Role of cascade genetic testing for the diagnosis and management of familial hypercholesterolemia: A case of compound heterozygous sitosterolemia

Background/Synopsis

Inherited sitosterolemia is a rare genetic condition that affects an estimated 1 in 50,000 individuals world-wide. It is caused by loss-of-function variants in the adenosine triphosphate-binding cassette genes G5 or G8 (ABCG5/G8) and leads to marked uptake of plant sterols, which can result in hypercholesterolemia and premature atherosclerosis.

Objective/Purpose

Describe the importance of cascade genetic testing in confirming the diagnosis of inherited sitosterolemia.

Methods

Literature and medical record review.

Results

A 27-year-old female with no significant past medical history was discovered on routine lipid panel testing to have an LDL cholesterol of 208 mg/dL. She was initiated on atorvastatin 10 mg daily with a less than expected LDL lowering to 170 mg/dL, despite good adherence to therapy. She was referred for evaluation in Lipid Clinic, where she was also noted to have xanthelasma, with a subsequent calculated Dutch Lipid Clinic Network score of 9, consistent with definite familial hypercholesterolemia. Her atorvastatin was switched to rosuvastatin 40 mg daily, which again led to a less than expected response, with an on-treatment directly measured LDL cholesterol of 130 mg/dL. She was subsequently referred for genetic testing. Results from genetic testing showed two heterozygous loss-of-function variants in the ABCG8 gene, namely c.1608G > A (p.Trp536*) and c.647_657dup (p.Arg220Valfs*37). Due to limitations of the genetic assay, it could not be determined whether the variants were present on the same or separate ABCG8 genes. Subsequent cascade testing of the patient's biological mother, who does not have a history of hypercholesterolemia (LDL 87 mg/dL) or premature atherosclerotic cardiovascular disease, demonstrated the presence of only the c.1608G > A (p.Trp536*) variant, suggesting that the patient is likely a compound heterozygote for ABCG8, resulting in a confirmed diagnosis of inherited sitosterolemia. She was initiated on a low plant sterol diet and ezetimibe 10 mg daily, which led to a reduction in directly measured LDL cholesterol to 46 mg/dL.

Conclusions

Our case of a patient with compound heterozygous inherited sitosterolemia highlights that among patients with definite or suspected familial hypercholesterolemia with a less than expected response to standard lipid-lowering therapy, genetic testing of the patient and first-degree family members can help to refine the diagnosis and tailor therapy.