The study demonstrates the successful application of exome sequencing to identify the gene causing Miller syndrome, a rare Mendelian disorder. By sequencing the exomes of four affected individuals from three independent families, the researchers captured and sequenced coding regions to a mean coverage of 40×. After filtering against public SNP databases and HapMap exomes, they identified a single candidate gene, *DHODH*, which encodes an enzyme involved in pyrimidine de novo biosynthesis. Sanger sequencing confirmed the presence of *DHODH* mutations in three additional families with Miller syndrome. This approach, involving exome sequencing of a small number of unrelated affected individuals, is shown to be a powerful and efficient strategy for identifying the genes underlying rare Mendelian disorders. The study highlights the potential of exome sequencing to transform the genetic analysis of monogenic traits and advance our understanding of rare diseases.The study demonstrates the successful application of exome sequencing to identify the gene causing Miller syndrome, a rare Mendelian disorder. By sequencing the exomes of four affected individuals from three independent families, the researchers captured and sequenced coding regions to a mean coverage of 40×. After filtering against public SNP databases and HapMap exomes, they identified a single candidate gene, *DHODH*, which encodes an enzyme involved in pyrimidine de novo biosynthesis. Sanger sequencing confirmed the presence of *DHODH* mutations in three additional families with Miller syndrome. This approach, involving exome sequencing of a small number of unrelated affected individuals, is shown to be a powerful and efficient strategy for identifying the genes underlying rare Mendelian disorders. The study highlights the potential of exome sequencing to transform the genetic analysis of monogenic traits and advance our understanding of rare diseases.