant model. Under the autosomal recessive model, this comparison revealed that only a single gene, DHODH, which encodes the enzyme, dihydroorotate dehydrogenase, was a shared candidate. Thus, comparison of exome data from two affected sibs and one unrelated, affected individual was sufficient to identify DHODH as the sole candidate gene for Miller syndrome. Comparison between the siblings in kindred 1 and the unrelated simplex cases in kindreds 2 and 3 reduced the number of candidate genes to 8 under a dominant model, while retaining DHODH as the sole candidate under the recessive model.
