Newborn

Register      Login

VOLUME 3 , ISSUE 1 ( January-March, 2024 ) > List of Articles

CASE REPORT

Many Term infants with Persistent Patency of the Ductus Arteriosus could be Trisomy 21 Mosaics

Akhil Maheshwari, Srijan Singh, Varun Sharma, Papagudi G Subramanian, Amita S Garg

Keywords : Anaphase lag, Case report, Copy-number alteration, Fluorescence in situ hybridization, Germinal trisomy 21 mosaicism, High-grade mosaics, Infant, Meiotic errors, Mitotic malsegregation, Newborn, Neonate, Nondisjunction, Postzygotic malsegregation, Somatic trisomy 21 mosaicism

Citation Information : Maheshwari A, Singh S, Sharma V, Subramanian PG, Garg AS. Many Term infants with Persistent Patency of the Ductus Arteriosus could be Trisomy 21 Mosaics. 2024; 3 (1):61-64.

DOI: 10.5005/jp-journals-11002-0090

License: CC BY-NC 4.0

Published Online: 26-03-2024

Copyright Statement:  Copyright © 2024; The Author(s).


Abstract

We report findings from a term infant with persistent patency of the ductus arteriosus (PDA). His fetal tests had shown some ambiguity for trisomy 21. However, he did not show any of the frequently-seen phenotypic features associated with trisomy 21 in utero or after birth, and the postnatal karyotype was reported as normal. One of our team members decided to request for a repeat karyotype and he was then identified as a mosaic for this aneuploidy. These observations are potentially important because the proportion of affected cells could very well be a determinant of the phenotypic variability seen in infants with Down syndrome. Hence, mosaicism might need to be meticulously excluded in patients who are presented with only one or more phenotypic features associated with trisomy 21. In this report, we have briefly reviewed the need for evaluation in such infants; the diagnosis requires specific evaluation of in-vitro cultured blood lymphocytes from the patients, siblings, and parents for somatic and germinal trisomy 21 mosaicism. The mechanisms underlying the origin of trisomy 21 mosaicism are still unclear; embryonic meiotic errors such as nondisjunction and anaphase lag, and subsequent mitotic malsegregation may be responsible. Uniparental disomy needs investigation. In the absence of somatic recombination, postzygotic malsegregation in an originally unaffected, disomy 21 zygote could also be a cause. The incidence of this condition in the community might be higher than hitherto believed.


