Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia

Abstract

Objective Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 ( ABCG5 ) or ATP-binding cassette sub-family G member 8 ( ABCG8 ). There are only few data on the pathogenicity of ABCG5 and ABCG8 . This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia. Methods This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targeted-sequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL. Results Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5–17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5–4.1] µg/mL) in 14 individuals. Conclusion The scheme proposed for assessing the pathogenicity of genetic variations ( ABCG5 and ABCG8 ) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia

“…To estimate the presence of deleterious ABCG5 or ABCG8 variant(s), it is useful to measure serum sitosterol levels. We have shown that a serum sitosterol level of 5 μg/mL or more is a useful “marker” for the presence of deleterious ABCG5 or ABCG8 variant(s) [ 63 ]. In addition, we can assume that patients whose serum sitosterol level is 10 μg/mL or more are highly likely to have sitosterolemia and have deleterious ABCG5 or ABCG8 variants in both alleles.…”