Homozygosity for the W151X stop mutation in the delta7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital anomalies syndrome caused by an abnormality in cholesterol metabolism. The clinical severity may vary from very mild to lethality in utero, making diagnosis difficult at both ends of the spectrum. Patients with severe SLOS might often escape diagnosis because they die before the correct diagnosis is made. We describe an Austrian family whose first child died neonatally with multiple congenital anomalies. The second pregnancy was terminated because the fetus showed similar severe anomalies ultrasonographically. A further pregnancy ended in a spontaneous first trimester abortion. Clinical diagnosis of SLOS was not considered until the autopsy of the fetus of the terminated pregnancy. Because no material for biochemical testing was available we performed mutational analysis of the DHCR7 gene from paraffin-embedded tissue and a Guthrie card focusing on mutations known to cause a severe SLOS phenotype. This demonstrated homozygosity for the mutation W151X, which has been demonstrated to be a functional null mutation. Our data confirm the concept that homozygosity for functional null alleles of the DHCR7 locus results in intrauterine or perinatal lethality. Furthermore, our findings suggest the usefulness of molecular studies of stored material in similarly affected cases where no material for biochemical analysis is available. Copyright 2000 Wiley-Liss, Inc.