Homozygous Familial Hypercholesterolemia

Nohara, Atsushi; Tada, Hayato; Ogura, Mariko; Okazaki, Sachiko; Ono, Koh; Shimano, Hitoshi; Daida, Hiroyuki; Dobashi, Kazushige; Hayashi, Toshio; Hori, Mika; Matsuki, Kota; Minamino, Tetsuo; Yokoyama, Shinji; Harada‐Shiba, Mariko

doi:10.5551/jat.rv17050

Cited by 68 publications

(76 citation statements)

References 79 publications

(71 reference statements)

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“… 2 Based on the number of pathogenic FH mutation, FH is classified into heterozygous FH (HeFH) with a single FH mutation and homozygous FH (HoFH) caused by mutations of both copies of FH genes. 3 The LDL cholesterol level in HeFH is about two times higher, and that in HoFH is four times higher than that of the general population. 1 Thus, patients with HoFH exhibit more severe phenotypes than those with HeFH.…”

Section: Introductionmentioning

confidence: 94%

“…Further, it is characterized by an extremely elevated LDL cholesterol level (>500 mg/dL), cutaneous xanthomas since childhood, premature CAD during childhood, and supravalvular aortic stenosis. 3 Typically, homozygous FH refers to double pathogenic mutations in the FH genes ( LDLR , PCSK9 , APOB , or LDLRAP1 ). The severity of this condition can be assessed based on genes and/or mutation types.…”

Section: Factors Contributing To the Phenotypic Variations Of Fhmentioning

confidence: 99%

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Individualized Treatment for Patients With Familial Hypercholesterolemia

Tada

Takamura

Kawashiri

2022

J Lipid Atheroscler

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Familial hypercholesterolemia (FH) is one of the most common and, therefore, important inherited disorders in preventive cardiology. This disease is mainly caused by a single pathogenic mutation in the low-density lipoprotein receptor or its associated genes. Moreover, it is correlated with a high risk of cardiovascular disease. However, the phenotype severity even in this monogenic disease significantly varies. Thus, the current study aimed to describe FH and its importance and the factors (inherited and acquired) contributing to differences in phenotype severity. Different lipid-modification therapies according to these factors can lead to individualized treatments, which are also essential in the general populations.

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Section: Introductionmentioning

confidence: 94%

Section: Factors Contributing To the Phenotypic Variations Of Fhmentioning

confidence: 99%

Individualized Treatment for Patients With Familial Hypercholesterolemia

Tada

Takamura

Kawashiri

2022

J Lipid Atheroscler

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“…Therefore, genetic testing is recommended for the diagnosis and risk stratification of patients with FH. More than 2000 pathogenic variants have been identified worldwide, and most of them are LDLR variants ( Nohara et al, 2021 ). Based on genotype, pathogenic variants can be classified as missense variants (which can estimate residual LDLR activity) or protein-truncating variants (PTVs), which may have lost their LDLR function.…”

Section: Introductionmentioning

confidence: 99%

Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia

et al. 2022

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Objective: It has been shown that pathogenic variants are associated with poor clinical outcomes in patients with familial hypercholesterolemia (FH). However, data on the effect of different types of pathogenic variants on FH phenotype is limited.Methods: We retrospectively investigated the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of major adverse cardiac events (MACEs), defined as cardiovascular death, myocardial infarction, unstable angina, or coronary artery revascularization, in patients with FH (N = 1,050, male/female = 490/560). Based on genotype, the patients were divided into the following three groups: patients without pathogenic variants, patients with missense variants, and patients with protein-truncating variants (PTVs). Cox proportional hazard model was used to identify the factors associated with MACEs.Results: The median follow-up duration was 12.6 years (interquartile range = 9.5–17.9 years). There were 665 patients with FH-mutation (277 patients with missense variants and 388 patients with PTVs) and 385 patients without FH-mutation. Over the follow-up duration, 175 MACEs were observed. We identified 89 different pathogenic variants in the 665 patients with FH. LDL cholesterol level was found to be significantly higher in patients with PTVs (256 mg/dl) than in patients with missense variants (236 mg/dl) and patients without pathogenic variants (216 mg/dl). It was also found that PTVs and missense variants are significantly associated with MACEs (hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.08–2.08, p = 0.0033 and HR = 3.24, 95% CI = 2.12–4.40, p = 3.9 × 10−6, respectively), independent of classical risk factors.Conclusion: Pathogenic variants, especially PTVs, are significantly associated with poor outcomes in patients with FH. Genetic testing is useful for the diagnosis and risk stratification of patients with FH.

