Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Smith-Lemli-Opitz Syndrome [Q87.1]

OMIM-Nummer: 270400, 602858 (DHCR7)

Dipl.-Biol. Birgit Busse, Dipl.-Biol. Wolfgang Rupprecht

Scientific Background

Depending on severity, the Smith-Lemli-Opitz syndrome (SLOS) is characterized by a broad range of signs and symptoms such as signs of dysmorphia (microcephaly, “mid-line defects”, microretrognathia, low-set ears, blepharoptosis, syndactyly of the 2nd and 3rd toe), psychomotor impairment, short stature as well as malformations such as cardiac defects and cleft lip (and palate). Furthermore, affected boys may exhibit genital malformations (e.g. hypospadias). The molecular cause is a defect in the last step of cholesterol biosynthesis which results in enrichment of 7-dehydrocholesterol (and its isomer 8-dehydrocholesterol). Since the usual enzymatic cholesterol assay cannot differentiate cholesterol from 7-dehydrocholesterol, gas chromatography/mass spectrometry is used for the biochemical detection of SLOS. An elevated dehydrocholesterol/cholesterol ratio is an indicator for SLOS.

Inheritance of SLOS is autosomal recessive. The prevalence is 1:10,000 to 1:30,000. Mutations in the DHCR7 gene, which encodes for the enzyme 7-dehydrocholesterol reductase, lead to a loss of enzyme activity and therefore to a lack of the last step in the synthesis of cholesterol. The most frequent mutation (c.964-1G>C) is located in Intron 8 of the DHCR7 gene. It can be detected in approx. 30% of all patients. The severity of SLOS depends on the type of mutation and its location. A clear genotype-phenotype correlation is not always present. Hence, patients with the same mutations may be affected with different severity. Therefore, other factors that might have an influence on the phenotype are being discussed. A study from the year 2004 proved a correlation between maternal ApoE genotype and the severity of SLOS in patients.