TY - JOUR
T1 - Whole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes
AU - Blue, Gillian M.
AU - Mekel, Mauk
AU - Das, Debjani
AU - Troup, Michael
AU - Rath, Emma
AU - Ip, Eddie
AU - Gudkov, Mikhail
AU - Perumal, Gopinath
AU - Harvey, Richard P.
AU - Sholler, Gary F.
AU - Gecz, Jozef
AU - Kirk, Edwin P.
AU - Liu, Jinfen
AU - Giannoulatou, Eleni
AU - Hong, Haifa
AU - Dunwoodie, Sally L.
AU - Winlaw, David S.
N1 - Funding Information:
This work is supported by a HeartKids Grant-in-Aid (2018). The MGRB was funded by the NSW State Government. GMB is supported by a National Heart Foundation Postdoctoral Fellowship (101894). EG is supported by a NSW Health Early-Mid Career Fellowship, a National Heart Foundation Future Leader Fellowship (101204). SLD is the recipient of a National Health and Medical Research Council (NHMRC) Project Grant ID1102373, Principal Research Fellowship ID1135886, and NHMRC Synergy Grant ID1181325, and a NSW Health Cardiovascular Research Capacity Program Senior Scientist Grant. RPH has a National Health and Medical Research Council Australia Fellowship (573705), a Senior Principal Research Fellowship (APP1118576), and is supported by funds from the National Heart Foundation of Australia and HeartKids Australia (G11S5629), the Australian Research Council (ARC) Special Research Initiative into Stem Cell Science (CT0094B; SR110001002), the New South Wales (NSW) Government Ministry of Health (Cardiovascular Disease Senior Scientist Grant; 20:20 campaign) and the NSW Cardiovascular Research Network (LM373). JG is supported by NHMRC Senior Principal Research Fellowship (APP1155224).
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85119045852&partnerID=8YFLogxK
U2 - 10.1016/j.ahj.2021.10.185
DO - 10.1016/j.ahj.2021.10.185
M3 - Article
C2 - 34670123
AN - SCOPUS:85119045852
SN - 0002-8703
VL - 244
SP - 1
EP - 13
JO - American Heart Journal
JF - American Heart Journal
ER -