Novel mutation in the Δ‐sterol reductase gene in three Lebanese sibs with Smith‐Lemli‐Opitz (RSH) syndrome

Nezarati, Marjan M.; Loeffler, Judith; Yoon, Grace; MacLaren, Linda; Fung, Ernest; Snyder, Floyd F.; Utermann, Gerd; Graham, Gail E.

doi:10.1002/ajmg.10367

Cited by 15 publications

(11 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The four most common mutations identified in SLOS patients of European and European–American ancestry are two Null mutations c.964-1G>C and p.Trp151X, which are associated with the most severe phenotype, and two missense mutations p.Val326Leu and p.Thr93Met, which are associated with less severe phenotypes 14 16. So far, little is known about the incidence of SLOS in Africa or Asia5 12 17 18 but patients from the Middle East have been described 19…”

mentioning

confidence: 99%

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

Witsch‐Baumgartner

Schwentner

Gruber

et al. 2007

Journal of Medical Genetics

View full text Add to dashboard Cite

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) (MIM 270 400) is an autosomal recessive multiple congenital anomalies/mental retardation syndrome caused by mutations in the Delta7-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.

show abstract

mentioning

confidence: 99%

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

Witsch‐Baumgartner

Schwentner

Gruber

et al. 2007

Journal of Medical Genetics

View full text Add to dashboard Cite

show abstract

“…Among the severely affected patients, which include intrauterine deaths, the frequency of 0 alleles and 4L alleles was significantly higher than among the mildly and moderately affected. SLOS patients with C-terminal mutations are the less severely affected as shown by two siblings with p.P467L and symptoms of attention deficits and hyperactivity disorder [53], and one patient with p.Y462H and c.964-1G>C and a severity score of 5 [31]. Although our study unequivocally established that the clinical and biochemical phenotypes correlate with the genotype, it is not possible to predict in an individual case the phenotype from the genotype and vice versa.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 77%

DHCR7 mutations causing the Smith—Lemli—Opitz syndrome

Witsch‐Baumgartner

2008

Future Lipidology

View full text Add to dashboard Cite

“…The severity of the Smith-Lemli-Opitz syndrome varies extremely between affected individuals, ranging from severe malformations and intrauterine death to very mild forms which may easily escape correct diagnosis. 23 Only part of this variation is explained by variation of the DHCR7 locus, 11 suggesting that modifier genes may operate. Recently, some modifier genes for human monogenic diseases have been identified or suggested.…”

Section: Discussionmentioning

confidence: 99%

“…23 Only part of this variation is explained by variation of the DHCR7 locus, 11 suggesting that modifier genes may operate. Recently, some modifier genes for human monogenic diseases have been identified or suggested.…”

Section: Discussionmentioning

confidence: 99%