Disorders of Cholesterol Biosynthesis, Genetics of

Abstract

Abstract Smith–Lemli–Opitz syndrome (SLOS) is the most common and best understood of the inborn errors of cholesterol metabolism. Comprising a heterogeneous group of disorders, inborn errors in cholesterol biosynthesis result in characteristic but variable phenotypes. SLOS is an inherited disorder caused by mutations in DHCR7 which encodes the final enzyme in the cholesterol synthetic pathway. There are eight other cholesterol biosynthesis disorders described in the pre‐Squalene and post‐Squalene pathways. Phenotypic features of SLOS and the other eight disorders are thought to be related to cholesterol deficiency and/or accumulation of cholesterol precursors and their metabolites. A better understanding of SLOS and these other inborn errors of cholesterol biosynthesis may shed light on the importance of cholesterol biosynthesis in embryo‐ and morphogenesis as well as provide clues to treatment. Key Concepts Developing brain tissue is dependent on endogenous cholesterol biosynthesis. Cholesterol is a fundamental component of cell membranes and myelin, a precursor of bile acids, Vitamin D and steroid hormones synthesis and is crucial in cellular signalling. Cholesterol influences embryonic and postnatal development. Cholesterol can play a role in autism and socio‐behavioural problems. Inborn errors of cholesterol metabolism are a heterogeneous group of at least nine disorders, with more likely to be identified.