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Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia

Introduction: Familial hypercholesterolaemia (FH) is a common autosomal dominant genetic condition, characterised by elevated LDL cholesterol (LDL-C), leading to premature cardiovascular disease (CVD). Early and accurate diagnosis, with implementation of preventative therapies, has a major impact on...

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Autores principales: Neves, Emma, Khan, Tina, Williams, Maggie, Carrera, Marta, Banya, Winston, Brugada, Ramon, Ferrer, Carles, Morris-Rosendahl, Deborah J, Barbir, Mahmoud
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Magdi Yacoub Heart Foundation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491391/
https://www.ncbi.nlm.nih.gov/pubmed/36185161
http://dx.doi.org/10.21542/gcsp.2021.31
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author Neves, Emma
Khan, Tina
Williams, Maggie
Carrera, Marta
Banya, Winston
Brugada, Ramon
Ferrer, Carles
Morris-Rosendahl, Deborah J
Barbir, Mahmoud
author_facet Neves, Emma
Khan, Tina
Williams, Maggie
Carrera, Marta
Banya, Winston
Brugada, Ramon
Ferrer, Carles
Morris-Rosendahl, Deborah J
Barbir, Mahmoud
author_sort Neves, Emma
collection PubMed
description Introduction: Familial hypercholesterolaemia (FH) is a common autosomal dominant genetic condition, characterised by elevated LDL cholesterol (LDL-C), leading to premature cardiovascular disease (CVD). Early and accurate diagnosis, with implementation of preventative therapies, has a major impact on reducing premature CVD, morbidity and mortality. Genetic testing is recommended to confirm clinical diagnosis in the proband and enable cascade testing in relatives. There is growing evidence that the risk of CVD conferred by hypercholesterolaemia depends not only on monogenic causes but also on polygenic factors. GENinCode has developed a novel genomic testing system (Lipid inCode(®)) which we have assessed against an accredited National Health Service (NHS UK) genetic screening service in order to validate its diagnostic and clinical utility. Methods: DNA samples from 40 index cases who had been referred for FH testing in an ISO15189-accredited NHS genetic screening service, were retrospectively tested using the Lipid inCode(®) assay. The results were compared with those from NHS testing. Results: There was absolute concordance in variant detection between both diagnostic tests for monogenic and polygenic FH, the only difference being in the interpretation and classification of DNA variants based on ACMG guidelines, which did not differ by more than one classification class.  The Lipid inCode(®) test was equivalent to the NHS test in providing comprehensive genetic analysis that included the assessment of both monogenic (FH) and polygenic determinants of blood cholesterol and including a pharmacogenomic assessment of predisposition to statin-related myopathy. Conclusion: The Lipid inCode(®) diagnostic test can be undertaken with rapid turnaround and gave the same results as those reported by standard NHS genetic laboratory testing. In addition to assessment of monogenic FH, the Lipid inCode(®) assay provides additional genetic data, such as polygenic factors contributing to hypercholesterolaemia, a polygenic risk score (PRS) for coronary artery disease (CAD), pharmacogenomic testing for statin myopathy, and genetic predisposition to raised Lp(a).
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spelling pubmed-94913912022-09-29 Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia Neves, Emma Khan, Tina Williams, Maggie Carrera, Marta Banya, Winston Brugada, Ramon Ferrer, Carles Morris-Rosendahl, Deborah J Barbir, Mahmoud Glob Cardiol Sci Pract Research Article Introduction: Familial hypercholesterolaemia (FH) is a common autosomal dominant genetic condition, characterised by elevated LDL cholesterol (LDL-C), leading to premature cardiovascular disease (CVD). Early and accurate diagnosis, with implementation of preventative therapies, has a major impact on reducing premature CVD, morbidity and mortality. Genetic testing is recommended to confirm clinical diagnosis in the proband and enable cascade testing in relatives. There is growing evidence that the risk of CVD conferred by hypercholesterolaemia depends not only on monogenic causes but also on polygenic factors. GENinCode has developed a novel genomic testing system (Lipid inCode(®)) which we have assessed against an accredited National Health Service (NHS UK) genetic screening service in order to validate its diagnostic and clinical utility. Methods: DNA samples from 40 index cases who had been referred for FH testing in an ISO15189-accredited NHS genetic screening service, were retrospectively tested using the Lipid inCode(®) assay. The results were compared with those from NHS testing. Results: There was absolute concordance in variant detection between both diagnostic tests for monogenic and polygenic FH, the only difference being in the interpretation and classification of DNA variants based on ACMG guidelines, which did not differ by more than one classification class.  The Lipid inCode(®) test was equivalent to the NHS test in providing comprehensive genetic analysis that included the assessment of both monogenic (FH) and polygenic determinants of blood cholesterol and including a pharmacogenomic assessment of predisposition to statin-related myopathy. Conclusion: The Lipid inCode(®) diagnostic test can be undertaken with rapid turnaround and gave the same results as those reported by standard NHS genetic laboratory testing. In addition to assessment of monogenic FH, the Lipid inCode(®) assay provides additional genetic data, such as polygenic factors contributing to hypercholesterolaemia, a polygenic risk score (PRS) for coronary artery disease (CAD), pharmacogenomic testing for statin myopathy, and genetic predisposition to raised Lp(a). Magdi Yacoub Heart Foundation 2021-12-31 /pmc/articles/PMC9491391/ /pubmed/36185161 http://dx.doi.org/10.21542/gcsp.2021.31 Text en Copyright ©2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Neves, Emma
Khan, Tina
Williams, Maggie
Carrera, Marta
Banya, Winston
Brugada, Ramon
Ferrer, Carles
Morris-Rosendahl, Deborah J
Barbir, Mahmoud
Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia
title Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia
title_full Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia
title_fullStr Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia
title_full_unstemmed Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia
title_short Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia
title_sort evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491391/
https://www.ncbi.nlm.nih.gov/pubmed/36185161
http://dx.doi.org/10.21542/gcsp.2021.31
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