The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder characterized by variable congenital malformations, facial dysmorphism, and mental retardation. Mutations in the DHCR7 gene have been identified in SLOS patients. This gene encodes for the enzyme D7sterol reductase which catalyses the last step of cholesterol biosynthesis. Among the 73 different mutations observed so far, including 10 novel mutations reported in this review, the majority are missense mutations ( 65) which cluster in three domains of the protein: in the transmembrane domain (TM mutations), in the fourth cytoplasmic loop (4L mutations), and at the C-terminus (CT mutations). Two nonsense mutations, one splice site mutation, two single nucleotide insertions, and three deletions which likely all represent null mutations were also described. Expression studies have demonstrated a decreased protein stability for all analyzed missense mutations. By comparing clinical severity scores, biochemical data, and mutations in SLOS patients a genotypephenotype correlation has been established. The null and 4L mutations are associated with a severe clinical phenotype, and TM and CT mutations are associated with a mild clinical phenotype. DHCR7 mutational spectra in SLOS patients of British, German, Italian, and Polish origin demonstrate significant geographic frequency differences of common DHCR7 mutations. Hum Mutat 17:172-182, 2001.