An insight into genetics of congenital heart defects associated with Down syndrome
Main Article Content
Abstract
Down syndrome is the most frequent live born human aneuploidy. Down syndrome is characterized by a set of phenotypically identified dysmorphism and various congenital malformations of which congenital heart defects is seen in about 50% of all cases. Atrio-ventricular Septal Defect is the most common form of congenital heart defect observed in Down syndrome. However, the exact molecular cause underlying the incidence of congenital heart defects and its differential phenotypic expression in DS are still not perfectly understood. In this review we have brought together findings from different studies and discussed multiple perspectives of the genetics of congenital cardiac defects in trisomy 21 background, viz., the contributions of triplicated dosage of chromosome 21 genes along with the effect of mutations in non- chromosome 21 disomic genes. Further, the roles of copy number variation and microRNAs have been discussed. We have also tried to shed light on the role of folate metabolism gene polymorphisms on congenital cardiac anomalies observed in Down syndrome. Lastly, we summarized the role of genes from different signaling pathways involved in cardiogenesis and also the recent developments in understanding of Down syndrome associated congenital heart defect from the studies on mice models. This review provides an overview regarding current state-of-art of knowledge related to Down syndrome associated congenital heart defects based on what have been discovered so far in this domain and hints at what prospect of research lies in this field in the future.
Keywords:
Down syndrome, genetics of congenital heart defects, heart defects, genetics
Article Details
How to Cite
GANGULY, Agnish et al.
An insight into genetics of congenital heart defects associated with Down syndrome.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3737>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3737.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. What conditions or disorders are commonly associated with Down syndrome? | NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development. https://www.nichd.nih.gov/health/topics/down/conditioninfo/associated. Accessed January 16, 2023.
3. Freeman SB, Bean LH, Allen EG, et al. Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project. Genet Med. 2008;10(3):173-180. doi:10.1097/GIM.0b013e3181634867
4. Morris JK, Garne E, Wellesley D, et al. Major congenital anomalies in babies born with Down syndrome: a EUROCAT population-based registry study. Am J Med Genet A. 2014;164A(12):2979-2986. doi:10.1002/ajmg.a.36780
5. Stoll C, Dott B, Alembik Y, Roth M-P. Associated congenital anomalies among cases with Down syndrome. Eur J Med Genet. 2015;58(12):674-680. doi:10.1016/j.ejmg.2015.11.003
6. Freeman SB, Taft LF, Dooley KJ, et al. Population-based study of congenital heart defects in Down syndrome. Am J Med Genet. 1998;80(3):213-217. doi:10.1002/(SICI)1096-8628(19981116)80:3<213::AID-AJMG6>3.0.CO;2-8
7. Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet. 2004;5(10):725-738. doi:10.1038/nrg1448
8. Sinet PM, Théophile D, Rahmani Z, et al. Mapping of the down syndrome phenotype on chromosome 21 at the molecular level. Biomed Pharmacother. 1994;48(5-6):247-252. doi:10.1016/0753-3322(94)90140-6
9. Ackerman C, Locke AE, Feingold E, et al. An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects. Am J Hum Genet. 2012;91(4):646-659. doi:10.1016/j.ajhg.2012.08.017
10. Letourneau A, Santoni FA, Bonilla X, et al. Domains of genome-wide gene expression dysregulation in Down’s syndrome. Nature. 2014;508(7496):345-350. doi:10.1038/nature13200
11. Korenberg JR, Bradley C, Disteche CM. Down syndrome: molecular mapping of the congenital heart disease and duodenal stenosis. Am J Hum Genet. 1992;50(2):294-302.
12. Pelleri MC, Gennari E, Locatelli C, et al. Genotype-phenotype correlation for congenital heart disease in Down syndrome through analysis of partial trisomy 21 cases. Genomics. 2017;109(5-6):391-400. doi:10.1016/j.ygeno.2017.06.004
13. Pelleri MC, Cicchini E, Locatelli C, et al. Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype. Hum Mol Genet. 2016;25(12):2525-2538. doi:10.1093/hmg/ddw116
14. Blom NA, Ottenkamp J, Wenink AGC, Gittenberger-de Groot AC. Deficiency of the vestibular spine in atrioventricular septal defects in human fetuses with down syndrome. Am J Cardiol. 2003;91(2):180-184. doi:10.1016/s0002-9149(02)03106-5
15. Gittenberger-de Groot AC, Calkoen EE, Poelmann RE, Bartelings MM, Jongbloed MRM. Morphogenesis and molecular considerations on congenital cardiac septal defects. Ann Med. 2014;46(8):640-652. doi:10.3109/07853890.2014.959557
16. Snarr BS, Wirrig EE, Phelps AL, Trusk TC, Wessels A. A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development. Dev Dyn. 2007;236(5):1287-1294. doi:10.1002/dvdy.21074
17. Briggs LE, Kakarla J, Wessels A. The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. Differentiation. 2012;84(1):117-130. doi:10.1016/j.diff.2012.05.006
18. Burns T, Yang Y, Hiriart E, Wessels A. The dorsal mesenchymal protrusion and the pathogenesis of atrioventricular septal defects. J Cardiovasc Dev Dis. 2016;3(4). doi:10.3390/jcdd3040029
19. Kosaki R, Kosaki K, Matsushima K, Mitsui N, Matsumoto N, Ohashi H. Refining chromosomal region critical for Down syndrome-related heart defects with a case of cryptic 21q22.2 duplication. Congenit Anom (Kyoto). 2005;45(2):62-64. doi:10.1111/j.1741-4520.2005.00065.x
20. Grossman TR, Gamliel A, Wessells RJ, et al. Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects. PLoS Genet. 2011;7(11):e1002344. doi:10.1371/journal.pgen.1002344
21. Dunlevy L, Bennett M, Slender A, et al. Down’s syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse. Cardiovasc Res. 2010;88(2):287-295. doi:10.1093/cvr/cvq193
22. Ghosh P, Bhaumik P, Dey SK. COL6A1 loss of function mutation underlie atrioventricular septal defects in down syndrome patients. Mol Cytogenet. 2014;7(Suppl 1):P24. doi:10.1186/1755-8166-7-S1-P24
23. Davies GE, Howard CM, Gorman LM, et al. Polymorphisms and linkage disequilibrium in the COL6A1 and COL6A2 gene cluster: novel DNA polymorphisms in the region of a candidate gene for congenital heart defects in Down’s syndrome. Hum Genet. 1993;90(5):521-525. doi:10.1007/BF00217452
24. Agarwala KL, Nakamura S, Tsutsumi Y, Yamakawa K. Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion. Brain Res Mol Brain Res. 2000;79(1-2):118-126. doi:10.1016/S0169-328X(00)00108-X
25. Barlow GM, Chen XN, Shi ZY, et al. Down syndrome congenital heart disease: a narrowed region and a candidate gene. Genet Med. 2001;3(2):91-101. doi:10.1097/00125817-200103000-00002
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