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: 26 apr. 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.
References
1. Weijerman ME, van Furth AM, Vonk Noordegraaf A, van Wouwe JP, Broers CJM, Gemke RJBJ. Prevalence, neonatal characteristics, and first-year mortality of Down syndrome: a national study. J Pediatr. 2008;152(1):15-19. doi:10.1016/j.jpeds.2007.09.045
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
26. Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X. A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Mol Genet. 1995;4(10):1935-1944. doi:10.1093/hmg/4.10.1935
27. Fuentes JJ, Genescà L, Kingsbury TJ, et al. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet. 2000;9(11):1681-1690. doi:10.1093/hmg/9.11.1681
28. de la Pompa JL, Timmerman LA, Takimoto H, et al. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature. 1998;392(6672):182-186. doi:10.1038/32419
29. Casas C, Martı́nez S, Pritchard MA, et al. Dscr1, a novel endogenous inhibitor of calcineurin signaling, is expressed in the primitive ventricle of the heart and during neurogenesis. Mech Dev. 2001;101(1-2):289-292. doi:10.1016/S0925-4773(00)00583-9
30. Lange AW, Molkentin JD, Yutzey KE. DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice. Dev Biol. 2004;266(2):346-360. doi:10.1016/j.ydbio.2003.10.036
31. Lignon JM, Bichler Z, Hivert B, et al. Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21. Physiol Genomics. 2008;33(2):230-239. doi:10.1152/physiolgenomics.00143.2007
32. Levanon D, Brenner O, Negreanu V, et al. Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis. Mech Dev. 2001;109(2):413-417. doi:10.1016/s0925-4773(01)00537-8
33. Mollo N, Aurilia M, Scognamiglio R, et al. Overexpression of the hsa21 transcription factor RUNX1 modulates the extracellular matrix in trisomy 21 cells. Front Genet. 2022;13:824922. doi:10.3389/fgene.2022.824922
34. Wang J, Sridurongrit S, Dudas M, et al. Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart. Dev Biol. 2005;286(1):299-310. doi:10.1016/j.ydbio.2005.07.035
35. Joziasse IC, Smith KA, Chocron S, et al. ALK2 mutation in a patient with Down’s syndrome and a congenital heart defect. Eur J Hum Genet. 2011;19(4):389-393. doi:10.1038/ejhg.2010.224
36. Robinson SW, Morris CD, Goldmuntz E, et al. Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet. 2003;72(4):1047-1052. doi:10.1086/374319
37. Asim A, Agarwal S, Panigrahi I, Sarangi AN, Muthuswamy S, Kapoor A. CRELD1 gene variants and atrioventricular septal defects in Down syndrome. Gene. 2018;641:180-185. doi:10.1016/j.gene.2017.10.044
38. Ghosh P, Bhaumik P, Ghosh S, et al. Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect. Am J Med Genet A. 2012;158A(11):2843-2848. doi:10.1002/ajmg.a.35626
39. Maslen CL, Babcock D, Robinson SW, et al. CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome. Am J Med Genet A. 2006;140(22):2501-2505. doi:10.1002/ajmg.a.31494
40. Maslen CL, Babcock D, Redig JK, Kapeli K, Akkari YM, Olson SB. CRELD2: gene mapping, alternate splicing, and comparative genomic identification of the promoter region. Gene. 2006;382:111-120. doi:10.1016/j.gene.2006.06.016
41. Ramachandran D, Zeng Z, Locke AE, et al. Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects. G3 (Bethesda). 2015;5(10):1961-1971. doi:10.1534/g3.115.019943
42. Alharbi KM, Al-Mazroea AH, Abdallah AM, Almohammadi Y, Carlus SJ, Basit S. Targeted Next-Generation Sequencing of 406 Genes Identified Genetic Defects Underlying Congenital Heart Disease in Down Syndrome Patients. Pediatr Cardiol. 2018;39(8):1676-1680. doi:10.1007/s00246-018-1951-3
43. Sailani MR, Makrythanasis P, Valsesia A, et al. The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome. Genome Res. 2013;23(9):1410-1421. doi:10.1101/gr.147991.112
44. Ramachandran D, Mulle JG, Locke AE, et al. Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genet Med. 2015;17(7):554-560. doi:10.1038/gim.2014.144
45. Xu J, Wu Q, Wang L, et al. Next-generation sequencing identified genetic variations in families with fetal non-syndromic atrioventricular septal defects. Int J Clin Exp Pathol. 2018;11(7):3732-3743.
