Blue, Gillian M. and Mekel, Mauk and Das, Debjani and Troup, Michael and Rath, Emma and Ip, Eddie and Gudkov, Mikhail and Perumal, Gopinath and Harvey, Richard P. and Sholler, Gary F. and Gecz, Jozef and Kirk, Edwin P. and Liu, Jinfen and Giannoulatou, Eleni and Hong, Haifa and Dunwoodie, Sally L. and Winlaw, David S. (2022) Whole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes. American Heart Journal, 244. pp.1-13. ISSN 00028703
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Abstract
BACKGROUND: 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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 14 Apr 2022 03:11 |
| Last Modified: | 24 Mar 2023 01:44 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1196 |
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