The genetic architecture of pediatric cardiomyopathy

dc.contributor.authorWare, Stephanie M.
dc.contributor.authorBhatnagar, Surbhi
dc.contributor.authorDexheimer, Phillip J.
dc.contributor.authorWilkinson, James D.
dc.contributor.authorSridhar, Arthi
dc.contributor.authorFan, Xiao
dc.contributor.authorShen, Yufeng
dc.contributor.authorTariq, Muhammad
dc.contributor.authorSchubert, Jeffrey A.
dc.contributor.authorColan, Steven D.
dc.contributor.authorShi, Ling
dc.contributor.authorCanter, Charles E.
dc.contributor.authorHsu, Daphne T.
dc.contributor.authorBansal, Neha
dc.contributor.authorWebber, Steven A.
dc.contributor.authorEveritt, Melanie D.
dc.contributor.authorKantor, Paul F.
dc.contributor.authorRossano, Joseph W.
dc.contributor.authorPahl, Elfriede
dc.contributor.authorRusconi, Paolo
dc.contributor.authorLee, Teresa M.
dc.contributor.authorTowbin, Jeffrey A.
dc.contributor.authorLal, Ashwin K.
dc.contributor.authorChung, Wendy K.
dc.contributor.authorMiller, Erin M.
dc.contributor.authorAronow, Bruce
dc.contributor.authorMartin, Lisa J.
dc.contributor.authorLipshultz, Steven E.
dc.contributor.authorPediatric Cardiomyopathy Registry Study Group
dc.contributor.departmentPediatrics, School of Medicine
dc.date.accessioned2023-08-03T15:38:53Z
dc.date.available2023-08-03T15:38:53Z
dc.date.issued2022
dc.description.abstractTo understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.
dc.eprint.versionFinal published version
dc.identifier.citationWare SM, Bhatnagar S, Dexheimer PJ, et al. The genetic architecture of pediatric cardiomyopathy. Am J Hum Genet. 2022;109(2):282-298. doi:10.1016/j.ajhg.2021.12.006
dc.identifier.urihttps://hdl.handle.net/1805/34720
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.ajhg.2021.12.006
dc.relation.journalAmerican Society of Human Genetics
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectExome
dc.subjectHeart
dc.subjectMolecular diagnosis
dc.subjectClinical interpretation
dc.subjectBioinformatics
dc.subjectVariant
dc.subjectInfant
dc.subjectAncestry
dc.titleThe genetic architecture of pediatric cardiomyopathy
dc.typeArticle
ul.alternative.fulltexthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8874151/
Files
Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
main.pdf
Size:
3.38 MB
Format:
Adobe Portable Document Format
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.99 KB
Format:
Item-specific license agreed upon to submission
Description: