Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia

BackgroundMutations in the LDLR gene are the most frequent cause of Familial hypercholesterolemia, an autosomal dominant disease characterised by elevated concentrations of LDL in blood plasma. In many populations, large genomic rearrangements account for approximately 10% of mutations in the LDLR gene.MethodsDNA diagnostics of large genomic rearrangements was based on Multiple Ligation dependent Probe Amplification (MLPA). Subsequent analyses of deletion and duplication breakpoints were performed using long-range PCR, PCR, and DNA sequencing.ResultsIn set of 1441 unrelated FH patients, large genomic rearrangements were found in 37 probands. Eight different types of rearrangements were detected, from them 6 types were novel, not described so far. In all rearrangements, we characterized their exact extent and breakpoint sequences.ConclusionsSequence analysis of deletion and duplication breakpoints indicates that intrachromatid non-allelic homologous recombination (NAHR) between Alu elements is involved in 6 events, while a non-homologous end joining (NHEJ) is implicated in 2 rearrangements. Our study thus describes for the first time NHEJ as a mechanism involved in genomic rearrangements in the LDLR gene.

• Publication year

  2010

• Venue

  BMC Medical Genetics

• Publication date

  2010-07-27

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/1471-2350-11-115PMID 20663204PMCID 2923121
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project

  2010cited by this paper
• Mapping Insertions, Deletions and SNPs on Venter's Chromosomes

  2009cited by this paper
• Epigenetic Nucleosomes: Alu Sequences and CG as Nucleosome Positioning Element

  2008cited by this paper
• Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

  2008cited by this paper
• Efficacy of statins in familial hypercholesterolaemia: a long term cohort study

  2008cited by this paper
• Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study

  2008cited by this paper
• Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia.

  2008cited by this paper
• Small Deletion Variants Have Stable Breakpoints Commonly Associated with Alu Elements

  2008cited by this paper
• The fine-scale and complex architecture of human copy-number variation.

  2008cited by this paper
• in Saccharomyces cerevisiae

  2007cited by this paper
• Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome

  2007cited by this paper
• Saccharomyces cerevisiae Sae2- and Tel1-Dependent Single-Strand DNA Formation at DNA Break Promotes Microhomology-Mediated End Joining

  2007cited by this paper
• Methylation of endogenous human retroelements in health and disease.

  2006cited by this paper
• Genomic characterization of five deletions in the LDL receptor gene in Danish Familial Hypercholesterolemic subjects

  2006cited by this paper
• Low-Density Lipoprotein Receptor Genotype and Response to Pravastatin in Children With Familial Hypercholesterolemia: Substudy of an Intima-Media Thickness Trial

  2005cited by this paper
• Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication

  2005cited by this paper
• Update of the molecular basis of familial hypercholesterolemia in The Netherlands

  2005cited by this paper
• Identification of deletions and duplications in the low density lipoprotein receptor gene by MLPA.

  2005cited by this paper
• Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease.

  2004cited by this paper
• Standardized nomenclature for Alu repeats

  2004cited by this paper
• Recently integrated human Alu repeats: finding needles in the haystack

  2004cited by this paper
• Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia.

  2004cited by this paper
• A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.

  2003cited by this paper
• Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese Published, JLR Papers in Press, July 1, 2003. DOI 10.1194/jlr.M200470-JLR200

  2003cited by this paper
• Enrichment for Histone H3 Lysine 9 Methylation at Alu Repeats in Human Cells*

  2003cited by this paper
• Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia

  2002cited by this paper
• The molecular basis of familial hypercholesterolemia in The Netherlands

  2001cited by this paper
• The Metabolic and Molecular Bases of Inherited Disease

  2001cited by this paper
• Large rearrangements of the LDL receptor gene and lipid profile in a FH Spanish population

  2001cited by this paper
• Homologous and Nonhomologous Recombination Resulting in Deletion: Effects of p53 Status, Microhomology, and Repetitive DNA Length and Orientation

  2000cited by this paper
• Potential gene conversion and source genes for recently integrated Alu elements.

  2000cited by this paper
• Alu repeats and human disease.

  1999influential reference
• Alu sequences

  1997cited by this paper
• Two novel partial deletions of LDL-receptor gene in Italian patients with familial hypercholesterolemia (FH Siracusa and FH Reggio Emilia).

  1996cited by this paper
• Four novel partial deletions of LDL-receptor gene in Italian patients with familial hypercholesterolemia.

  1995cited by this paper
• RNA polymerase III. Genes, factors and transcriptional specificity.

  1993cited by this paper
• Molecular genetics of the LDL receptor gene in familial hypercholesterolemia

  1992cited by this paper
• Evolution of the master Alu gene(s)

  1991cited by this paper
• Characterization of three mutations of the low density lipoprotein receptor gene in Italian patients with familial hypercholesterolemia.

  1991cited by this paper
• The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.

  1990cited by this paper
• Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

  1989cited by this paper
• Association between a specific apo B mutation and familial defective apoB100

  1989cited by this paper
• Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding.

  1987cited by this paper
• Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.

  1987cited by this paper
• Clustering and subfamily relationships of the Alu family in the human genome.

  1987cited by this paper
• Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia.

