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Whole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes: WGS in transposition of the great arteries

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dc.contributor.authorBlue, G.M.
dc.contributor.authorMekel, M.
dc.contributor.authorDas, D.
dc.contributor.authorTroup, M.
dc.contributor.authorRath, E.
dc.contributor.authorIp, E.
dc.contributor.authorGudkov, M.
dc.contributor.authorPerumal, G.
dc.contributor.authorHarvey, R.P.
dc.contributor.authorSholler, G.F.
dc.contributor.authorGecz, J.
dc.contributor.authorKirk, E.P.
dc.contributor.authorLiu, J.
dc.contributor.authorGiannoulatou, E.
dc.contributor.authorHong, H.
dc.contributor.authorDunwoodie, S.L.
dc.contributor.authorWinlaw, D.S.
dc.date.issued2022
dc.description.abstractBackground: The most common cyanotic congenital heart disease (CHD) requiring management as a neonate is transposition of great arteries (TGA). Clinically, up to 50% of TGA patients develop some form of neurodevelopmental disability (NDD), thought to have a significant genetic component. A “ciliopathy” and links with laterality disorders have been proposed. This first report of whole genome sequencing in TGA, sought to identify clinically relevant variants contributing to heart, brain and laterality defects. Methods: Initial whole genome sequencing analyses on 100 TGA patients focussed on established disease genes related to CHD (n = 107), NDD (n = 659) and heterotaxy (n = 74). Single variant as well as copy number variant analyses were conducted. Variant pathogenicity was assessed using the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. Results: Fifty-five putatively damaging variants were identified in established disease genes associated with CHD, NDD and heterotaxy; however, no clinically relevant variants could be attributed to disease. Notably, case-control analyses identified significantly more predicted-damaging, silent and total variants in TGA cases than healthy controls in established CHD genes ( P < .001), NDD genes ( P < .001) as well as across the three gene panels ( P < .001). Conclusion: We present compelling evidence that the majority of TGA is not caused by monogenic rare variants and is most likely oligogenic and/or polygenic in nature, highlighting the complex genetic architecture and multifactorial influences on this CHD sub-type and its long-term sequelae. Assessment of variant burden in key heart, brain and/or laterality genes may be required to unravel the genetic contributions to TGA and related disabilities. (Am Heart J 2022;244:1–13.)
dc.description.statementofresponsibilityGillian M. Blue, Mauk Mekel, Debjani Das, Michael Troup, Emma Rath, Eddie Ip, Mikhail Gudkov, Gopinath Perumal, FRCS, Cth, Richard P. Harvey, Gary F. Sholler, Jozef Gecz, Edwin P. Kirk, Jinfen Liu, Eleni Giannoulatou, Haifa Hong, Sally L. Dunwoodie, and David S. Winlaw
dc.identifier.citationAmerican Heart Journal, 2022; 244:1-13
dc.identifier.doi10.1016/j.ahj.2021.10.185
dc.identifier.issn0002-8703
dc.identifier.issn1097-6744
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttps://hdl.handle.net/2440/146082
dc.language.isoen
dc.publisherElsevier
dc.rights© 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
dc.source.urihttps://doi.org/10.1016/j.ahj.2021.10.185
dc.subjectclinical application/patient care; pathogenic variants; polygenic/complex inheritance; transposition of the great arteries; whole genome sequencing
dc.subject.meshArteries
dc.subject.meshBrain
dc.subject.meshHumans
dc.subject.meshHeart Defects, Congenital
dc.subject.meshTransposition of Great Vessels
dc.subject.meshInfant, Newborn
dc.subject.meshWhole Genome Sequencing
dc.titleWhole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes: WGS in transposition of the great arteries
dc.typeJournal article
pubs.publication-statusPublished online

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