Exome sequencing successfully identified the gene responsible for Miller syndrome, a rare Mendelian disorder. The study sequenced the exomes of four individuals from three unrelated families, achieving high coverage and identifying variants in the DHODH gene, which encodes a key enzyme in pyrimidine biosynthesis. Sanger sequencing confirmed DHODH mutations in additional families with Miller syndrome. The study highlights the power of exome sequencing in identifying genes for rare Mendelian disorders, especially when traditional methods fail. Miller syndrome is characterized by severe facial and limb malformations, and its genetic basis was previously unknown. The study found that DHODH mutations cause Miller syndrome, which is likely inherited in an autosomal recessive manner. The DHODH gene was identified through exome sequencing and validated by Sanger sequencing in multiple families. The study also demonstrated that exome sequencing can efficiently identify candidate genes for rare disorders, even when only a small number of affected individuals are available. The study emphasizes the importance of exome sequencing in uncovering the genetic basis of rare diseases. It shows that exome sequencing can be a powerful and cost-effective strategy for identifying genes underlying rare Mendelian disorders. The findings suggest that DHODH mutations are responsible for Miller syndrome, and the study provides insights into the role of pyrimidine metabolism in craniofacial and limb development. The study also highlights the potential of exome sequencing in identifying genetic causes of other rare diseases and improving diagnosis and treatment strategies. The results demonstrate that exome sequencing can be a valuable tool in the discovery of genes for rare disorders and may transform the genetic analysis of monogenic traits.Exome sequencing successfully identified the gene responsible for Miller syndrome, a rare Mendelian disorder. The study sequenced the exomes of four individuals from three unrelated families, achieving high coverage and identifying variants in the DHODH gene, which encodes a key enzyme in pyrimidine biosynthesis. Sanger sequencing confirmed DHODH mutations in additional families with Miller syndrome. The study highlights the power of exome sequencing in identifying genes for rare Mendelian disorders, especially when traditional methods fail. Miller syndrome is characterized by severe facial and limb malformations, and its genetic basis was previously unknown. The study found that DHODH mutations cause Miller syndrome, which is likely inherited in an autosomal recessive manner. The DHODH gene was identified through exome sequencing and validated by Sanger sequencing in multiple families. The study also demonstrated that exome sequencing can efficiently identify candidate genes for rare disorders, even when only a small number of affected individuals are available. The study emphasizes the importance of exome sequencing in uncovering the genetic basis of rare diseases. It shows that exome sequencing can be a powerful and cost-effective strategy for identifying genes underlying rare Mendelian disorders. The findings suggest that DHODH mutations are responsible for Miller syndrome, and the study provides insights into the role of pyrimidine metabolism in craniofacial and limb development. The study also highlights the potential of exome sequencing in identifying genetic causes of other rare diseases and improving diagnosis and treatment strategies. The results demonstrate that exome sequencing can be a valuable tool in the discovery of genes for rare disorders and may transform the genetic analysis of monogenic traits.