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. 2022 May 1;29(5):667-677.
doi: 10.5551/jat.62807. Epub 2021 May 20.

Genetic Analysis of Japanese Children Clinically Diagnosed with Familial Hypercholesterolemia

Keiko Nagahara  1 , Tsuyoshi Nishibukuro  2 , Yasuko Ogiwara  2 , Kento Ikegawa  2 , Hayato Tada  3 , Masakazu Yamagishi  3 , Masa-Aki Kawashiri  3 , Ayako Ochi  1 , Junya Toyoda  1 , Yuya Nakano  1 , Masanori Adachi  1 , Katsumi Mizuno  1 , Yukihiro Hasegawa  2 , Kazushige Dobashi  1   4
Affiliations

Genetic Analysis of Japanese Children Clinically Diagnosed with Familial Hypercholesterolemia

Keiko Nagahara et al. J Atheroscler Thromb. .

Abstract

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.

Keywords: FH; Gene; LDL receptor; LDL-cholesterol; PCSK9.

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Figures

Fig.1. Frequency histogram of the distribution of low-density lipoprotein cholesterol (LDL-C) values in our 33 patients
Fig.1. Frequency histogram of the distribution of low-density lipoprotein cholesterol (LDL-C) values in our 33 patients
Closed bar: variant-positive children (n=16), open bar: variant-negative children (n=17).
None
See this image and copyright information in PMC

Comment in

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