Homozygosity for the W151X stop mutation in the Delta 7-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 syndro me caused by an abnormality in cholesterol metabolism. The clinical severit y 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 descri be an Austrian family whose first child died neonatally with multiple conge nital anomalies. The second pregnancy was terminated because the fetus show ed 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 muta tional analysis of the DHCR7 gene from paraffin-embedded tissue and a Guthr ie card focusing on mutations known to cause a severe SLOS phenotype, This demonstrated homozygosity for the mutation W151X, which has been demonstrat ed to be a functional null mutation. Our data confirm the concept that homo zygosity for functional null alleles of the DHCR7 locus results in intraute rine or perinatal lethality. Furthermore, our findings suggest the usefulne ss of molecular studies of stored material in similarly affected cases wher e no material for biochemical analysis is available. (C) 2000 Wiley-Liss, I nc.