Genetic Epidemiology of the Smith-Lemli-Opitz Syndrome

The Smith-Lemli-Opitz syndrome (SLOS, MIM 270400) is an autosomal recessive mental retardation/malformation syndrome.The clinical presentation ranges from mild dysmorphisms with moderate mental impairment to severe malformation including cleft palate, syndactyly/polydactyly/visceral heart and kidney malformations and intrauterine death. The frequency of this syndrome was estimated in European populations between 1:15.000 to 1:40.000 but exact prevalence figures are presently not available. It has been speculated that the high frequency of the syndrome and presumed restriction to Europeans reflects heterosis. The basic defect of SLOS was found to be in the conversion of 7DHC to cholesterol, the last step of cholesterol synthesis, which is catalyzed by the enzyme delta7-sterol reductase (DHCR7, E.C. 1.3.1.21). Among 200 patients with the SLOS 73 different mutations in the DHCR7 gene have been observed. However some of these including two null mutations (IVS8-1G>C and W151X) associated with the most severe phenotypes are frequent. New data suggest that there may be a discrepancy between high DHCR7 allele frequencies and the observed prevalence of the SLOS. Project aims: We plan to study the carrier frequencies of common SLOS causing mutations in the DHCR7 gene in different European and Non-European populations and the haplotypes on which these mutations occur. Analysis of carrier frequencies in random population samples will provide unbiased frequency estimates and allow to estimate the expected frequency of the disease. To gain insights into the geographic distribution and the age of the mutations detailed analysis of the haplotypes from SLOS patients/families will be performed. Together the data on DHCR7 mutation frequencies, their geographic distributions in Europe and possibly elsewhere, and their associations with DHCR7 haplotypes will allow to construct the history of SLOS causing mutations in Europeans. This will help to distinguish whether the assumed high frequency of DHCR7 mutations in Europeans is due to recurrent mutations, founder effects and random drift, to selection, or to a combination thereof.