Identification of a homozygous variant in ABCG5 by panel sequencing in a Pakistani family with sitosterolemia: Genotype-phenotype correlation and management considerations.

Sitosterolemia is a rare autosomal recessive disorder characterized by impaired excretion of plant sterols, leading to their accumulation in tissues and organs. We identified a hitherto unreported homozygous variant, in ATP-binding cassette sub-family G member 5 (ABCG5) (NM_022436.3) c.274A > G p.(Lys92Glu), segregating in two affected siblings (Sit1C and Sit1F) of a consanguineous Pakistani family, during genetic workup for hereditary hemolytic anemia. Both patients had anemia, history of gum bleeding and easy bruising. Peripheral film revealed stomatocytes and macrothrombocytopenia. Plasma sitosterol level was found to be significantly high (27.7 mg/dL and 25.1 mg/dL for Sit1C and F, respectively), confirming diagnosis of sitosterolemia in both patients. Treatment with ezetimibe, a sterol absorption inhibitor, resulted in significant decrease in sitosterol as well as low-density lipoprotein-cholesterol, in these patients. This study confirms the potential of panel sequencing as a diagnostic tool for sitosterolemia. Definitive diagnosis has significant clinical implications for genetic counseling and management strategies, such as dietary modifications and successful management with ezetimibe.