title: Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.
abstract: Smith-Lemli-Opitz syndrome/RSH (SLOS) is a multiple congenital anomaly syndrome caused by mutations in the gene for Delta7-sterol reductase (DHCR7) which catalyses the last step in the biosynthesis of cholesterol. SLOS is among the common recessive disorders in Europeans but almost absent in most other populations. More than 40 mutations in the DHCR7 gene some of which are frequent have been described in SLOS patients of various origins. Here we report mutation analysis of the DHCR7 gene in SLOS patients from Poland (n = 15), Germany/Austria (n = 22) and Great Britain (n = 22). Altogether 35 different mutations were identified and the two null mutations IVS8-1G > C and W151X were the most frequent in the total sample. In all three populations three mutations accounted for >0.5 of SLOS chromosomes. The mutational spectra were, however, significantly different across these populations with each of the common mutations showing an east-west gradient (W151X, V326L) or vice versa (IVS8-1G > C). W151X is the most frequent (0.33) mutation in Polish SLOS patients. It has an intermediate frequency in German/Austrian patients (0.18) and is rare among British patients (0.02). V326L shows the same distribution pattern (Poland 0.23, Germany/Austria 0.18, Britain 0.02). In contrast IVS8-1G > C is most frequent in Britain (0.34) intermediate in Germany/Austria (0.20) and rare in Poland (0.03). All analysed IVS8-1G > C and V326L alleles shared the same DHCR7 haplotype, whereas the W151X mutation occurred on different haplotypes. There is evidence for both recurrent mutations and founder effects. Together this suggests that the common SLOS mutations in Europe have different geographic and historic origins and spread across the continent in opposite directions.
authors.affiliation: Institute of Medical Biology and Human Genetics, Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Witsch-Baumgartner
authors.forename: E
authors.initials: E
authors.lastname: Ciara
authors.forename: J
authors.initials: J
authors.lastname: Löffler
authors.forename: H J
authors.initials: HJ
authors.lastname: Menzel
authors.forename: U
authors.initials: U
authors.lastname: Seedorf
authors.forename: J
authors.initials: J
authors.lastname: Burn
authors.forename: G
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: G F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: B U
authors.initials: BU
authors.lastname: Fitzky
authors.forename: H
authors.initials: H
authors.lastname: Mundy
authors.forename: P
authors.initials: P
authors.lastname: Clayton
authors.forename: R I
authors.initials: RI
authors.lastname: Kelley
authors.forename: M
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.forename: G
authors.initials: G
authors.lastname: Utermann
mesh_terms: D000483:Alleles; D001317:Austria; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005060:Europe; D005787:Gene Frequency; D005858:Germany; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011044:Poland; D018807:Polymorphism, Single-Stranded Conformational; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics* / Q000473:pathology; D006113:United Kingdom
chemical_list: D004247:DNA; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase