Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement

Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, Mafalda

doi:10.1038/gim.2015.71

Cited by 34 publications

(30 citation statements)

References 39 publications

(51 reference statements)

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“…ADH due to "gain of function" PCSK9 mutations is uncommon, occurring in less than 1% of cases (9)(10)(11). Note that PCSK9 inhibitors are a promising new class of drugs for LDL-C reduction ( 20,21 ).…”

Section: Supplementary Abstractmentioning

confidence: 99%

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Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Wintjens

Bozon²,

Belabbas

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identifi ed APOE sequence changes were predicted to impact protein function. Abstract Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor ( LDLR ), APOB , and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADHassociated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR , 3.1% in APOB , and 1.7% in PCSK9 . We identifi ed 18 new variants in LDLR and 2 in PCSK9 . Three LDLR variants, including two newly identifi ed, were studied by minigene reporter assay confi rming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identifi ed in three patients with isolated severe hypercholesterolemia giving a

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Section: Supplementary Abstractmentioning

confidence: 99%

“…LDLR is the gene most frequently associated with ADH and is also the best characterized. It is responsible for the disease called familial hypercholesterolemia (FH) (9)(10)(11). With the exception of a few founder populations, the spectrum of LDLR causing FH mutations is large.…”

Section: Supplementary Abstractmentioning

confidence: 99%

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Wintjens

Bozon²,

Belabbas

et al. 2016

Journal of Lipid Research

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“…The observed elevated prevalence of APOB mutations (particularly the 34 specific mutations), in accordance with the report from Yang et al 34 showing that 18 out of 30 families were identified by harboring LDLR or APOB mutations with frequencies of 77.8% (14/18) and 22.2% (4/18), respectively, might indicate an important gene effect of APOB mutations on Chinese FH. Moreover, investigators from Taiwan and other ethnicities have suggested recently that the number of APOB mutations is increasing, 16,36 most notably in Taiwan. 34,38 The elevated prevalence of APOB mutations among Chinese patients might be possible, as pointed out by Andersen et al 38 Additionally, most currently available genetic testing in APOB is focused on exon 26 and p.Arg3500Trp rather than on the entire coding region.…”

Section: Et Al Familial Hypercholesterolemia In China 577mentioning

confidence: 99%

“…40,41 Therefore, it may be beneficial to undertake sequencing of the entire APOB gene because other rare variants in the gene may be responsible for the patient's clinical phenotype. 36,39 In the present study, we screened the whole exons in APOB and found some mutations in nonhot region. The hot exon of 26 showed a frequency of 37.8% in APOB mutations.…”

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Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

Zhu

et al. 2017

ATVB

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Large-scale clinical studies of FH have been reported from many countries, 2,7-16 but the features of FH in China are largely unknown. 17 Furthermore, the actual prevalence of FH is likely to be underestimated in the past, and the FH trait is masked by the CAD phenotype or more common risk factors without the genetically elevated cholesterol levels.3 Hence, the aim of present study was to investigate patients with FH phenotype and further provide molecular data on mutations for patients with FH in the Division of Dyslipidemia of Fu Wai Hospital, the only national center of dyslipidemia in China.© 2016 American Heart Association, Inc. Objective-Familial hypercholesterolemia (FH) is characterized by an elevated low-density lipoprotein cholesterol and increased risk of premature coronary artery disease. However, the general picture and mutational spectrum of FH in China are far from recognized, representing a missed opportunity for the investigation. Approach and Results-A total of 8050 patients undergoing coronary angiography were enrolled. The diagnosis of clinical FH was made using Dutch Lipid Clinic Network criteria, and the information of relatives was obtained by inquiring for the probands or from their own medical records of certain clinics/hospitals. Molecular analysis of FH was performed using target exome sequencing in LDLR (low-density lipoprotein cholesterol receptor gene), APOB (apolipoprotein B gene), and PCSK9 (proprotein convertase subtilisin/kexin type 9 gene). As a result, 3.5% of the patients with definite/ probable FH phenotype (definite 1.0% and probable 2.5%) were identified. Women FH had fewer premature coronary artery disease (women <60, or men <55 years of age) when compared with men FH (70.6% versus 82.7%; P<0.001), whereas angiographic extension of coronary artery disease was significantly increased with FH diagnosis in both men and women (P<0.001). Patterns of medication use in definite/probable FH were as follows: nontreated, 20.6%; low intensity, 6.0%; moderate intensity, 68.3%; and high intensity, 5.0%. However, none of them had achieved the lowdensity lipoprotein cholesterol <100 mg/dL. Additionally, mutational analysis was performed in 245 definite/probable FH cases, and risk variants were identified in 115 patients, giving a detection rate of 46.9%. Conclusions-We showed firsthand a common identification but poor treatment of patients with FH phenotype in Chinese coronary angiography patients. Genetic data in our FH cases might contribute to update the frequency and spectrum of Chinese FH scenarios. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Prevalence of FHBasic characteristics of the study population are summarized in Table 1. The mean (±SD) age of the participants was 57.2±10.5 years, of whom 68.7% were men and 83.8% were with CAD and 37.8% with pCAD (<55 years for men and <60 years for women). The mean total cholesterol and LDL-C were 165.25±50.58 and 101.54±43.63 mg/dL, respectively. In the sample, there were 1.0% def...

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“…Autosomal dominant FH is attributed to mutations in three different genes: LDL receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) (1,(3)(4)(5). Other FH genes have been searched for using exome sequencing without success (2).…”

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confidence: 99%

The panorama of familial hypercholesterolemia in Latin America: a systematic review

Mehta

Zubirán

Martagón

et al. 2016

Journal of Lipid Research

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penetrance. Autosomal dominant FH is attributed to mutations in three different genes: LDL receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) (1,(3)(4)(5). Other FH genes have been searched for using exome sequencing without success (2). FH caused by mutations in LDLR adaptor protein (LDLRAP) is known as autosomal recessive FH (2). FH is the most common monogenic disorder leading to premature CHD; despite this fact, it is notoriously underdiagnosed and undertreated worldwide (6).Homozygous FH (HoFH) is characterized by extremely high levels of LDL-C (460-1,160 mg/dl) and early onset coronary artery disease (typically by the second decade of life) (7). Mean LDL-C concentration in untreated patients is close to 615 mg/dl (7,8). Patients are classified into two groups based on the level of LDLR activity, either <2% (receptor negative) or 2-25% (receptor defective). Receptor defective patients have a better prognosis than receptor negative cases (9-11).Heterozygous FH (HeFH) is caused by a single inherited copy of a mutation. The frequency of a heterozygous mutation is >90, 5, and <1% in the LDLR, APOB, and PCSK9 genes, respectively (5). A causal mutation in one of these genes is identified in 60-80% of cases. Affected individuals are characterized by LDL-C levels two to three times greater than normal (190-400 mg/dl). The mean untreated LDL-C concentration is 199.9 mg/dl (12). HeFH is suspected

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Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement

Cited by 34 publications

References 39 publications

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

The panorama of familial hypercholesterolemia in Latin America: a systematic review

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