The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia

Benito‐Vicente, Asier; Alves, Ana Catarina; Etxebarria, Aitor; Medeiros, A.M.; Martín, César; Bourbon, Mafalda

doi:10.1038/gim.2015.14

Cited by 37 publications

(32 citation statements)

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“…ac.uk/ldlr/LOVDv.1.1.0) has revealed that only 13% (83/651) of all reported missense, nonsense, and splicing variants have functional studies. The lack of in vitro analysis for the majority of the missense and splicing variants described internationally can lead to FH misdiagnosis 27 and therefore represents a serious problem for FH diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…26 For three synonymous variants, functional studies are reported here for the first time and were proven to be non-pathogenic, and one splicing variant has been recently proven not to be a disease-causing mutation. 27 In APOB, four have been shown to be present in more than 1% of the normolipidemic subjects panel and, for this reason, are considered to be a polymorphism. 7 In PCSK9, one variant has been described as non-pathogenic.…”

Section: Update On Genetic Variantsmentioning

confidence: 99%

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

Medeiros

Alves

Bourbon

2016

Genetics in Medicine

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Purpose: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder of lipid metabolism caused by mutations in LDLR, APOB, and PCSK9. To fulfill the World Health Organization recommendation, the Portuguese FH Study was established. Here, we report the results of the past 15 years and present practical considerations concerning the genetic diagnosis of FH based on our experience. Methods:Our approach comprises a biochemical and molecular study and is divided into five phases, including the study of whole APOB and functional assays.Results: A total of 2,122 individuals were enrolled. A putative pathogenic variant was identified in 660 heterozygous patients: LDLR (623), APOB (33), and PCSK9 (4); 8 patients presented with homozygous FH. A detection rate of 41.5% was observed. A stricter biochemical criteria was shown to improve patient identification. Overall, we have identified 3.4% and 80% of all heterozygous and homozygous patients, respectively, estimated to exist in our country. Conclusion:The Portuguese FH Study has established the genetic diagnosis of FH in Portugal and is committed to continue the investigation of the genetic complexity of FH. Genetic diagnosis of FH should be expanded to include the study of all coding/flanking regions of APOB and functional in vitro studies, to improve the correct patient identification, and to avoid misdiagnosis.

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Section: Discussionmentioning

confidence: 99%

Section: Update On Genetic Variantsmentioning

confidence: 99%

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

Medeiros

Alves

Bourbon

2016

Genetics in Medicine

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“…Since putative splicing variants are suspected to interfere with correct mRNA splicing, it is possible to study a patient's mRNA from lymphocytes to check if one or more transcripts are produced. Several variants have been characterized this way [9,20 && ,26,21…”

Section: Putative Splicing Variantsmentioning

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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“…Beyond the scope of our review, we suggest you refer to the study of Benito-Vicente et al (2015) 70) on the integrated analysis required for familial hypercholesterolemia. In short, in silico analysis 87,88) has failed to accurately predict the pathogenicity of the mutations (overestimating) reported in the FH database 70,89) , leaving researchers struggling to test functionality. As such segregation studies or in-vivo functional analysis 90) are needed with the lipid and molecular profiles of affected and non-affected relatives should be taken into account.…”

Section: Complexities Of Pathogenicitymentioning

confidence: 99%

“…While these cost and time saving measures are imperative for cost effectiveness consideration, they also cast a doubt on regions not studied. Many related studies point out that these measures cause an increasing number of false negative cases, suggesting the need for more comprehensive analysis 5,9,13,14,19,41,[60][61][62][63][64][65][66][67][68][69][70] . In recent years, the landscape of genetic testing of FH has become more precarious in the notion that FH and elevations in LDL are a monogenic disorder.…”

Section: Hybrid Modelmentioning

confidence: 99%

Cascade Screening in Familial Hypercholesterolemia: Advancing Forward

Santos

Frauches

Chacra

2015

J Atheroscler Thromb

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Familial hypercholesterolemia is a genetic disorder associated with elevated LDL-cholesterol and high lifetime cardiovascular risk. Both clinical and molecular cascade screening programs have been implemented to increase early definition and treatment. In this systematic review, we discuss the main issues found in 65 different articles related to cascade screening and familial hypercholesterolemia, covering a range of topics including different types/strategies, considerations both positive and negative regarding cascade screening in general and associated with the different strategies, cost and coverage consideration, direct and indirect contact with patients, public policy around life insurance and doctor -patient confidentiality, the "right to know," and public health concerns regarding familial hypercholesterolemia.J Atheroscler Thromb, 2015; 22: 869-880.

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The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia

Cited by 37 publications

References 37 publications

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

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

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

Cascade Screening in Familial Hypercholesterolemia: Advancing Forward

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