Efficacy of clinical diagnostic criteria for familial hypercholesterolemia genetic testing in Poland

Mickiewicz, Agnieszka; Chmara, Magdalena; Futema, Marta; Fijałkowski, Marcin; Chlebus, Krzysztof; Gałąska, Rafał; Bandurski, Tomasz; Pajkowski, Marcin; Żuk, Monika; Wasąg, Bartosz; Limon, Janusz; Rynkiewicz, Andrzej; Gruchała, Marcin

doi:10.1016/j.atherosclerosis.2016.03.025

Cited by 20 publications

(16 citation statements)

References 24 publications

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“…Silva et al [ 23 ] tested six FH-related genes in patients with LDL-C level above or equal to 5.4 mmol/L in Brazil and found that the LDL-C ≥ 5.96 mmol/L cutoff was identified as the best value in the age groups ≤ 40 years. Using molecular techniques for LDLR and APOB , Mickiewicz et al [ 12 ] demonstrated that LDL-C thresholds for FH were 5.79 mmol/L in individuals aged < 40 with baseline LDL-C level ≥ 4.9 mmol/L. In present study, 4.56 mmol/L had the best tradeoff between sensitivity and specificity to diagnose a FH genetically confirmed mutation.…”

Section: Discussionmentioning

confidence: 48%

“…Previous studies showed that maximal coronary flow and flow reserve were significantly lower in young patients with FH than in matched healthy control participants, which supported the concept that the abnormal serum lipid profile is associated with abnormal coronary flow response [ 15 , 16 ]. Clinically, compared to hypercholesterolemic patients aged ≥ 40 years, a twofold higher FH mutation detection rate was found in individuals aged < 40 years [ 12 ]. Moreover, people younger than 35 years are in reproductive age and early detection of FH may be beneficial to reproductive options [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recent data reported that phenotypic diagnosis of FH was relatively common in these high-risk patients [ 11 ]. Genetic testing showed that hypercholesterolemic individuals aged < 40 years were more likely to carry an FH-causing mutation than individuals ≥ 40 years [ 12 ]. All these data suggested that genetic testing should be made to detect FH in patients with very early-onset CAD and to initiate statin therapy to prevent the development of CAD.…”

Section: Introductionmentioning

confidence: 99%

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Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease

Cao

Sun

et al. 2018

J Transl Med

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BackgroundPatients with monogenic familial hypercholesterolemia (FH) have high risk for coronary artery disease (CAD). A recent FH Expert Panel suggested that FH was underdiagnosed and undertreated which needs early diagnosis. Moreover, the proportion of DNA-confirmed FH patients hospitalized with very early-onset (≤ 35 years) CAD remains uncertain.MethodsOne hundred and five patients with age ≤ 35 years and LDL-C ≥ 3.4 mmol/L were tested for 9 genes (LDLR, APOB, PCSK9, APOE, STAP1, LIPA, LDLRAP1, ABCG5/8). Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) criteria for FH were also performed.ResultsThe prevalence of genetically confirmed FH was 38.1% (n = 40) in 105 patients. DLCN categorized 26.7% patients to probable and definite FH while SB identified 17.1% of patients with possible to definite FH. Twenty-five (62.5%) and seventeen (42.5%) patients with pathogenic mutations were undiagnosed according to SB and DLCN criteria. FH variant carriers, especially homozygotes, had significantly higher plasma LDL-C levels. The best LDL-C threshold for genetically confirmed FH was 4.56 mmol/L in the present study.ConclusionsFH is really a common cause for very young CAD patients (≤ 35 years) with a 38.1% of causative mutations in China and best LDL-C threshold for predicting mutations was 4.56 mmol/L. The underdiagnostic rate of clinical criteria was around 42.5–62.5%, suggesting that the expanded genetic testing could indeed promote the diagnosis of FH.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1737-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease

Cao

Sun

et al. 2018

J Transl Med

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“…The primary indication to LA treatment was HeFH with symptomatic CVD and LDL-C concentration of more than 160 mg/dL despite maximally tolerated intensive lipid-lowering medications [14]. Seven female patients with definite FH according to the modified Dutch Lipid Network Criteria and confirmed a mutation in LDLR or APOB gene, fulfilling the criteria of severe FH by the IAS, were enrolled into the study [4,24]. At the initiation of LA treatment, all patients had a history of a documented CVD and at least three additional high risk-features for severe FH.…”

Section: Patientsmentioning

confidence: 99%

Long-term lipoprotein apheresis in the treatment of severe familial hypercholesterolemia refractory to high intensity statin therapy: Three year experience at a lipoprotein apheresis centre

et al. 2020

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Background: Severe familial hypercholesterolemia (FH) individuals, refractory to conventional lipidlowering medications are at exceptionally high risk of cardiovascular events. The established therapeutic option of last choice is lipoprotein apheresis (LA). Herein, it was sought to investigate the clinical usefulness of LA in a highly selected group of severe heterozygous FH (HeFH), as recently described by the International Atherosclerosis Society (IAS), for their efficacy in lipid reduction and safety. Methods: Efficacy and safety of LA were investigated in 318 sessions of 7 severe HeFH females with cardiovascular disease, over a mean period of 26.9 ± 6.5 months. Relative reduction of low density lipoprotein cholesterol (LDL-C) ≥ 60%, clinical complications and vascular access problems were evaluated and compared between the direct adsorption of lipoproteins (DALI) and lipoprotein filtration (Membrane Filtration Optimized Novel Extracorporeal Treatment [MONET]). Additionally, lipoprotein (a) [Lp(a)], total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and fibrinogen concentrations were investigated.

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“…Increasing awareness of the disorder and access to modern DNA sequence facilities contribute to the growing databases of LDLR variants. For instance, in 2016, 31 novel alterations in the LDLR have been reported mainly in the German, Poland and South African populations [16][17][18] Table 2). The majority of the VUS are classified as such because they do not have functional studies and represent 42% of all variants reported to be cause of familial hypercholesterolaemia.…”

Section: Low-density Lipoprotein Receptor Variants Updatementioning

confidence: 99%

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

Bourbon

Alves

Sijbrands

2017

Current Opinion in Lipidology

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Purpose of reviewTo present up to date evidence on the pathogenicity of low-density lipoprotein receptor (LDLR) variants and to propose a strategy that is suitable for implementation in the clinical work-up of familial hypercholesterolaemia. Recent findingsMore than 1800 variants have been described in the LDLR gene of patients with a clinical diagnosis of familial hypercholesterolaemia; however, less than 15% have functional evidence of pathogenicity. SummaryThe spectrum of variants in the LDLR identified in patients with clinical familial hypercholesterolaemia is increasing as novel variants are still being reported. However, over 50% of all LDLR variants need further evidence before they can be confirmed as mutations causing disease. Even with applying the recent American College of Medical Genetics variant classification, a large number of variants are still considered variants of unknown significance. Before obtaining an undisputable confirmation of the effect on the expression and activity of the LDLR, reporting these variants as part of a clinical diagnosis to the patient holds the risk that it might need to be withdrawn in a later stage. An investment should be made to develop functional assays to characterize LDLR variants of unknown significance for a better patient diagnosis and to prevent confusion in the physician's office.

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Efficacy of clinical diagnostic criteria for familial hypercholesterolemia genetic testing in Poland

Cited by 20 publications

References 24 publications

Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease

Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease

Long-term lipoprotein apheresis in the treatment of severe familial hypercholesterolemia refractory to high intensity statin therapy: Three year experience at a lipoprotein apheresis centre

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

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