Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS) is caused by mutations in the DHCR7 gene leading to deficient activity of 7-dehydrocholesterol reductase (DKCR7; EC 1.3.1.21), the final enzyme of the cholesterol biosynthetic pathway, resulting in low cholesterol and high concentrations of its direct precursor 7-dehydrocholesterol in plasma and tissues. We here report mutations identified in the DHCR7 gene of 13 children diagnosed with SLOB by clinical and biochemical criteria. We found a high frequency of the previously described IVS8-1 G > C splice acceptor site mutation (two homozygotes, eight compound heterozygotes). In addition, 13 missense mutations and one splice acceptor mutation were detected in eleven patients with a mild to moderate SLOS-phenotype. The mutations include three novel missense mutations (W182L, C183Y, F255L) and one novel splice acceptor site mutation (IVS8-1 G > T). Two patients, homozygous for the IVS8-1 G>C mutation, presented with a severe clinical phenotype and. died shortly after birth. Seven patients with a mild to moderate SLOB-phenotype disclosed compound heterozygosity of the IVS8-1 G > C mutation in combination with different novel and known missense mutations.