The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
<div><p>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 domi...
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| مؤلفون آخرون: | , |
| منشور في: |
2021
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| _version_ | 1864513515284332544 |
|---|---|
| author | Amina Kamar (295977) |
| author2 | Athar Khalil (5906330) Georges Nemer (295984) |
| author2_role | author author |
| author_facet | Amina Kamar (295977) Athar Khalil (5906330) Georges Nemer (295984) |
| author_role | author |
| dc.creator.none.fl_str_mv | Amina Kamar (295977) Athar Khalil (5906330) Georges Nemer (295984) |
| dc.date.none.fl_str_mv | 2021-01-15T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3389/fgene.2020.572045 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/The_Digenic_Causality_in_Familial_Hypercholesterolemia_Revising_the_Genotype_Phenotype_Correlations_of_the_Disease/25878289 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics digenic familial hypercholesterolemia LDLR PCSK9 APOB LDLRAP1 |
| dc.title.none.fl_str_mv | The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><p>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.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Frontiers in Genetics<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3389/fgene.2020.572045" target="_blank">https://dx.doi.org/10.3389/fgene.2020.572045</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_04dd64375acfe1d12543c83b91caea3f |
| identifier_str_mv | 10.3389/fgene.2020.572045 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25878289 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the DiseaseAmina Kamar (295977)Athar Khalil (5906330)Georges Nemer (295984)Biological sciencesGeneticsdigenicfamilial hypercholesterolemiaLDLRPCSK9APOBLDLRAP1<div><p>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.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Frontiers in Genetics<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3389/fgene.2020.572045" target="_blank">https://dx.doi.org/10.3389/fgene.2020.572045</a></p>2021-01-15T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3389/fgene.2020.572045https://figshare.com/articles/journal_contribution/The_Digenic_Causality_in_Familial_Hypercholesterolemia_Revising_the_Genotype_Phenotype_Correlations_of_the_Disease/25878289CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/258782892021-01-15T03:00:00Z |
| spellingShingle | The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease Amina Kamar (295977) Biological sciences Genetics digenic familial hypercholesterolemia LDLR PCSK9 APOB LDLRAP1 |
| status_str | publishedVersion |
| 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 | The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease |
| topic | Biological sciences Genetics digenic familial hypercholesterolemia LDLR PCSK9 APOB LDLRAP1 |