To illustrate the utility of ANNOVAR in identifying causal genes responsible for rare Mendelian diseases, we synthesized a whole-genome data set with ∼4.2 million SNPs and ∼0.5 million indels. These variants include all variants generated by Illumina on a male subject (14), as well as two known causal mutations for Miller syndrome (G152R and G202A in the DHODH gene). Miller syndrome is a rare Mendelian disease recently solved by exome-sequencing on four probands and Sanger sequencing on three additional families (3), so the main goal of our experiment is to examine whether and how we can utilize ANNOVAR to trim down the potential candidate genes for a rare recessive disease. In addition, since one of the causal mutations was predicted as ‘benign’ when a function filter by PolyPhen is imposed (3), we investigated whether alternative and faster filtering strategies can be utilized. We acknowledge that since the full variants data from the original study were not available, here we have to rely on a synthesized variants set to illustrate the usage of ANNOVAR on real data.
