Low-density lipoprotein receptor mutational analysis in diagnosis of familial hypercholesterolemia

Bourbon, Mafalda; Alves, Ana Catarina; Sijbrands, Eric J.G.

doi:10.1097/mol.0000000000000404

Cited by 38 publications

(34 citation statements)

References 54 publications

(34 reference statements)

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“…The principal new finding here is that NGS data for the LDLR gene that is processed bioinformatically from patient samples referred for assessment of FH has a 100% concordance rate for calling of large-scale CNVs using MLPA as the “gold standard” reference method. The ability to detect the full spectrum of mutations in LDLR is critical in obtaining a molecular diagnosis for FH, especially since up to 10% or more of such mutations are large-scale CNVs rather than small-scale DNA sequence variants, depending on the cohort and ascertainment ( 18 ). The current procedure for diagnostic laboratories often includes targeted NGS followed by MLPA.…”

Section: Discussionmentioning

confidence: 99%

Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia

Iacocca

Wang

Dron

et al. 2017

Journal of Lipid Research

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Familial hypercholesterolemia (FH) is a heritable condition of severely elevated LDL cholesterol, caused predominantly by autosomal codominant mutations in the LDL receptor gene (LDLR). In providing a molecular diagnosis for FH, the current procedure often includes targeted next-generation sequencing (NGS) panels for the detection of small-scale DNA variants, followed by multiplex ligation-dependent probe amplification (MLPA) in LDLR for the detection of whole-exon copy number variants (CNVs). The latter is essential because ∼10% of FH cases are attributed to CNVs in LDLR; accounting for them decreases false negative findings. Here, we determined the potential of replacing MLPA with bioinformatic analysis applied to NGS data, which uses depth-of-coverage analysis as its principal method to identify whole-exon CNV events. In analysis of 388 FH patient samples, there was 100% concordance in LDLR CNV detection between these two methods: 38 reported CNVs identified by MLPA were also successfully detected by our NGS method, while 350 samples negative for CNVs by MLPA were also negative by NGS. This result suggests that MLPA can be removed from the routine diagnostic screening for FH, significantly reducing associated costs, resources, and analysis time, while promoting more widespread assessment of this important class of mutations across diagnostic laboratories.

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Section: Discussionmentioning

confidence: 99%

Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia

Iacocca

Wang

Dron

et al. 2017

Journal of Lipid Research

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“…Elevated circulating LDL levels are highly related to the development of atherosclerosis and coronary heart disease. Mutations of LDLR cause an autosomal dominant disorder, familial hypercholesterolemia (FH), which is characterized by elevated plasma concentrations of LDL cholesterol and early coronary heart disease ( 12 ). During the initial stages of atherosclerosis, LDL particles are transported across the EC barrier and accumulate in the subendothelial space.…”

Section: Transcytosis Of Ldl In Ecmentioning

confidence: 99%

Endothelial Transcytosis of Lipoproteins in Atherosclerosis

Zhang

Sessa

Fernández‐Hernando

2018

Front. Cardiovasc. Med.

101

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Seminal studies from Nikolai Anichckov identified the accumulation of cholesterol in the arteries as the initial event that lead to the formation of atherosclerotic plaques. Further studies by Gofman and colleagues demonstrated that high levels of circulating low-density lipoprotein cholesterol (LDL-C) was responsible for the accelerated atherosclerosis observed in humans. These findings were confirmed by numerous epidemiological studies which identified elevated LDL-C levels as a major risk factor for cardiovascular disease. LDL infiltrates in the arterial wall and interacts with the proteoglycan matrix promoting the retention and modification of LDL to a toxic form, which results in endothelial cell (EC) activation and vascular inflammation. Despite the relevance of LDL transport across the endothelium during atherogenesis, the molecular mechanism that control this process is still not fully understood. A number of studies have recently demonstrated that low density lipoprotein (LDL) transcytosis across the endothelium is dependent on the function of caveolae, scavenger receptor B1 (SR-B1), activin receptor-like kinase 1 (ALK1), and LDL receptor (LDLR), whereas high-density lipoproteins (HDL) and its major protein component apolipoprotein AI transcytose ECs through SR-B1, ATP-Binding cassette transporter A1 (ABCA1) and ABCG1. In this review article, we briefly summarize the function of the EC barrier in regulating lipoprotein transport, and its relevance during the progression of atherosclerosis. A better understanding of the mechanisms that mediate lipoprotein transcytosis across ECs will help to develop therapies targeting the early events of atherosclerosis and thus exert potential benefits for treating atherosclerotic vascular disease.

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“…It is unsurprising that of the many LDLR variants found in patients with FH contained in large databases, only a small percentage have been correlated with functional studies and that as a consequence, a large percentage fits into the “variant of uncertain significance” category. Of 1891 purportedly FH‐causing LDLR variants found in the Leiden Open Variation Databases 2 and 3 and the Human Gene Mutation databases, less than 10% had been fully characterised by functional studies and more than 85% had no functional testing at all, with 42% being of unknown significance . The ClinVar database lists 3711 variants, with 566 variants likely pathogenic and 933 variants pathogenic.…”

Section: Pathophysiology and Molecular Geneticsmentioning

confidence: 99%

“…15 Mutation databases, less than 10% had been fully characterised by functional studies and more than 85% had no functional testing at all, with 42% being of unknown significance. 19 The ClinVar database lists 3711 variants, with 566 variants likely pathogenic and 933 variants pathogenic. However, there are 826 variants of unknown significance, and 464 variants listed with conflicting interpretations thus confirming the significant work required to investigate and correctly classify these variants.…”

Section: Variants In Ldlrmentioning

confidence: 99%

Widening the spectrum of genetic testing in familial hypercholesterolaemia: Will it translate into better patient and population outcomes?

2019

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Familial hypercholesterolaemia (FH) is caused by pathogenic variants in LDLR, APOB or PCSK9. Impaired low‐density lipoprotein (LDL) receptor function leads to decreased LDL catabolism and premature atherosclerotic cardiovascular disease (ASCVD). Thousands of LDLR variants are known, but assignation of pathogenicity requires accurate phenotyping, family studies and assessment of LDL receptor function. Precise, genetic diagnosis of FH using targeted next generation sequencing allows for optimal treatment, distinguishing FH from pathogenically distinct disorders requiring different treatment. Polygenic hypercholesterolaemia resulting from an accumulation of LDL cholesterol‐raising single nucleotide polymorphisms (SNPs) could also be suspected by this approach. Similarly, ASCVD risk could be estimated by broader sequencing of cholesterol and non‐cholesterol‐related genes. Both of these areas require further research. The clinical management of FH, focusing on the primary or secondary prevention of ASCVD, has been boosted by PCSK9 inhibitor therapy. The efficacy of PCSK9 inhibitors in homozygous FH may be partly predicted by the LDLR variants. While expanded genetic testing in FH is clinically useful in providing an accurate diagnosis and enabling cost‐effective testing of relatives, further research is needed to establish its value in improving clinical outcomes.

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Low-density lipoprotein receptor mutational analysis in diagnosis of familial hypercholesterolemia

Cited by 38 publications

References 54 publications

Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia

Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia

Endothelial Transcytosis of Lipoproteins in Atherosclerosis

Widening the spectrum of genetic testing in familial hypercholesterolaemia: Will it translate into better patient and population outcomes?

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