Maternal ABCA1 genotype is associated with severity of Smith–Lemli–Opitz syndrome and with viability of patients homozygous for null mutations

Abstract

The Smith-Lemli-Opitz syndrome (SLOS [MIM 270400]) is an autosomal recessive malformation syndrome that shows a great variability with regard to severity. SLOS is caused by mutations in the D7sterol-reductase gene (DHCR7), which disrupt cholesterol biosynthesis. Phenotypic variability of the disease is already known to be associated with maternal apolipoprotein E (ApoE) genotype. The aim of this study was to detect additional modifiers of the SLOS phenotype. We examined the association of SLOS severity with variants in the genes for ApoC-III, lecithin-cholesterol acyltransferase, cholesteryl-ester transfer protein, ATP-binding cassette transporter A1 (ABCA1), and methylene tetrahydrofolate reductase. Our study group included 59 SLOS patients, their mothers, and 49 of their fathers. In addition, we investigated whether ApoE and ABCA1 genotypes are associated with the viability of severe SLOS cases (n ¼ 21) caused by two null mutations in the DHCR7 gene. Maternal ABCA1 genotypes show a highly significant correlation with clinical severity in SLOS patients (P ¼ 0.007). The rare maternal p.1587Lys allele in the ABCA1 gene was associated with milder phenotypes. ANOVA analysis demonstrated an association of maternal ABCA1 genotypes with severity scores (logarithmised) of SLOS patients of P ¼ 0.004. Maternal ABCA1 explains 15.4% (R 2 ) of severity of SLOS patients. There was no association between maternal ApoE genotype and survival of the SLOS fetus carrying two null mutations. Regarding ABCA1 p.Arg1587Lys in mothers of latter SLOS cases, a significant deviation from HardyWeinberg equilibrium (HWE) was observed (P ¼ 0.005). ABCA1 is an additional genetic modifier in SLOS. Modifying placental cholesterol transfer pathways may be an approach for prenatal therapy of SLOS.

Metabolic Adaptations in Pregnancy: A Review

“…ABCA1 has also been recently identified as a gene whose variants in the mother significantly correlated with the severity of SLOS phenotype of the infant. This observation suggested that placental cholesterol transfer pathways are not only vital for fetal development but also present as a plausible target for prenatal SLOS therapy [36]. Furthermore, maternally derived cholesterol plays a role in the growth and the development of fetuses unaffected with SLOS.…”

The Role of Maternal-Fetal Cholesterol Transport in Early Fetal Life: Current Insights1

“…Recently, Lanthaler and colleagues [52] also discovered that specific maternal ABCA1 genotypes are associated with the severity of SLOS in offspring. From these studies we can conclude that disturbances in maternal cholesterol levels are associated with adverse pregnancy outcomes.…”

Normal IQ is possible in Smith‐Lemli‐Opitz syndrome

“…The correlation of maternal ApoE genotype with disease severity persisted after stratification for DHCR7 genotype. Furthermore, Lanthaler, Steichen-Gersdorf, Kollerits, Zschocke, and Witsch-Baumgartner (2013) reported that maternal ABCA1 genotype is an additional genetic modifier in SLOS. The p.Arg1587Lys polymorphism in maternal A BCA1 gene was associated with milder clinical phenotypes.…”