46. Park SC, Mathews RA, Zuberbuhler JR, Rowe RD, Neches WH, Lenox CC. Down syndrome with congenital heart malformation. Am J Dis Child. 1977;131(1):29-33. doi:10.1001/archpedi.1977.02120140031003
47. Lo NS, Leung PM, Lau KC, Yeung CY. Congenital cardiovascular malformations in Chinese children with Down’s syndrome. Chin Med J. 1989;102(5):382-386.
48. Trevino CE, Holleman AM, Corbitt H, et al. Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome. Sci Rep. 2020;10(1):18051. doi:10.1038/s41598-020-74650-4
49. Burnicka-Turek O, Steimle JD, Huang W, et al. Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet. 2016;25(14):3011-3028. doi:10.1093/hmg/ddw155
50. Gabriel GC, Young CB, Lo CW. Role of cilia in the pathogenesis of congenital heart disease. Semin Cell Dev Biol. 2021;110:2-10. doi:10.1016/j.semcdb.2020.04.017
51. Li Y, Klena NT, Gabriel GC, et al. Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 2015;521(7553):520-524. doi:10.1038/nature14269
52. Klena NT, Gibbs BC, Lo CW. Cilia and ciliopathies in congenital heart disease. Cold Spring Harb Perspect Biol. 2017;9(8). doi:10.1101/cshperspect.a028266
53. Ripoll C, Rivals I, Ait Yahya-Graison E, et al. Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways. PLoS One. 2012;7(8):e41616. doi:10.1371/journal.pone.0041616
54. Goddeeris MM, Rho S, Petiet A, et al. Intracardiac septation requires hedgehog-dependent cellular contributions from outside the heart. Development. 2008;135(10):1887-1895. doi:10.1242/dev.016147
55. Wiegering A, Rüther U, Gerhardt C. The role of hedgehog signalling in the formation of the ventricular septum. J Dev Biol. 2017;5(4). doi:10.3390/jdb5040017
56. Chen YQ, Li T, Guo WY, Su FJ, Zhang YX. Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score. Genet Mol Res. 2016;15(2). doi:10.4238/gmr.15027601
57. Latronico MVG, Catalucci D, Condorelli G. MicroRNA and cardiac pathologies. Physiol Genomics. 2008;34(3):239-242. doi:10.1152/physiolgenomics.90254.2008
58. Wang L, Li Z, Song X, Liu L, Su G, Cui Y. Bioinformatic analysis of genes and micrornas associated with atrioventricular septal defect in down syndrome patients. Int Heart J. 2016;57(4):490-495. doi:10.1536/ihj.15-319
59. Coppola A, Romito A, Borel C, et al. Cardiomyogenesis is controlled by the miR-99a/let-7c cluster and epigenetic modifications. Stem Cell Res. 2014;12(2):323-337. doi:10.1016/j.scr.2013.11.008
60. Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;8(8):CD006612. doi:10.1002/14651858.CD006612.pub5
61. Bean LJH, Allen EG, Tinker SW, et al. Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project. Birth Defects Res Part A Clin Mol Teratol. 2011;91(10):885-893. doi:10.1002/bdra.22848
62. Yi K, Ma Y-H, Wang W, et al. The Roles of Reduced Folate Carrier-1 (RFC1) A80G (rs1051266) Polymorphism in Congenital Heart Disease: A Meta-Analysis. Med Sci Monit. 2021;27:e929911. doi:10.12659/MSM.929911
63. Ganguly A, Department of Zoology, University of Calcutta, Kolkata, India, Halder P, et al. Risk of Atrioventricular Septal Defects in Down syndrome: Association of MTHFR C677T and RFC1 A80G polymorphisms in Indian Bengali cohort. J Human Gen Genom. 2021;5(1):0-0. doi:10.52547/jhgg.5.1.69
64. Pei L, Zhu H, Zhu J, Ren A, Finnell RH, Li Z. Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial defects and congenital heart defects in China. Ann Epidemiol. 2006;16(5):352-356. doi:10.1016/j.annepidem.2005.02.014
