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


RESULTS
More 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.


CONCLUSIONS
The 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LDLR, reporting these variants as part of a clinical diagnosis to the patient holds the risk that it might need to be withdrawn in a later stage.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.
aUnidade de I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge bBioISI - Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal cDepartment of internal Medicine, Erasmus University Rotterdam, Rotterdam, the Netherlands.
Mafalda
M
Bourbon
Ana C
AC
Alves
Eric J
EJ
Sijbrands
D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000235:genetics*; D009154:Mutation
D008077:Lipoproteins, LDL