  1986cited by this paper
• Nonviral retroposons: genes, pseudogenes, and transposable elements generated by the reverse flow of genetic information.

  1986cited by this paper
• Polymorphism and evolution of Alu sequences in the human low density lipoprotein receptor gene.

  1985cited by this paper
• Analysis of transcription of the human Alu family ubiquitous repeating element by eukaryotic RNA polymerase III.

  1981cited by this paper
• Bmc Medical Genetics

  year unknowncited by this paper

• A nationwide genetic and phenotypic spectrum of 63 probands of homozygous familial hypercholesterolemia in Taiwan.

  2026cites this paper
• The analysis of the breakpoint of large rearrangements of LDLR gene in a Taiwanese cohort of patients with familial hypercholesterolemia.

  2025cites this paper
• Oxford Nanopore long-read sequencing with CRISPR/Cas9-mediated target selection for accurate characterization of copy number variants in the LDLR gene.

  2025cites this paper
• Copy number variations: The potential association genetic cause in severe cardiovascular diseases with unknown aetiology

  2024cites this paper
• LDLR gene rearrangements in Czech FH patients likely arise from one mutational event

  2024influential citation
• Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family

  2023cites this paper
• Reducing Premature Coronary Artery Disease in Malaysia by Early Identification of Familial Hypercholesterolemia Using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT): Protocol for a Mixed Methods Evaluation Study

  2023cites this paper
• Calling and Phasing of Single-Nucleotide and Structural Variants of the LDLR Gene Using Oxford Nanopore MinION

  2023cites this paper
• Research Progress in the Clinical Treatment of Familial Hypercholesterolemia.

  2023cites this paper
• Identification of a novel large duplication (exon2_6dup): copy number variation in the LDLR gene in a large family with familial hypercholesterolemia by whole-genome sequencing.

  2022cites this paper
• Identification of New Copy Number Variation and the Evaluation of a CNV Detection Tool for NGS Panel Data in Polish Familial Hypercholesterolemia Patients

  2022cites this paper
• Mutational Spectrum of LDLR and PCSK9 Genes Identified in Iranian Patients With Premature Coronary Artery Disease and Familial Hypercholesterolemia

  2021cites this paper
• Whole genome sequence analysis of blood lipid levels in >66,000 individuals

  2021cites this paper
• Genetics, Screening, and Treatment of Familial Hypercholesterolemia: Experience Gained From the Implementation of the Vietnam Familial Hypercholesterolemia Registry

  2020cites this paper
• Integrated identification of key genes and pathways in Alzheimer’s disease via comprehensive bioinformatical analyses

  2019cites this paper
• Human Genomic Variants and Inherited Disease

  2019cites this paper
• Role of DNA copy number variation in dyslipidemias

  2018cites this paper
• Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia

  2018cites this paper
• Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel.

  2018cites this paper
• New Findings in the Molecular and Clinical Diagnosis of Familial Hypercholesterolemiaerolemia

  2018cites this paper
• Molecular genetic background of an autosomal dominant hypercholesterolemia in the Czech Republic.

  2017cites this paper
• Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia[S]

  2017cites this paper
• Low-density lipoprotein receptor mutational analysis in diagnosis of familial hypercholesterolemia

  2017cites this paper
• Proprotein convertase subtilisin/kexin 9 V4I variant with LDLR mutations modifies the phenotype of familial hypercholesterolemia.

  2016cites this paper
• Lipid levels in HIV-positive men receiving anti-retroviral therapy are not associated with copy number variation of reverse cholesterol transport pathway genes

  2015cites this paper
• Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

  2015cites this paper
• Structural genetic variation and dyslipidemia among men in the Multicenter AIDS Cohort Study

  2014cites this paper
• Examining Selective Pressures Shaping Retrotransposon Distribution Within Genes

  2014cites this paper
• Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia[S]

  2014cites this paper
• Human gene mutation in inherited disease: Molecular mechanisms and clinical consequences

  2013cites this paper
• Duplication of exon 7-12 in the low-density lipoprotein receptor gene in three Danish patients with familial hypercholesterolemia.

  2013cites this paper
• Genomic characterization of two deletions in the LDLR gene in Tunisian patients with familial hypercholesterolemia.

  2012cites this paper
• Inherited and de novo 22q11.2 distal duplications in two patients with autistic features, speech delay and no dysmorphology

  2012cites this paper
• The logarithm of the triglyceride/HDL-cholesterol ratio is related to the history of cardiovascular disease in patients with familial hypercholesterolemia.

  2012cites this paper
• Alu Mobile Elements: From Junk DNA to Genomic Gems

  2012cites this paper
• Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia: a systematic review and economic evaluation.

  2012cites this paper
• Cardio-ankle vascular index in heterozygous familial hypercholesterolemia.

  2012cites this paper
• The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.

  2012cites this paper
• Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution

  2011cites this paper
• On the sequence‐directed nature of human gene mutation: The role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease

  2011cites this paper
• Reducing Premature Coronary Artery Disease in Malaysia by Early Identification of Familial Hypercholesterolemia Using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT): Protocol for a Mixed Methods Evaluation Study

  year unknowncites this paper