Manara - Qatar Research Repository
10.3389_fgene.2020.572045.pdf (1.03 MB)

The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease

Download (1.03 MB)
journal contribution
submitted on 2024-05-23, 08:43 and posted on 2024-05-23, 08:43 authored by Amina Kamar, Athar Khalil, Georges Nemer

Genetically inherited defects in lipoprotein metabolism affect more than 10 million individuals around the globe with preponderance in some parts where consanguinity played a major role in establishing founder mutations. Mutations in four genes have been so far linked to the dominant and recessive form of the disease. Those players encode major proteins implicated in cholesterol regulation, namely, the low-density lipoprotein receptor (LDLR) and its associate protein 1 (LDLRAP1), the proprotein convertase substilin/kexin type 9 (PCSK9), and the apolipoprotein B (APOB). Single mutations or compound mutations in one of these genes are enough to account for a spectrum of mild to severe phenotypes. However, recently several reports have identified digenic mutations in familial cases that do not necessarily reflect a much severe phenotype. Yet, data in the literature supporting this notion are still lacking. Herein, we review all the reported cases of digenic mutations focusing on the biological impact of gene dosage and the potential protective effects of single-nucleotide polymorphisms linked to hypolipidemia. We also highlight the difficulty of establishing phenotype–genotype correlations in digenic familial hypercholesterolemia cases due to the complexity and heterogeneity of the phenotypes and the still faulty in silico pathogenicity scoring system. We finally emphasize the importance of having a whole exome/genome sequencing approach for all familial cases of familial hyperlipidemia to better understand the genetic and clinical course of the disease.

Other Information

Published in: Frontiers in Genetics
See article on publisher's website:


Open Access funding provided by the Qatar National Library.



  • English



Publication Year

  • 2021

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU

Usage metrics

    College of Health and Life Sciences - HBKU



    Ref. manager