65. Chango A, Emery-Fillon N, de Courcy GP, et al. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab. 2000;70(4):310-315. doi:10.1006/mgme.2000.3034
66. Locke AE, Dooley KJ, Tinker SW, et al. Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome. Genet Epidemiol. 2010;34(6):613-623. doi:10.1002/gepi.20518
67. Carlus SJ, Abdallah AM, Al-Mazroea AH, Al-Harbi MK, Al-Harbi KM. Interaction between MTHFR Polymorphisms and Maternal Age Increases the Risk of Congenital Heart Defects in Down Syndrome. Pak J Zool. 2019;51(3). doi:10.17582/journal.pjz/2019.51.3.865.870
68. Elsayed GM, Elsayed SM, Ezz-Elarab SS. Maternal MTHFR C677T genotype and septal defects in offspring with Down syndrome: A pilot study. Egyptian Journal of Medical Human Genetics. 2014;15(1):39-44. doi:10.1016/j.ejmhg.2013.09.003
69. Božović IB, Vraneković J, Cizmarević NS, Mahulja-Stamenković V, Prpić I, Brajenović-Milić B. MTHFR C677T and A1298C polymorphisms as a risk factor for congenital heart defects in Down syndrome. Pediatr Int. 2011;53(4):546-550. doi:10.1111/j.1442-200X.2010.03310.x
70. Brandalize APC, Bandinelli E, dos Santos PA, Roisenberg I, Schüler-Faccini L. Evaluation of C677T and A1298C polymorphisms of the MTHFR gene as maternal risk factors for Down syndrome and congenital heart defects. Am J Med Genet A. 2009;149A(10):2080-2087. doi:10.1002/ajmg.a.32989
71. Coppedè F. The genetics of folate metabolism and maternal risk of birth of a child with Down syndrome and associated congenital heart defects. Front Genet. 2015;6:223. doi:10.3389/fgene.2015.00223
72. Reutter H, Betz RC, Ludwig M, Boemers TM. MTHFR 677 TT genotype in a mother and her child with Down syndrome, atrioventricular canal and exstrophy of the bladder: implications of a mutual genetic risk factor? Eur J Pediatr. 2006;165(8):566-568. doi:10.1007/s00431-006-0116-1
73. Asim A, Agarwal S, Panigrahi I, Saiyed N, Bakshi S. MTHFR promoter hypermethylation may lead to congenital heart defects in Down syndrome. Intractable Rare Dis Res. 2017;6(4):295-298. doi:10.5582/irdr.2017.01068
74. Asim A, Agarwal S, Panigrahi I. MTRR gene variants may predispose to the risk of Congenital Heart Disease in Down syndrome patients of Indian origin. Egyptian Journal of Medical Human Genetics. 2017;18(1):61-66. doi:10.1016/j.ejmhg.2016.02.006
75. Li H, Cherry S, Klinedinst D, et al. Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population. Circ Cardiovasc Genet. 2012;5(3):301-308. doi:10.1161/CIRCGENETICS.111.960872
76. Li H, Edie S, Klinedinst D, et al. Penetrance of congenital heart disease in a mouse model of down syndrome depends on a trisomic potentiator of a disomic modifier. Genetics. 2016;203(2):763-770. doi:10.1534/genetics.116.188045
77. Liu C, Morishima M, Yu T, et al. Genetic analysis of Down syndrome-associated heart defects in mice. Hum Genet. 2011;130(5):623-632. doi:10.1007/s00439-011-0980-2
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
26. Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X. A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Mol Genet. 1995;4(10):1935-1944. doi:10.1093/hmg/4.10.1935
27. Fuentes JJ, Genescà L, Kingsbury TJ, et al. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet. 2000;9(11):1681-1690. doi:10.1093/hmg/9.11.1681
