To confirm that mutations in DHODH were responsible for Miller syndrome, we screened three additional unrelated kindreds (one pair of affected siblings and two simplex cases) by directed Sanger sequencing. All four individuals were found to be compound heterozygotes for missense mutations in DHODH that are predicted to be deleterious. Collectively, 11 different mutations in 6 kindreds were identified in DHODH by a combination of exome and targeted resequencing (Table 4 and Figure 2). Each parent of an affected individual who was tested was found to be heterozygous carriers and none of the mutations appeared to have arisen de novo. In the kindred with affected siblings, none of the unaffected siblings were compound heterozygotes. None of these mutations were found in 200 control chromosomes from individuals of matched geographical ancestry that were genotyped. Ten of these mutations were missense mutations, two of which affected the same amino acid codon, and one was a 1-bp indel that is predicted to cause a frameshift and a termination codon seven amino acids downstream. One mutation, c1036T, was shared between two unrelated individuals with
