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Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations
  1. M Witsch-Baumgartner1,
  2. I Schwentner1,
  3. M Gruber1,
  4. P Benlian2,
  5. J Bertranpetit3,
  6. E Bieth4,
  7. F Chevy2,
  8. N Clusellas5,
  9. X Estivill6,
  10. G Gasparini7,
  11. M Giros5,
  12. R I Kelley8,
  13. M Krajewska-Walasek9,
  14. J Menzel1,
  15. T Miettinen10,
  16. M Ogorelkova6,
  17. M Rossi11,
  18. I Scala11,
  19. A Schinzel12,
  20. K Schmidt1,
  21. D Schönitzer13,
  22. E Seemanova14,
  23. K Sperling15,
  24. M Syrrou16,
  25. P J Talmud17,
  26. B Wollnik18,
  27. M Krawczak19,
  28. D Labuda20,
  29. G Utermann1
  1. 1
    Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Austria
  2. 2
    Biochimie – Biologie Moleculaire, INSERM U538, Hopital Saint Antoine, Paris, France
  3. 3
    Unitat de Biologia Evolutiva, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
  4. 4
    Department de Genetique Medicale, Hopital Purpan, Toulouse, France
  5. 5
    Seccio de Citogenetica I Genetica Clinica, Errors Congenits del Metabolism, BGM, Hospital Clinic, Barcelona, Spain
  6. 6
    Genes and Disease Program, and CeGen Barcelona Genotyping Node, Center for Genomic Regulation (CRG), Barcelona, Spain
  7. 7
    Medical Genetics, Department of Reproductive Sciences and Development, IRCCS-Burlo-Garofolo, University of Trieste, Trieste, Italy
  8. 8
    Clinical Mass Spectrometry Laboratory, Kennedy Krieger Institute, Baltimore, Maryland, USA
  9. 9
    Department of Medical Genetics, the Children’s Memorial Health Institute, Warsaw, Poland
  10. 10
    Biomedicum Helsinki, University Helsinki, Finland
  11. 11
    Department of Pediatrics, Federico II University, Naples, Italy
  12. 12
    Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
  13. 13
    Central Institute for Blood Transfusion and Immunology, Innsbruck, Austria
  14. 14
    Department of Clinical Genetics, Charles University Motol Hospital, Prague, Czech Republic
  15. 15
    Institute of Human Genetics, Charité, University Medicine Berlin, Berlin, Germany
  16. 16
    Cytogenetics Unit, Laboratory of General Biology, Medical School, University of Ioannina, Greece
  17. 17
    Department of Medicine, University College London, London, UK
  18. 18
    Center of Molecular Medicine Cologne (CMMC), Institute of Human Genetics, University Cologne, Cologne, Germany
  19. 19
    Institute of Medical Informatics and Statistics, Christian-Albrechts-University Kiel, Germany
  20. 20
    Centre de Recherche, Hopital Sainte Justine, Universite de Montreal, Quebec, Canada
  1. Dr M Witsch-Baumgartner, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Schoepfstrasse 41, 6020 Innsbruck, Austria; Witsch-Baumgartner{at}


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. 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.

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  • Competing interests: None declared.