28. de la Pompa JL, Timmerman LA, Takimoto H, et al. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature. 1998;392(6672):182-186. doi:10.1038/32419
29. Casas C, Martı́nez S, Pritchard MA, et al. Dscr1, a novel endogenous inhibitor of calcineurin signaling, is expressed in the primitive ventricle of the heart and during neurogenesis. Mech Dev. 2001;101(1-2):289-292. doi:10.1016/S0925-4773(00)00583-9
30. Lange AW, Molkentin JD, Yutzey KE. DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice. Dev Biol. 2004;266(2):346-360. doi:10.1016/j.ydbio.2003.10.036
31. Lignon JM, Bichler Z, Hivert B, et al. Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21. Physiol Genomics. 2008;33(2):230-239. doi:10.1152/physiolgenomics.00143.2007
32. Levanon D, Brenner O, Negreanu V, et al. Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis. Mech Dev. 2001;109(2):413-417. doi:10.1016/s0925-4773(01)00537-8
33. Mollo N, Aurilia M, Scognamiglio R, et al. Overexpression of the hsa21 transcription factor RUNX1 modulates the extracellular matrix in trisomy 21 cells. Front Genet. 2022;13:824922. doi:10.3389/fgene.2022.824922
34. Wang J, Sridurongrit S, Dudas M, et al. Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart. Dev Biol. 2005;286(1):299-310. doi:10.1016/j.ydbio.2005.07.035
35. Joziasse IC, Smith KA, Chocron S, et al. ALK2 mutation in a patient with Down’s syndrome and a congenital heart defect. Eur J Hum Genet. 2011;19(4):389-393. doi:10.1038/ejhg.2010.224
36. Robinson SW, Morris CD, Goldmuntz E, et al. Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet. 2003;72(4):1047-1052. doi:10.1086/374319
37. Asim A, Agarwal S, Panigrahi I, Sarangi AN, Muthuswamy S, Kapoor A. CRELD1 gene variants and atrioventricular septal defects in Down syndrome. Gene. 2018;641:180-185. doi:10.1016/j.gene.2017.10.044
38. Ghosh P, Bhaumik P, Ghosh S, et al. Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect. Am J Med Genet A. 2012;158A(11):2843-2848. doi:10.1002/ajmg.a.35626
39. Maslen CL, Babcock D, Robinson SW, et al. CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome. Am J Med Genet A. 2006;140(22):2501-2505. doi:10.1002/ajmg.a.31494
40. Maslen CL, Babcock D, Redig JK, Kapeli K, Akkari YM, Olson SB. CRELD2: gene mapping, alternate splicing, and comparative genomic identification of the promoter region. Gene. 2006;382:111-120. doi:10.1016/j.gene.2006.06.016
41. Ramachandran D, Zeng Z, Locke AE, et al. Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects. G3 (Bethesda). 2015;5(10):1961-1971. doi:10.1534/g3.115.019943
42. Alharbi KM, Al-Mazroea AH, Abdallah AM, Almohammadi Y, Carlus SJ, Basit S. Targeted Next-Generation Sequencing of 406 Genes Identified Genetic Defects Underlying Congenital Heart Disease in Down Syndrome Patients. Pediatr Cardiol. 2018;39(8):1676-1680. doi:10.1007/s00246-018-1951-3
43. Sailani MR, Makrythanasis P, Valsesia A, et al. The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome. Genome Res. 2013;23(9):1410-1421. doi:10.1101/gr.147991.112
44. Ramachandran D, Mulle JG, Locke AE, et al. Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genet Med. 2015;17(7):554-560. doi:10.1038/gim.2014.144
45. Xu J, Wu Q, Wang L, et al. Next-generation sequencing identified genetic variations in families with fetal non-syndromic atrioventricular septal defects. Int J Clin Exp Pathol. 2018;11(7):3732-3743.
