Spectrum of LDLR gene mutations, including a novel mutation causing familial hypercholesterolaemia, in North-western Greece

Diakou, Maria; Miltiadous, George; Xenophontos, Stavroulla; Manoli, Panayiotis; Cariolou, Marios A.; Elisaf, Moses

doi:10.1016/j.ejim.2011.01.003

Cited by 13 publications

(9 citation statements)

References 46 publications

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“…Not surprisingly, given the geographical and historical location of Croatia, several of the identified mutations have been previously identified in neighbouring countries. The p.(S286R) mutation was described as a disease‐causing Greek mutation (Traeger‐Synodinos et al., ; Diakou et al., ). Two of our subjects, a father (Za11, Table ) and his hyperlipidaemic daughter, carried the mutation.…”

Section: Discussionmentioning

confidence: 99%

Mutation detection in Croatian patients with Familial Hypercholesterolemia

Pećin

Whittall

Futema

et al. 2012

Annals of Human Genetics

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SummaryFamilial hypercholesterolemia (FH) is caused by mutations in the genes for LDLR, APOB or PCSK9, and identification of the causative mutation provides definitive diagnosis so that the patient can be treated, their relatives tested and, therefore, premature heart disease prevented.DNA of eight unrelated individuals with clinically diagnosed FH were analyzed using a High-Resolution Melting method (HRM) for the LDLR gene (coding region, promoter and intron/exon boundaries), the APOB gene (part exon 26) and the PCSK9 gene (exon7). Variations found were sequenced and the effect on function of confirmed variants examined using predictive algorithms. Gross deletions and insertions were analysed using MLPA.Three novel LDLR variants were found, p.(S470C), p.(C698R) and c.2312-2A>C. All were predicted to be pathogenic using predictive algorithms. Three previously reported disease-causing mutations were identified (p.(G20R), p.(N272T) and p.(S286R); the latter was also carried by a hypercholesterolaemic relative. One patient carried the pathogenic APOB variant p.(R3527Q). No large LDLR deletions nor insertions were found, neither were any PCSK9 variants identified.HRM is a sensitive method for screening for mutations. While the causative mutation has been identified in 88% of these clinically defined FH patients, there appears to be a high degree of allelic heterogeneity in Croatian patients.

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Section: Discussionmentioning

confidence: 99%

Mutation detection in Croatian patients with Familial Hypercholesterolemia

Pećin

Whittall

Futema

et al. 2012

Annals of Human Genetics

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“…However, according to the present study, the order of the common mutations is altered and the c.81C > G and 1706-10G > A mutations, which were not previously considered as very frequent mutations 1646G > A (n ¼ 2), and c.81C > G (n ¼ 2), and one patient originating from Cyprus carried the mutation c.1646G > A (data not shown in figure). [23,31], show high frequency. As a second line of analysis, whole gene sequencing will be necessary to characterize the remaining, rare genetic defects.…”

Section: Discussionmentioning

confidence: 94%

Familial Hypercholesterolemia in Greek children and their families: Genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum

Mollaki¹,

Progias²,

Drogari³

2014

Atherosclerosis

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“…Second, the FH phenotype may be explained by mutations in the apoB‐100 or PCSK9 genes. It should be noted however that no mutations have been found in the apoB‐100 (Dedoussis et al., , b) or PCSK9 (Diakou et al., ) genes in FH patients of Greek origin and therefore, analysis of apoB‐100 and PCSK9 is not used in routine diagnosis of FH in Greece. Third, one cannot exclude other, unknown genetic factors that may lead to the FH phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…However, most of these studies screened for the most common mutations, using mainly methods that can identify known mutations. No mutations have been found in apoB‐100 (Dedoussis et al., , b) or PCSK9 (Diakou et al., ) in FH patients of Greek origin, suggesting that the Greek population is genetically homogeneous or that there are other mutations that have not been identified yet. The present study specifically aimed to characterize the newly detected LDLR variants in Greek FH children and their families and assess their pathogenicity by in silico analysis.…”

Section: Introductionmentioning

confidence: 99%

NovelLDLRVariants in Patients with Familial Hypercholesterolemia:In SilicoAnalysis as a Tool to Predict Pathogenic Variants in Children and Their Families

Mollaki

Progias

Drogari

2013

Annals of Human Genetics

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SummaryFamilial hypercholesterolemia (FH) is an autosomal dominant disease with a frequency of 1:500 in its heterozygous form. To date, mutations in the low-density lipoprotein receptor gene (LDLR) are the only identified causes of FH in the Greek population, causing high levels of low-density lipoprotein (LDL) and total cholesterol and premature atherosclerosis. The Greek FH population is genetically homogeneous, but most previous studies screened for the most common mutations only. The study aimed to characterize and assess novel LDLR variants. LDLR was examined by whole-gene DNA sequencing in 561 FH patients from 262 families of Greek origin. Novel LDLR variants were analyzed in silico using various software predicting pathogenicity and changes in protein stability. Twelve novel LDLR variants were identified, six of which are putative disease-causing variants: c.977C>G in exon 7, c.1124A>C in exon 8, c.1381G>T in exon 10, c.628_643dup{636del}, c.661-673dup in exon 4, and 13 c.1987+1_+33del in intron 13. All six putative variants were confirmed in the hypercholesterolemic members of the family. The results show that in silico analysis is a valuable tool to predict potential pathogenicity of novel variants, especially for populations that have not been extensively studied. The identification of novel pathogenic variants will facilitate the molecular diagnosis of FH from early childhood.

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Spectrum of LDLR gene mutations, including a novel mutation causing familial hypercholesterolaemia, in North-western Greece

Cited by 13 publications

References 46 publications

Mutation detection in Croatian patients with Familial Hypercholesterolemia

Mutation detection in Croatian patients with Familial Hypercholesterolemia

Familial Hypercholesterolemia in Greek children and their families: Genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum

NovelLDLRVariants in Patients with Familial Hypercholesterolemia:In SilicoAnalysis as a Tool to Predict Pathogenic Variants in Children and Their Families

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