Smith-Lemli-Opitz syndrome: carrier frequency and spectrum of DHCR7 mutations in Canada.

Smith-Lemli-Opitz syndrome (SLOS, OMIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis resulting from deficient 3β-hydroxysterol ∆-reductase (DHCR7) activity. 2 Patients with SLOS have a characteristic facial phenotype, various degrees of cleft palate and of syndactyly of toes 2 and 3, failure to thrive, behavioural problems, and mental retardation in addition to variable combinations of external and internal malformations. The spectrum of severity extends from prenatal death with holoprosencephaly or other lethal malformations to minimally physically affected patients with normal intelligence or minimal intellectual impairment. Most patients with SLOS have abnormally low levels of plasma cholesterol and all have raised levels of its immediate precursor, 7-dehydrocholesterol (7DHC). The DHCR7 gene has been mapped to chromosome 11q13, spans approximately 14 kb, and encodes a protein of 475 amino acid residues. To date, 85 different DHCR7 mutations have been identified in more than 200 SLOS patients. 7 8 Missense mutations comprise over 85% of the known alleles, although the two most common alleles are a splice acceptor site mutation (IVS8-1G→C) and a nonsense mutation (W151X). SLOS is most common among people of European descent, with estimated incidences ranging from 1 in 10 000 to 1 in 60 000 depending on the diagnostic criteria and the reference population. Several groups have shown that the carrier rate for the most common mutation, IVS8-1G→C, is approximately 1 in 100 for white populations in North America, and even higher in some European populations. Haplotypes of DHCR7 single nucleotide polymorphisms (SNPs) have been used to investigate the origin and distribution patterns of SLOS mutations in different populations, showing both founder effects and recurrent mutations. In this report, we summarise our molecular diagnostic experiences with SLOS in Canada. DHCR7 mutations and SNPs were identified in 30 unrelated SLOS patients and their families using a panel of allele specific assays and direct nucleotide sequencing. The carrier rate of SLOS in Canada was investigated by screening approximately 3000 anonymous subjects of various ethnic backgrounds for the five most common DHCR7 mutations (IVS8-1G→C, T93M, W151X, V326L, and R404C).