What causes Smith-Lemli-Opitz syndrome (SLOS)?

Updated: Jan 27, 2021
  • Author: Robert D Steiner, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Analysis of family pedigrees has revealed that Smith-Lemli-Opitz syndrome is transmitted in an autosomal recessive fashion as an multiple congenital anomaly (MCA)/intellectual disability (ID) syndrome. Three different groups reported the molecular genetic basis for Smith-Lemli-Opitz syndrome simultaneously.

Smith-Lemli-Opitz syndrome is caused by mutations in the DHCR7 gene, the gene that codes for the enzyme DHCR7 that normally converts 7DHC to cholesterol in the final step of the cholesterol synthetic pathway. Mapping of the DHCR7 gene established the chromosomal position on band 11q12.13. Subsequent mutational analyses by several groups have identified a wide variety of different mutations within the DHCR7 gene, with several common mutations. [27]

Most patients with Smith-Lemli-Opitz syndrome have proven to be compound heterozygotes. This genetic heterogeneity points to possible phenotype-genotype corollaries.

The cause of the intellectual disability, behavioral abnormalities, and malformations is unclear, but cholesterol deficiency, accumulation of potentially toxic precursors, and/or oxysterols or esterified oxysterols may be implicated. [28]

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