Cargando…

Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis

OBJECTIVE: This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives. METHODS: A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from...

Descripción completa

Detalles Bibliográficos
Autores principales: Christian, Susan, Cirino, Allison, Hansen, Brittany, Harris, Stephanie, Murad, Andrea M, Natoli, Jaime L, Malinowski, Jennifer, Kelly, Melissa A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987756/
https://www.ncbi.nlm.nih.gov/pubmed/35387861
http://dx.doi.org/10.1136/openhrt-2021-001815
_version_ 1784682811984183296
author Christian, Susan
Cirino, Allison
Hansen, Brittany
Harris, Stephanie
Murad, Andrea M
Natoli, Jaime L
Malinowski, Jennifer
Kelly, Melissa A
author_facet Christian, Susan
Cirino, Allison
Hansen, Brittany
Harris, Stephanie
Murad, Andrea M
Natoli, Jaime L
Malinowski, Jennifer
Kelly, Melissa A
author_sort Christian, Susan
collection PubMed
description OBJECTIVE: This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives. METHODS: A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool. RESULTS: A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003). CONCLUSIONS: This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study.
format Online
Article
Text
id pubmed-8987756
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-89877562022-04-22 Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis Christian, Susan Cirino, Allison Hansen, Brittany Harris, Stephanie Murad, Andrea M Natoli, Jaime L Malinowski, Jennifer Kelly, Melissa A Open Heart Meta-Analysis OBJECTIVE: This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives. METHODS: A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool. RESULTS: A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003). CONCLUSIONS: This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study. BMJ Publishing Group 2022-04-06 /pmc/articles/PMC8987756/ /pubmed/35387861 http://dx.doi.org/10.1136/openhrt-2021-001815 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Meta-Analysis
Christian, Susan
Cirino, Allison
Hansen, Brittany
Harris, Stephanie
Murad, Andrea M
Natoli, Jaime L
Malinowski, Jennifer
Kelly, Melissa A
Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis
title Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis
title_full Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis
title_fullStr Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis
title_full_unstemmed Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis
title_short Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis
title_sort diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis
topic Meta-Analysis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987756/
https://www.ncbi.nlm.nih.gov/pubmed/35387861
http://dx.doi.org/10.1136/openhrt-2021-001815
work_keys_str_mv AT christiansusan diagnosticvalidityandclinicalutilityofgenetictestingforhypertrophiccardiomyopathyasystematicreviewandmetaanalysis
AT cirinoallison diagnosticvalidityandclinicalutilityofgenetictestingforhypertrophiccardiomyopathyasystematicreviewandmetaanalysis
AT hansenbrittany diagnosticvalidityandclinicalutilityofgenetictestingforhypertrophiccardiomyopathyasystematicreviewandmetaanalysis
AT harrisstephanie diagnosticvalidityandclinicalutilityofgenetictestingforhypertrophiccardiomyopathyasystematicreviewandmetaanalysis
AT muradandream diagnosticvalidityandclinicalutilityofgenetictestingforhypertrophiccardiomyopathyasystematicreviewandmetaanalysis
AT natolijaimel diagnosticvalidityandclinicalutilityofgenetictestingforhypertrophiccardiomyopathyasystematicreviewandmetaanalysis
AT malinowskijennifer diagnosticvalidityandclinicalutilityofgenetictestingforhypertrophiccardiomyopathyasystematicreviewandmetaanalysis
AT kellymelissaa diagnosticvalidityandclinicalutilityofgenetictestingforhypertrophiccardiomyopathyasystematicreviewandmetaanalysis