Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by high blood-cholesterol levels mostly caused by mutations in the low-density lipoprotein receptor (LDLr). With a prevalence as high as 1/200 in some populations, genetic screening for pathogenic LDLr mutations is a cost-effective approach in families classified as ‘definite’ or ‘probable’ FH and can help to early diagnosis. However, with over 2000 LDLr variants identified, distinguishing pathogenic mutations from benign mutations is a long-standing challenge in the field. In 1998, the World Health Organization (WHO) highlighted the importance of improving the diagnosis and prognosis of FH patients thus, identifying LDLr pathogenic variants is a longstanding challenge to provide an accurate genetic diagnosis and personalized treatments. In recent years, accessible methodologies have been developed to assess LDLr activity in vitro, providing experimental reproducibility between laboratories all over the world that ensures rigorous analysis of all functional studies. In this review we present a broad spectrum of functionally characterized missense LDLr variants identified in patients with FH, which is mandatory for a definite diagnosis of FH.
Highlights
Familial hypercholesterolemia (FH) DiagnosisThere are neither conclusive clinical criteria for the diagnosis of FH nor standardized processes for phenotypic diagnosis [10]
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by high blood-cholesterol levels mostly caused by mutations in the low-density lipoprotein receptor (LDLr)
In this review we present a broad spectrum of functionally characterized missense LDLr variants identified in patients with FH, which is mandatory for a definite diagnosis of FH
Summary
There are neither conclusive clinical criteria for the diagnosis of FH nor standardized processes for phenotypic diagnosis [10]. Correctly interpreting the clinical significance of LDLr variants continues to be a constant challenge for molecular diagnostic practice and clinical diagnosis can only be confirmed when a mutation is functionally characterized and proven to affect LDL metabolism. LDLr variants can be grouped into 2 categories: truncating and nontruncating variants Truncating variants such as nonsense variants, out-of-frame indels, most splicing variants, and partial gene deletions are known to have a deleterious effect on the function of the LDLr protein and are considered to be pathogenic variants without the need of functional characterization [19]. The procedure for functional validation has become widespread because new and cost-effective methodologies allow evaluation of these nontruncating variants through radioactive assays and fluorescence-based approaches. Functional validation of these variants can be performed both ex vivo and in vitro by using fluorescently labelled -antibodies or -LDL to determine LDLr activity in heterologous cell models to directly demonstrate disease causality
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