Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy.

Akl C Fahed,Fadi F Bitar,Ruby Khalaf,Raya Safa,Rabih R Andary,Rony Salloum,Georges Nemer,Inaam El‐Rassy,Elie Moubarak,Sami T Azar

doi:10.1002/mgg3.203

Abstract

BackgroundThe familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low‐density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype.MethodsWe used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR‐associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype‐phenotype correlation in our previous screening.ResultsWe showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLR and LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes.ConclusionThe p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.

Highlights

Familial hypercholesterolemia (FH) (MIM#143890) is an inherited disorder caused by a defect that impairs the normal uptake in the liver of low-density lipoprotein cholesterol (LDL-C) from the blood (Khachadurian 1964; Pullinger et al 2003; Soutar and Naoumova 2007; Kolovou et al 2011)
We previously reported major findings from this database based on sequencing of lowdensity lipoprotein cholesterol receptor (LDLR), proprotein convertase subtilin/kexin 9 (PCSK9), and APOB on 80 patients, and we noted that 27.5% of patients belonging to four families did not have a genetic explanation for the phenotype
Twenty-one families carried mutations in LDLR gene and whose phenotype was explained by these mutations

Summary

Methods

We used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR-associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype-phenotype correlation in our previous screening

Results

Introduction

Methodology

Discussion