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

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 f...

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Autores principales: Kamar, Amina, Khalil, Athar, Nemer, Georges
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844333/
https://www.ncbi.nlm.nih.gov/pubmed/33519890
http://dx.doi.org/10.3389/fgene.2020.572045
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author Kamar, Amina
Khalil, Athar
Nemer, Georges
author_facet Kamar, Amina
Khalil, Athar
Nemer, Georges
author_sort Kamar, Amina
collection PubMed
description 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.
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spelling pubmed-78443332021-01-30 The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease Kamar, Amina Khalil, Athar Nemer, Georges Front Genet Genetics 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. Frontiers Media S.A. 2021-01-15 /pmc/articles/PMC7844333/ /pubmed/33519890 http://dx.doi.org/10.3389/fgene.2020.572045 Text en Copyright © 2021 Kamar, Khalil and Nemer. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Kamar, Amina
Khalil, Athar
Nemer, Georges
The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
title The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
title_full The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
title_fullStr The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
title_full_unstemmed The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
title_short The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
title_sort digenic causality in familial hypercholesterolemia: revising the genotype–phenotype correlations of the disease
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844333/
https://www.ncbi.nlm.nih.gov/pubmed/33519890
http://dx.doi.org/10.3389/fgene.2020.572045
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