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Age and origin of major Smith-Lemli-Opitz Syndrome (SLOS) mutations in European populations
  1. Martina Witsch-Baumgartner (witsch-baumgartner{at}
  1. Medical University Innsbruck, Austria
    1. Ilona Schwentner (ilona.schwentner{at}
    1. Medical University Innsbruck, Austria
      1. Martin Gruber (alois.gruber{at}
      1. Medical University Innsbruck, Austria
        1. Pascale Benlian (pascale.benlian{at}
        1. Hopital Saint Antoine, France
          1. Jaume Bertranpetit (jaume.bertranpetit{at}
          1. Universitat Pompeu Fabra, Spain
            1. Eric Bieth (bieth.e{at}
            1. Hopital Purpan, France
              1. Francoise Chevy (chevy.francoise{at}
              1. Hopital Saint Antoine, France
                1. Nuria Clusellas (ncasals{at}
                1. Servei de Bioqimica Clinica I Genetica Molecular, Spain
                  1. Xavier Estivill (xavier.estivill{at}
                  1. QUINTILES S.L., Spain
                    1. Paolo Gasparini (gasparini{at}
                    1. Department of Reproductive Sciences and Development, Italy
                      1. Marisa Giros (mgiros{at}
                      1. Servei de Bioqimica Clinica I Genetica Molecular, Spain
                        1. Richard I. Kelley (rkelley3{at}
                        1. Kennedy Krieger Institute, United States
                          1. Malgorzata Krajewska-Walasek (m.walasek{at}
                          1. Children's Memorial Health Institute, Poland
                            1. Jürgen Menzel (hans-juergen.menzel{at}
                            1. Medical University Innsbruck, Austria
                              1. Tatu A. Miettinen (tamietti{at}
                              1. Biomedicum/Helsinki University Central Hospital, Finland
                                1. Miroslava Ogorelkova (miroslava.ogorelkova{at}
                                1. QUINTILES S.L., Spain
                                  1. Massimiliano Rossi (masrossi{at}
                                  1. Federico II University, Italy
                                    1. Iris Scala (andria{at}
                                    1. Federico II University, Italy
                                      1. Albert Schinzel (schinzel{at}
                                      1. Institute of Medical genetics, Switzerland
                                        1. Konrad Schmidt ({at}
                                        1. Medical University Innsbruck, Austria
                                          1. Diether Schönitzer (d.schoenitzer{at}
                                          1. Central Institute for Blood Transfusion and Immunology, Austria
                                            1. Eva Seemanova (eva.seemanova{at}
                                            1. 2nd Medical School of Charles University, Czech Republic
                                              1. Karl Sperling (karl.sperling{at}
                                              1. Charité, University Medicine Berlin, Germany
                                                1. Maria Syrrou (msyrrou{at}
                                                1. University of Ioannina, Greece
                                                  1. Philippa Talmud (rmhapjt{at}
                                                  1. University College London, United Kingdom
                                                    1. Bernd Wollnik (bernd.wollnik{at}
                                                    1. University Cologne, Germany
                                                      1. Michael Krawczak (krawczak{at}
                                                      1. Christian-Albrechts-University Kiel, Germany
                                                        1. Damian Labuda (damian.labuda{at}
                                                        1. CHU Sainte-Justine, Canada
                                                          1. Gerd Utermann (gerd.utermann{at}
                                                          1. Medical University Innsbruck, Austria


                                                            Background: Smith-Lemli-Opitz Syndrome (SLOS [MIM 270 400] is an autosomal recessive multiple congenital anomalies/mental retardation syndrome caused by mutations in the ∆7-sterol reductase (DHCR7, E.C. gene. The prevalence of SLOS has been estimated to range between 1:15000 and 1:60000 in populations of European origin. We have analyzed the frequency, origin, and age of DHCR7 mutations in European populations. Methods and Results: In 263 SLOS patients ten 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 ten 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 analyzed in 50 of the SLOS families in order to estimate the age of the three major SLOS causing mutations. Conclusion: 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.

                                                            • Smith-Lemli-Opitz Syndrome
                                                            • age estimation
                                                            • carrier frequency

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