Massively parallel sequencing of the exomes of four individuals with Miller syndrome, combined with filtering to exclude benign and unrelated variants, has identified causative mutations in DHODH. This approach will accelerate discovery of the genetic bases of hundreds of other rare mendelian disorders.
Figure 1 Exome sequencing and filtering strategy. In Ng et al.3, the list of variants from the exome sequences of four individuals with Miller syndrome was first screened to select for genes found to have two nonsynonymous, splice site or indel sequence variants in each of the individuals. This list was then compared to the exome sequences of eight healthy controls2 and dbSNP to exclude common variation and combined with a filtering strategy used to narrow the list of likely candidate genes underlying this