46. Park SC, Mathews RA, Zuberbuhler JR, Rowe RD, Neches WH, Lenox CC. Down syndrome with congenital heart malformation. Am J Dis Child. 1977;131(1):29-33. doi:10.1001/archpedi.1977.02120140031003
47. Lo NS, Leung PM, Lau KC, Yeung CY. Congenital cardiovascular malformations in Chinese children with Down’s syndrome. Chin Med J. 1989;102(5):382-386.
48. Trevino CE, Holleman AM, Corbitt H, et al. Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome. Sci Rep. 2020;10(1):18051. doi:10.1038/s41598-020-74650-4
49. Burnicka-Turek O, Steimle JD, Huang W, et al. Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet. 2016;25(14):3011-3028. doi:10.1093/hmg/ddw155
50. Gabriel GC, Young CB, Lo CW. Role of cilia in the pathogenesis of congenital heart disease. Semin Cell Dev Biol. 2021;110:2-10. doi:10.1016/j.semcdb.2020.04.017
51. Li Y, Klena NT, Gabriel GC, et al. Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 2015;521(7553):520-524. doi:10.1038/nature14269
52. Klena NT, Gibbs BC, Lo CW. Cilia and ciliopathies in congenital heart disease. Cold Spring Harb Perspect Biol. 2017;9(8). doi:10.1101/cshperspect.a028266
53. Ripoll C, Rivals I, Ait Yahya-Graison E, et al. Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways. PLoS One. 2012;7(8):e41616. doi:10.1371/journal.pone.0041616
54. Goddeeris MM, Rho S, Petiet A, et al. Intracardiac septation requires hedgehog-dependent cellular contributions from outside the heart. Development. 2008;135(10):1887-1895. doi:10.1242/dev.016147
55. Wiegering A, Rüther U, Gerhardt C. The role of hedgehog signalling in the formation of the ventricular septum. J Dev Biol. 2017;5(4). doi:10.3390/jdb5040017
56. Chen YQ, Li T, Guo WY, Su FJ, Zhang YX. Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score. Genet Mol Res. 2016;15(2). doi:10.4238/gmr.15027601
57. Latronico MVG, Catalucci D, Condorelli G. MicroRNA and cardiac pathologies. Physiol Genomics. 2008;34(3):239-242. doi:10.1152/physiolgenomics.90254.2008
58. Wang L, Li Z, Song X, Liu L, Su G, Cui Y. Bioinformatic analysis of genes and micrornas associated with atrioventricular septal defect in down syndrome patients. Int Heart J. 2016;57(4):490-495. doi:10.1536/ihj.15-319
59. Coppola A, Romito A, Borel C, et al. Cardiomyogenesis is controlled by the miR-99a/let-7c cluster and epigenetic modifications. Stem Cell Res. 2014;12(2):323-337. doi:10.1016/j.scr.2013.11.008
60. Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;8(8):CD006612. doi:10.1002/14651858.CD006612.pub5
61. Bean LJH, Allen EG, Tinker SW, et al. Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project. Birth Defects Res Part A Clin Mol Teratol. 2011;91(10):885-893. doi:10.1002/bdra.22848
62. Yi K, Ma Y-H, Wang W, et al. The Roles of Reduced Folate Carrier-1 (RFC1) A80G (rs1051266) Polymorphism in Congenital Heart Disease: A Meta-Analysis. Med Sci Monit. 2021;27:e929911. doi:10.12659/MSM.929911
63. Ganguly A, Department of Zoology, University of Calcutta, Kolkata, India, Halder P, et al. Risk of Atrioventricular Septal Defects in Down syndrome: Association of MTHFR C677T and RFC1 A80G polymorphisms in Indian Bengali cohort. J Human Gen Genom. 2021;5(1):0-0. doi:10.52547/jhgg.5.1.69
