Postmortem diagnosis of sitosterolaemia by next-generation sequencing in a patient with severe hypercholesterolaemia and cardiovascular failure

Background and aims

Sitosterolaemia (STSL; OMIN #210250) is a disorder of lipid metabolism and a rare autosomal recessive condition caused by loss-of-function biallelic mutations in the adenosine triphosphate-binding cassette, subfamily G member 5 (ABCG5) gene (NM_022,436.2) or in the adjacent ABCG8 gene (NM_022,437.2). STSL patients often have high plasma total sterols and present a heterogeneous phenotype. Here, we describe a male patient with a post-mortem diagnosis of STSL who was admitted to the emergency department with advanced heart failure, tendon xanthomas and findings from the follow up with his living family members.

Methods

We established a family pedigree and performed whole-exome next-generation sequencing for the patient and Sanger sequencing of DNA samples obtained from his living family members. Plasma sterol (β-sitosterol) level was measured by gas chromatography/mass spectrometry.

Results

Both the patient and his younger brother carried a homozygous mutation of p. R263Q (c.788G > A) in the ABCG8 gene. The patient's plasma plant sterol level was extremely high (β-sitosterol: 107.5 μg/ml), and the plasma β-sitosterol level of his younger brother without tendon xanthomas was also abnormally high (51.5 μg/ml). The β-sitoserol levels of other living family members including ones with a heterozygous mutation of p. R263Q (c.788G > A) were normal (i.e. undetectable). Based on the results of genetic detection and very high plasma level of β-sitosterol, we made a definitive diagnosis of STSL.

Conclusions

Emergency physicians should be aware of the need to further investigate individuals with xanthomas and cardiovascular disease using biochemical and genetic analyses to aid in diagnosis and intervention.