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Article: Evaluating High‐Confidence Genes in Conotruncal Cardiac Defects by Gene Burden Analyses

TitleEvaluating High‐Confidence Genes in Conotruncal Cardiac Defects by Gene Burden Analyses
Authors
Keywordscardiac defects
congenital heart disease
conotruncal
gene burden
genetic testing
Issue Date21-Feb-2023
PublisherAmerican Heart Association
Citation
Journal of the American Heart Association Cardiovascular and Cerebrovascular Disease, 2023, v. 12, n. 4 How to Cite?
Abstract

BackgroundIn nonsyndromic conotruncal cardiac defects, the use of next-generation sequencing for clinical diagnosis is increasingly adopted, but gene-disease associations in research are only partially translated to diagnostic panels, suggesting a need for evidence-based consensus. Methods and ResultsIn an exome data set of 245 patients with conotruncal cardiac defects, we performed burden analysis on a high-confidence congenital heart disease gene list (n=132) with rare (<0.01%) and ultrarare (absent in the Genome Aggregation Database) protein-altering variants. Overall, we confirmed an excess of rare variants compared with ethnicity-matched controls and identified 2 known genes (GATA6, NOTCH1) and 4 candidate genes supported by the literature (ANKRD11, DOCK6, NPHP4, and STRA6). Ultrarare variant analysis was performed in combination with 3 other published studies (n=1451) and identified 3 genes (FLT4, NOTCH1, TBX1) to be significant, whereas a subgroup analysis involving 391 Chinese subjects identified only GATA6 as significant. ConclusionsWe suggest that these significant genes in our rare and ultrarare burden analyses warrant prioritization for clinical testing implied for rare inherited and de novo variants. Additionally, associations on ClinVar for these genes were predominantly variants of uncertain significance. Therefore, a more stringent assessment of gene-disease associations in a larger and ethnically diverse cohort is required to be prudent for future curation of conotruncal cardiac defect genes.


Persistent Identifierhttp://hdl.handle.net/10722/337095
ISSN
2023 Impact Factor: 5.0
2023 SCImago Journal Rankings: 2.126
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChui, MMC-
dc.contributor.authorMak, CCY-
dc.contributor.authorYu, MHC-
dc.contributor.authorWong, SYY-
dc.contributor.authorLun, KS-
dc.contributor.authorYung, TC-
dc.contributor.authorKwong, AKY-
dc.contributor.authorChow, PC-
dc.contributor.authorChung, BHY-
dc.date.accessioned2024-03-11T10:18:04Z-
dc.date.available2024-03-11T10:18:04Z-
dc.date.issued2023-02-21-
dc.identifier.citationJournal of the American Heart Association Cardiovascular and Cerebrovascular Disease, 2023, v. 12, n. 4-
dc.identifier.issn2047-9980-
dc.identifier.urihttp://hdl.handle.net/10722/337095-
dc.description.abstract<p> BackgroundIn nonsyndromic conotruncal cardiac defects, the use of next-generation sequencing for clinical diagnosis is increasingly adopted, but gene-disease associations in research are only partially translated to diagnostic panels, suggesting a need for evidence-based consensus. Methods and ResultsIn an exome data set of 245 patients with conotruncal cardiac defects, we performed burden analysis on a high-confidence congenital heart disease gene list (n=132) with rare (<0.01%) and ultrarare (absent in the Genome Aggregation Database) protein-altering variants. Overall, we confirmed an excess of rare variants compared with ethnicity-matched controls and identified 2 known genes (GATA6, NOTCH1) and 4 candidate genes supported by the literature (ANKRD11, DOCK6, NPHP4, and STRA6). Ultrarare variant analysis was performed in combination with 3 other published studies (n=1451) and identified 3 genes (FLT4, NOTCH1, TBX1) to be significant, whereas a subgroup analysis involving 391 Chinese subjects identified only GATA6 as significant. ConclusionsWe suggest that these significant genes in our rare and ultrarare burden analyses warrant prioritization for clinical testing implied for rare inherited and de novo variants. Additionally, associations on ClinVar for these genes were predominantly variants of uncertain significance. Therefore, a more stringent assessment of gene-disease associations in a larger and ethnically diverse cohort is required to be prudent for future curation of conotruncal cardiac defect genes. <br></p>-
dc.languageeng-
dc.publisherAmerican Heart Association-
dc.relation.ispartofJournal of the American Heart Association Cardiovascular and Cerebrovascular Disease-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectcardiac defects-
dc.subjectcongenital heart disease-
dc.subjectconotruncal-
dc.subjectgene burden-
dc.subjectgenetic testing-
dc.titleEvaluating High‐Confidence Genes in Conotruncal Cardiac Defects by Gene Burden Analyses-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1161/JAHA.122.028226-
dc.identifier.scopuseid_2-s2.0-85148479235-
dc.identifier.volume12-
dc.identifier.issue4-
dc.identifier.eissn2047-9980-
dc.identifier.isiWOS:000941478800015-
dc.identifier.issnl2047-9980-

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