64. Pei L, Zhu H, Zhu J, Ren A, Finnell RH, Li Z. Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial defects and congenital heart defects in China. Ann Epidemiol. 2006;16(5):352-356. doi:10.1016/j.annepidem.2005.02.014
65. Chango A, Emery-Fillon N, de Courcy GP, et al. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab. 2000;70(4):310-315. doi:10.1006/mgme.2000.3034
66. Locke AE, Dooley KJ, Tinker SW, et al. Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome. Genet Epidemiol. 2010;34(6):613-623. doi:10.1002/gepi.20518
67. Carlus SJ, Abdallah AM, Al-Mazroea AH, Al-Harbi MK, Al-Harbi KM. Interaction between MTHFR Polymorphisms and Maternal Age Increases the Risk of Congenital Heart Defects in Down Syndrome. Pak J Zool. 2019;51(3). doi:10.17582/journal.pjz/2019.51.3.865.870
68. Elsayed GM, Elsayed SM, Ezz-Elarab SS. Maternal MTHFR C677T genotype and septal defects in offspring with Down syndrome: A pilot study. Egyptian Journal of Medical Human Genetics. 2014;15(1):39-44. doi:10.1016/j.ejmhg.2013.09.003
69. Božović IB, Vraneković J, Cizmarević NS, Mahulja-Stamenković V, Prpić I, Brajenović-Milić B. MTHFR C677T and A1298C polymorphisms as a risk factor for congenital heart defects in Down syndrome. Pediatr Int. 2011;53(4):546-550. doi:10.1111/j.1442-200X.2010.03310.x
70. Brandalize APC, Bandinelli E, dos Santos PA, Roisenberg I, Schüler-Faccini L. Evaluation of C677T and A1298C polymorphisms of the MTHFR gene as maternal risk factors for Down syndrome and congenital heart defects. Am J Med Genet A. 2009;149A(10):2080-2087. doi:10.1002/ajmg.a.32989
71. Coppedè F. The genetics of folate metabolism and maternal risk of birth of a child with Down syndrome and associated congenital heart defects. Front Genet. 2015;6:223. doi:10.3389/fgene.2015.00223
72. Reutter H, Betz RC, Ludwig M, Boemers TM. MTHFR 677 TT genotype in a mother and her child with Down syndrome, atrioventricular canal and exstrophy of the bladder: implications of a mutual genetic risk factor? Eur J Pediatr. 2006;165(8):566-568. doi:10.1007/s00431-006-0116-1
73. Asim A, Agarwal S, Panigrahi I, Saiyed N, Bakshi S. MTHFR promoter hypermethylation may lead to congenital heart defects in Down syndrome. Intractable Rare Dis Res. 2017;6(4):295-298. doi:10.5582/irdr.2017.01068
74. Asim A, Agarwal S, Panigrahi I. MTRR gene variants may predispose to the risk of Congenital Heart Disease in Down syndrome patients of Indian origin. Egyptian Journal of Medical Human Genetics. 2017;18(1):61-66. doi:10.1016/j.ejmhg.2016.02.006
75. Li H, Cherry S, Klinedinst D, et al. Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population. Circ Cardiovasc Genet. 2012;5(3):301-308. doi:10.1161/CIRCGENETICS.111.960872
76. Li H, Edie S, Klinedinst D, et al. Penetrance of congenital heart disease in a mouse model of down syndrome depends on a trisomic potentiator of a disomic modifier. Genetics. 2016;203(2):763-770. doi:10.1534/genetics.116.188045
77. Liu C, Morishima M, Yu T, et al. Genetic analysis of Down syndrome-associated heart defects in mice. Hum Genet. 2011;130(5):623-632. doi:10.1007/s00439-011-0980-2