Genetic Analysis of Japanese Children Clinically Diagnosed with Familial Hypercholesterolemia

Aim: This study aimed to elucidate the gene and lipid profiles of children clinically diagnosed with familial hypercholesterolemia (FH). Methods: A total of 21 dyslipidemia-related Mendelian genes, including FH causative genes (LDLR,APOB, andPCSK9) and LDL-altering genes (APOE,LDLRAP1, andABCG5/8), were sequenced in 33 Japanese children (mean age, 9.7±4.2 years) with FH from 29 families. Results: Fifteen children (45.5%) with pathogenic variants inLDLR (eight different heterozygous variants) and one child (3.0%) with thePCSK9 variant were found. Among 17 patients without FH causative gene variants, 3 children had variants in LDL-altering genes, anAPOE variant and twoABCG8 variants. The mean serum total cholesterol (280 vs 246 mg/dL), LDL-cholesterol (LDL-C, 217 vs 177 mg/dL), and non-HDL cholesterol (228 vs 188 mg/dL) levels were significantly higher in the pathogenic variant-positive group than in the variant-negative group. In the variant-positive group, 81.3% of patients had LDL-C levels ≥ 180 mg/dL but 35.3% in the variant-negative group. The mean LDL-C level was significantly lower in children with missense variants, especially with the p.Leu568Val variant, than in children with other variants inLDLR, whereas the LDL-altering variants had similar effects on the increase in serum LDL-C toLDLR p.Leu568Val. Conclusion: Approximately half of the children clinically diagnosed with FH had pathogenic variants in FH causative genes. The serum LDL-C levels tend to be high in FH children with pathogenic variations, and the levels are by the types of variants. Genetic analysis is useful; however, further study on FH without any variants is required.