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“…These mutations affect LDLR binding to LDL containing APOB and APOE, resulting in the disturbance of LDL metastasis in blood and excessive siltation in tissues, leading to multiple cutaneous xanthoma and atherosclerosis. The prevalence of heterozygous FH (HeFH) is 1:200-300, whereas homozygous FH (HoFH) presents in a proportion of 1:170,000-300,000 individuals 15 . Generally, serum TC levels in heterozygous patients are between 6.5 and 14.3 mmol/L, and LDL-C levels are > 4.9 mmol/L 16 , while serum TC levels in homozygous patients are usually >18 mmol/L and LDL-C levels are >13 mmol/L 17 .…”

Section: Introductionmentioning

confidence: 99%

Analysis of Low-Density Lipoprotein Receptor Gene Mutations in A Family with Familial Hypercholesterolemia

et al. 2022

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Background: Familial hypercholesterolemia (FH) is a common monogenic autosomal dominant hereditary disease, mainly caused by pathogenic mutations in the low-density lipoprotein receptor (LDLR) gene. It is characterized by severely elevated LDL cholesterol (LDL-C) levels, cutaneous xanthomatosis, and premature coronary heart disease.Materials and Methods: Whole exome sequencing of the proband with familial hypercholesterolemia was performed to identify the target gene and screen for suspicious pathogenic mutations. Sanger sequencing of family members was conducted to analyze family genetic-phenotypic associations. In addition, the changes in the structure and function of mutant LDLR were predicted using biological information analysis.Results: Next Generation Sequencing revealed that the proband carried two heterozygous missense point mutations c.G1027A (p.G343S) and c.G1879A (p.A627T) in LDLR (NM_000527), which could lead to FH syndrome. In this pedigree, the proband and her brother with hypercholesterolemia and xanthelasma carried the compound heterozygous mutations p.G343S and p.A627T. Her father, children, and nephew carried the p.G343S mutation, and her mother and niece carried the p.A627T mutation. The total cholesterol (TC) of a compound heterozygote was 20.50–21.35 mmol/L, the cholesterol of a heterozygote was 6.52–8.81 mmol/L, and the TC of other family members without a mutation was 2.94–3.61 mmol/L. G343S and A627T had a slight effect on the protein structure of LDLR, as simulated by Chimera. In addition, Rredictprotein software predicted that G343S and A627T affected the disordered region, protein interaction binding region, and RNA binding region of the LDLR. Gly343 and Ala627 are highly conserved in mammals and play a vital role in maintaining the function of the LDLR. YinOYang 1.2 predicted that these two sites had great potential for O-GlcNac modification, and GPS 5.0 predicted that the variants modified phosphorylation. Mutations may affect protein post-translational modification, thus changing the structure, function, location, and fate of the protein.Conclusions：The mutations c.G1027A in LDLR exon 7 and c.G1879A in exon 13 may be the molecular genetic basis of FH in this family. Compared to patients with a heterozygous variant, patients with compound heterozygous variants had much higher levels of cholesterol and had xanthoma

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Homozygous Familial Hypercholesterolemia

Cited by 68 publications

References 79 publications

Individualized Treatment for Patients With Familial Hypercholesterolemia

Individualized Treatment for Patients With Familial Hypercholesterolemia

Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia

Analysis of Low-Density Lipoprotein Receptor Gene Mutations in A Family with Familial Hypercholesterolemia

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