Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review

Pharmacogenomics J. 2016 Oct;16(5):411-29. doi: 10.1038/tpj.2016.48. Epub 2016 Jul 12.


Mendelian diseases contain important biological information regarding developmental effects of gene mutations that can guide drug discovery and toxicity efforts. In this review, we focus on Smith-Lemli-Opitz syndrome (SLOS), a rare Mendelian disease characterized by compound heterozygous mutations in 7-dehydrocholesterol reductase (DHCR7) resulting in severe fetal deformities. We present a compilation of SLOS-inducing DHCR7 mutations and the geographic distribution of those mutations in healthy and diseased populations. We observed that several mutations thought to be disease causing occur in healthy populations, indicating an incomplete understanding of the condition and highlighting new research opportunities. We describe the functional environment around DHCR7, including pharmacological DHCR7 inhibitors and cholesterol and vitamin D synthesis. Using PubMed, we investigated the fetal outcomes following prenatal exposure to DHCR7 modulators. First-trimester exposure to DHCR7 inhibitors resulted in outcomes similar to those of known teratogens (50 vs 48% born-healthy). DHCR7 activity should be considered during drug development and prenatal toxicity assessment.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Abnormalities, Drug-Induced / enzymology
  • Abnormalities, Drug-Induced / epidemiology
  • Abnormalities, Drug-Induced / genetics*
  • Animals
  • Cholesterol / metabolism
  • Enzyme Inhibitors / adverse effects*
  • Evolution, Molecular
  • Female
  • Gene Frequency
  • Genetic Drift
  • Genetic Predisposition to Disease
  • Heredity
  • Humans
  • Maternal Exposure / adverse effects*
  • Mutation*
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
  • Oxidoreductases Acting on CH-CH Group Donors / genetics*
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Pharmacogenetics*
  • Phenotype
  • Pregnancy
  • Risk Assessment
  • Risk Factors
  • Smith-Lemli-Opitz Syndrome / drug therapy
  • Smith-Lemli-Opitz Syndrome / enzymology
  • Smith-Lemli-Opitz Syndrome / epidemiology
  • Smith-Lemli-Opitz Syndrome / genetics*
  • Vitamin D / metabolism


  • Enzyme Inhibitors
  • Vitamin D
  • Cholesterol
  • Oxidoreductases Acting on CH-CH Group Donors
  • 7-dehydrocholesterol reductase