Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome

The Smith-Lemli-Opitz syndrome (SLOS; also known as the RSH syndrome) is an autosomal recessive genetic disorder, leading to characteristic multi-orga n developmental abnormalities, dysmorphic facies, limb malformations and me ntal retardation. Mutations in the gene for Delta(7)-dehydrocholesterol red uctase (Delta(7)-reductase), which catalyzes the last step in cholesterol b iosynthesis, cause the disease. We screened 32 patients with SLOS, 28 from the USA and four from Sweden. Twenty-two different nucleotide changes, pred icted to be disease-causing mutations, were identified; 20 missense mutatio ns, one nonsense mutation and one splice-site mutation involving the exon 9 acceptor site (IVS8 -1G-->C) were detected. All probands were heterozygous for mutations. Twelve of these mutations have not been reported previously , including missense mutations L148R, F168I, D175H, P179L, P243R, F284L, N2 87K, F302L, R404S, Y462H, R469P and one nonsense mutation E37X. Coupled wit h previously reported mutations, these findings bring the total of differen t Delta(7)-reductase mutations to 36. These are distributed throughout the coding sequence of the Delta 7-reductase gene except exons 3 and 5, with a clustering in exon 9. Three mutations account for 54% of those observed in our cohort, the splice acceptor site mutation IVS8 -1G-->C (22/64 alleles, 34%), T93M (8/64, 12.5%) and V326L (5/64, 7.8%). Severity of SLOS was negat ively correlated with both plasma cholesterol and relative plasma cholester ol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutatio ns and phenotype, suggesting that the degree of severity may be affected by other factors. We estimate that between 33 and 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol. T hus, factors other than plasma cholesterol are additionally involved in det ermining severity.