Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations

Abstract

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) (MIM 270 400) is an autosomal recessive multiple congenital anomalies/mental retardation syndrome caused by mutations in the Delta7-sterol reductase (DHCR7, E.C.1.3.1.21) gene. The prevalence of SLOS has been estimated to range between 1:15000 and 1:60000 in populations of European origin. METHODS AND RESULTS: We have analysed the frequency, origin, and age of DHCR7 mutations in European populations. In 263 SLOS patients 10 common alleles (c.964-1G>C, p.Trp151X, p.Thr93Met, p.Val326Leu, p.Arg352Trp, p.Arg404Cys, p.Phe302Leu, p.Leu157Pro, p.Gly410Ser, p.Arg445Gln) were found to constitute approximately 80% of disease-causing mutations. As reported before, the mutational spectra differed significantly between populations, and frequency peaks of common mutations were observed in North-West (c.964-1G>C), North-East (p.Trp151X, p.Val326Leu) and Southern Europe (p.Thr93Met). SLOS was virtually absent from Finland. The analysis of nearly 8000 alleles from 10 different European populations confirmed a geographical distribution of DHCR7 mutations as reported in previous studies. The common Null mutations in Northern Europe (combined ca. 1:70) occurred at a much higher frequency than expected from the reported prevalence of SLOS. In contrast the most common mutation in Mediterranean SLOS patients (p.Thr93Met) had a low population frequency. Haplotypes were constructed for SLOS chromosomes, and for wild-type chromosomes of African and European origins using eight cSNPs in the DHCR7 gene. The DHCR7 orthologue was sequenced in eight chimpanzees (Pan troglodytes) and three microsatellites were analysed in 50 of the SLOS families in order to estimate the age of the three major SLOS-causing mutations. CONCLUSIONS: The results indicate a time of first appearance of c.964-1G>C and p.Trp151X some 3000 years ago in North-West and North-East Europe, respectively. The p.Thr93Met mutations on the J haplotype has probably first arisen approximately 6000 years ago in the Eastern Mediterranean. Together, it appears that a combination of founder effects, recurrent mutations, and drift have shaped the present frequency distribution of DHCR7 mutations in Europe.

Identifying modifier genes of monogenic disease: strategies and difficulties

“…Several genetic variants might be involved and may interact to modulate the eVect of the primary mutation. It is even possible that phenotypic variability may be explained not by the patients' modiWer genotypes but by their mothers' genotypes, as recently reported for the maternal Apo E genotype in Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al 2008).…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…In North American populations, the carrier frequency of c.964-1G>C (IVS8-1G>C) is 1% [reviewed in ( 79 )]. In Poland, the combined carrier frequency of p.W151X and p.V326L was found to be 2.4% ( 80 ), and in European populations, the combined carrier frequency of IVS8-1G>C and p.W151X ranges from 1.0 to 2.3% ( 71 ). Extrapolation of carrier frequency of common DHCR7 mutations to estiAlthough near normal intelligence is possible ( 54 ), moderate to severely impaired cognitive function is typical.…”

“…In contrast, p.W151X and p.V326L are higher in Eastern Europe and demonstrate a westward gradient across Northern Europe. IVS8-1G>C and p.W151X are estimated to have arisen approximately 3,000 years ago in northwest and northeast Europe, respectively ( 71 ). The most common missense mutation, p.T93M, is frequently observed in individuals of Mediterranean heritage ( 70,(72)(73)(74) and is estimated to have arisen approximately 6,000 years ago ( 71 ).…”

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

“…The other mutations tested were R352Q and T93M, which is recognized as a founder mutation for SLOS (40) and observed in ϳ10% of patients (37). Because expression levels of the SLOS mutants were so low, cholesterol treatment showed no additional reduction (Fig.…”