Most variants underlying rare Mendelian diseases either affect highly conserved sequence and/or are predicted to be deleterious. Accordingly, we also sought to investigate to what extent the pool of candidate genes could be reduced by combining variant filtering with predictions of whether NS/SS/I variants were “damaging.” This strategy further reduced the pool of candidate genes for each of the comparison made previously (Table 1). However, DHODH was not identified as a candidate under a recessive model in any of these comparisons. Review of predicted biophysical consequences of DHODH variants revealed that the effect of one variant, c.G605A, found in both siblings in kindred 1, was benign. As a result, DHODH was eliminated from further consideration as a candidate under a recessive model in kindred 1 and all subsequent comparisons. However, because the other variant found in kindred 1, c.G454A, was predicted to be damaging, as was every other novel DHODH variant identified, DHODH was the only candidate gene for Miller syndrome under a dominant model in a comparison of kindreds 1, 2, and 3.
