Genetic Analysis of Japanese Children Clinically Diagnosed with Familial Hypercholesterolemia

• Published in: Journal of Atherosclerosis and Thrombosis Vol. 29; no. 5; pp. 667 - 677
• Main Authors: Nagahara, Keiko, Nishibukuro, Tsuyoshi, Ogiwara, Yasuko, Ikegawa, Kento, Tada, Hayato, Yamagishi, Masakazu, Kawashiri, Masa-aki, Ochi, Ayako, Toyoda, Junya, Nakano, Yuya, Adachi, Masanori, Mizuno, Katsumi, Hasegawa, Yukihiro, Dobashi, Kazushige
• Format: Journal Article
• Language: English
• Published: Japan Japan Atherosclerosis Society 01.05.2022
• Subjects: Adolescent; Apolipoproteins E - genetics; Child; Child, Preschool; Cholesterol; Cholesterol, LDL; Gene; Humans; Hyperlipoproteinemia Type II - diagnosis; Hyperlipoproteinemia Type II - genetics; Japan - epidemiology; LDL receptor; LDL-cholesterol; Original; PCSK9; Phenotype; Proprotein Convertase 9 - genetics; Receptors, LDL - genetics; Japan; LDL-cholesterol; PCSK9; FH; Gene; LDL receptor
• ISSN: 1340-3478; 1880-3873; 1880-3873
• DOI: 10.5551/jat.62807

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, and PCSK9) and LDL-altering genes (APOE, LDLRAP1, and ABCG5/8), 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 in LDLR (eight different heterozygous variants) and one child (3.0%) with the PCSK9 variant were found. Among 17 patients without FH causative gene variants, 3 children had variants in LDL-altering genes, an APOE variant and two ABCG8 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 in LDLR, whereas the LDL-altering variants had similar effects on the increase in serum LDL-C to LDLR 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.