Autosomal Recessive Hypercholesterolemia Due to a Novel Homozygous LDLRAP1 Frameshift Mutation

Autosomal recessive hypercholesterolemia (ARH) is a rare genetic disorder caused by biallelic pathogenic variants in LDLRAP1 and may closely mimic homozygous familial hypercholesterolemia.

A 15-year-old boy presented with painless xanthomas over the buttocks and elbows and severe hypercholesterolemia. Total cholesterol was 516 mg/dL, low-density lipoprotein cholesterol (LDL-C) 499 mg/dL, triglycerides 47 mg/dL, and high-density lipoprotein cholesterol 35 mg/dL. Cardiac evaluation was normal, secondary causes were excluded, and first-degree relatives had normal lipid profiles. Whole-exome sequencing identified a novel homozygous LDLRAP1 frameshift variant, c.112dupA (p.Thr38AsnfsTer27), confirming ARH. Computed tomography coronary angiography and computed tomography aortogram showed no atherosclerotic disease, and lipoprotein(a) was 36 mg/dL.

The patient was treated with atorvastatin, ezetimibe, and bempedoic acid, resulting in a marked reduction in low-density lipoprotein cholesterol to 80 mg/dL at 3-month follow-up. He remained asymptomatic, although no significant xanthoma regression was observed. This case expands the LDLRAP1 mutational spectrum and highlights the importance of genetic testing in severe pediatric hypercholesterolemia with normal family lipid profiles.

Early genetic diagnosis helps distinguish ARH from phenotypically similar disorders and guides treatment and counseling.