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

M. Witsch-Baumgartner, I. Schwentner, M. Gruber, P. Benlian, J. Bertranpetit, E. Bieth, F. Chevy, N. Clusellas, X. Estivill, G. Gasparini, M. Giros, R. I. Kelley, M. Krajewska-Walasek, J. Menzel, T. Miettinen, M. Ogorelkova, M. Rossi, I. Scala, A. Schinzel, K. SchmidtD. Schönitzer, E. Seemanova, K. Sperling, M. Syrrou, P. J. Talmud, B. Wollnik, M. Krawczak, D. Labuda, G. Utermann

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)200-209
Number of pages10
JournalJournal of Medical Genetics
Volume45
Issue number4
DOIs
Publication statusPublished - Apr 2008
Externally publishedYes

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Smith-Lemli-Opitz Syndrome
Mutation
Population
Pan troglodytes
Haplotypes
Chromosomes
Alleles
Founder Effect
Sterols
Finland
Intellectual Disability
Microsatellite Repeats
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., ... Utermann, G. (2008). Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. Journal of Medical Genetics, 45(4), 200-209. https://doi.org/10.1136/jmg.2007.053520

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

In: Journal of Medical Genetics, Vol. 45, No. 4, 04.2008, p. 200-209.

Research output: Contribution to journalArticle

Witsch-Baumgartner, M, Schwentner, I, Gruber, M, Benlian, P, Bertranpetit, J, Bieth, E, Chevy, F, Clusellas, N, Estivill, X, Gasparini, G, Giros, M, Kelley, RI, 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, PJ, Wollnik, B, Krawczak, M, Labuda, D & Utermann, G 2008, 'Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations', Journal of Medical Genetics, vol. 45, no. 4, pp. 200-209. https://doi.org/10.1136/jmg.2007.053520
Witsch-Baumgartner M, Schwentner I, Gruber M, Benlian P, Bertranpetit J, Bieth E et al. Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. Journal of Medical Genetics. 2008 Apr;45(4):200-209. https://doi.org/10.1136/jmg.2007.053520
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. / Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. In: Journal of Medical Genetics. 2008 ; Vol. 45, No. 4. pp. 200-209.
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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.",
author = "M. Witsch-Baumgartner and I. Schwentner and M. Gruber and P. Benlian and J. Bertranpetit and E. Bieth and F. Chevy and N. Clusellas and X. Estivill and G. Gasparini and M. Giros and Kelley, {R. I.} and M. Krajewska-Walasek and J. Menzel and T. Miettinen and M. Ogorelkova and M. Rossi and I. Scala and A. Schinzel and K. Schmidt and D. Sch{\"o}nitzer and E. Seemanova and K. Sperling and M. Syrrou and Talmud, {P. J.} and B. Wollnik and M. Krawczak and D. Labuda and G. Utermann",
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T1 - Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations

AU - Witsch-Baumgartner, M.

AU - Schwentner, I.

AU - Gruber, M.

AU - Benlian, P.

AU - Bertranpetit, J.

AU - Bieth, E.

AU - Chevy, F.

AU - Clusellas, N.

AU - Estivill, X.

AU - Gasparini, G.

AU - Giros, M.

AU - Kelley, R. I.

AU - Krajewska-Walasek, M.

AU - Menzel, J.

AU - Miettinen, T.

AU - Ogorelkova, M.

AU - Rossi, M.

AU - Scala, I.

AU - Schinzel, A.

AU - Schmidt, K.

AU - Schönitzer, D.

AU - Seemanova, E.

AU - Sperling, K.

AU - Syrrou, M.

AU - Talmud, P. J.

AU - Wollnik, B.

AU - Krawczak, M.

AU - Labuda, D.

AU - Utermann, G.

PY - 2008/4

Y1 - 2008/4

N2 - 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.

AB - 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.

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