Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. Issue 4 (26th October 2007)

• Record Type: Journal Article
• Authors: Witsch-Baumgartner, M; Schwentner, I; Gruber, M; Benlian, P; Bertranpetit, J; Bieth, E; Chevy, F; Clusellas, N; Estivill, X; Gasparini, G; Giros, M; Kelley, R I; Krajewska-Walasek, M; Menzel, J; Miettinen, T; Ogorelkova, M; Rossi, M; Scala, I; Schinzel, A; Schmidt, K; Schönitzer, D; Seemanova, E; Sperling, K; Syrrou, M; Talmud, P J; Wollnik, B; Krawczak, M; Labuda, D; Utermann, G
• Is Part Of: Journal of medical genetics. Volume 45:Issue 4(2008)
• Page Start: 200
• Page End: 209
• Publication Date: 2007-10-26
• Subjects: Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2007.053520
• Languages: English
• ISSNs: 1468-6244

Abstract

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 Δ7-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.