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What is the role for genetic screening in the setting of an individual with severe hypercholesterolemia, such as the patient illustrated in Figure 1? This Figure illustrates the results of the first step in assessing a severe hypercholesterolemia patient such as this: taking a family history.
When there is a clear family history of a pattern of substantially elevated LDL-C levels in at least one parent - or perhaps at least one sibling or in some cases at least one child - this suggests a differential diagnosis of autosomal dominant inheritance of familial hypercholesterolemia (FH). For the physician this should indicate that the underlying cause will be LDL receptor mutations, APOB mutations, or more rarely PCSK9 gain-of-function mutations.
On the other hand, if the family history is negative, this is more suggestive of the autosomal recessive form of FH. In this case the physician should think about sitosterolemia due to ABCG5 or G8 mutations or to mutations in the gene LDLR RAP1.