First case of sitosterolemia caused by double heterozygous mutations in ABCG5 and ABCG8 genes.

We present the first case of sitosterolemia caused by double heterozygous mutations in adenosine triphosphate-binding cassette subfamily G members 5 and 8 (ABCG5 and ABCG8) genes. A 1-year-old girl was admitted to Kanazawa University Hospital due to her hyper low-density lipoprotein (LDL)-cholesterolemia (453 mg/dL) as well as intertriginous xanthomas associated with breastfeeding. Initially, she was suspected as familial hypercholesterolemia (FH). However, her LDL cholesterol level significantly reduced after her weaning from breastfeeding. In addition, cascade screening did not show any evidence supporting dominant inheritance pattern as FH. Genetic analyses were performed using custom panel focusing on exome regions of 21 lipid-associated genes, including FH-causing genes (LDL receptor, proprotein convertase subtilisin/kexin type 9, apolipoprotein B), and ABCG5 and ABCG8 genes. In addition to a single deleterious mutation in ABCG5 gene (NM_022436.2:c.1166G>A or NP_071881.1:p.Arg389His), single deleterious mutation in ABCG8 gene (NM_022437.2:c.1285A>C or NP_071882.1:p.Met429Leu) was also identified. Segregations of those mutations from her parents were confirmed. Her serum sitosterol level was significantly elevated to 15.9 μg/mL, leading to her definite diagnosis as sitosterolemia. The ABCG5 and ABCG8 proteins form heterodimers and act as a complex. To the best of our knowledge, this is the first case exhibiting sitosterolemia caused by both ABCG5 and ABCG8 gene mutations.