PDF Share
  1. Hulten MA, Jonasson J, Iwarsson E, et al. Trisomy 21 mosaicism: We may all have a touch of Down syndrome. Cytogenet Genome Res 2013;139(3):189–192. DOI: 10.1159/000346028.
  2. Patterson D, Costa AC. Down syndrome and genetics: A case of linked histories. Nat Rev Genet. 2005;6(2):137–147. DOI: 10.1038/nrg1525.
  3. Zhang Y, Zhong M, Zheng D. Chromosomal mosaicism detected by karyotyping and chromosomal microarray analysis in prenatal diagnosis. J Cell Mol Med 2021;25(1):358–366. DOI: 10.1111/jcmm.16080.
  4. Ko JM. Genetic syndromes associated with congenital heart disease. Korean Circ J 2015;45(5):357–361. DOI: 10.4070/kcj.2015.45.5.357.
  5. Martinez–Glez V, Tenorio J, Nevado J, et al. A six-attribute classification of genetic mosaicism. Genet Med 2020;22(11):1743–1757. DOI: 10.1038/s41436-020-0877-3.
  6. Leon E, Zou YS, Milunsky JM. Mosaic Down syndrome in a patient with low-level mosaicism detected by microarray. Am J Med Genet A 2010;152A(12):3154–3156. DOI: 10.1002/ajmg.a.33739.
  7. Plaiasu V. Down syndrome: Genetics and cardiogenetics. Maedica (Bucur) 2017;12(3):208–213. PMID: 29218069.
  8. Jacobs EG, Leung MP, Karlberg J. Distribution of symptomatic congenital heart disease in Hong Kong. Pediatr Cardiol 2000;21(2): 148–157. DOI: 10.1007/s002469910025.
  9. Lo NS, Leung PM, Lau KC, et al. Congenital cardiovascular malformations in Chinese children with Down's syndrome. Chin Med J (Engl) 1989;102(5):382–386. PMID: 2530065.
  10. Kim MA, Lee YS, Yee NH, et al. Prevalence of congenital heart defects associated with Down syndrome in Korea. J Korean Med Sci 2014;29(11):1544–1549. DOI: 10.3346/jkms.2014.29.11.1544.
  11. de Rubens Figueroa J, del Pozzo Magaña B, Hach JLP, et al. Rev Esp Cardiol 2003;56(9):894–899. DOI: 10.1016/s0300-8932(03)76978-4.
  12. Vida VL, Barnoya J, Larrazabal LA, et al. Congenital cardiac disease in children with Down's syndrome in Guatemala. Cardiol Young 2005;15(3):286–290. DOI: 10.1017/S1047951105000582.
  13. Elmagrpy Z, Rayani A, Shah A, et al. Down syndrome and congenital heart disease: Why the regional difference as observed in the Libyan experience? Cardiovasc J Afr 2011;22(6):306–309. DOI: 10.5830/CVJA-2010-072.
  14. Baird PA, Sadovnick AD. Life expectancy in Down syndrome. J Pediatr 1987;110(6):849–854. DOI: 10.1016/s0022-3476(87)80395-5.
  15. Baird PA, Sadovnick AD. Life tables for Down syndrome. Hum Genet 1989;82(3):291–292. DOI: 10.1007/BF00291175.
  16. Esbensen AJ. Health conditions associated with aging and end of life of adults with Down syndrome. Int Rev Res Ment Retard 2010;39(C):107–126. DOI: 10.1016/S0074-7750(10)39004-5.
  17. Ali FE, Al-Bustan MA, Al-Busairi WA, et al. Cervical spine abnormalities associated with Down syndrome. Int Orthop 2006;30(4):284–289. DOI: 10.1007/s00264-005-0070-y.
  18. Xavier AC, Taub JW. Acute leukemia in children with Down syndrome. Haematologica 2010;95(7):1043–1045. DOI: 10.3324/haematol.2010. 024968.
  19. Kim GE, Sin DS, Kim SS, et al. End-stage renal disease in a Down syndrome patient caused by delayed diagnosis of nonneurogenic bladder: A case report. Medicine (Baltimore) 2019;98(15):e15145. DOI: 10.1097/MD.0000000000015145.
  20. Danopoulos S, Deutsch GH, Dumortier C, et al. Lung disease manifestations in Down syndrome. Am J Physiol Lung Cell Mol Physiol 2021;321(5):L892–L899. DOI: 10.1152/ajplung.00434.2020.
  21. Dierssen M. Down syndrome: The brain in trisomic mode. Nat Rev Neurosci 2012;13(12):844–858. DOI: 10.1038/nrn3314.
  22. Truty R, Rojahn S, Ouyang K, et al. Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals. Am J Hum Genet 2023;110(4):551–564. DOI: 10.1016/j.ajhg.2023.02.013.
  23. Thorpe J, Osei–Owusu IA, Avigdor BE, et al. Mosaicism in human health and disease. Annu Rev Genet 2020;54:487–510. DOI: 10.1146/annurev-genet-041720-093403.
  24. Ghosh S, Feingold E, Dey SK. Etiology of Down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am J Med Genet A 2009;149A(7):1415–1420. DOI: 10.1002/ajmg.a.32932.
  25. Day T, Taylor PD. Chromosomal drive and the evolution of meiotic nondisjunction and trisomy in humans. Proc Natl Acad Sci USA 1998;95(5):2361–2365. DOI: 10.1073/pnas.95.5.2361.
  26. Oliver TR, Feingold E, Yu K, et al. New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet 2008;4(3):e1000033. DOI: 10.1371/journal.pgen.1000033.
  27. DiLuigi A, Weitzman VN, Pace MC, et al. Meiotic arrest in human oocytes is maintained by a Gs signaling pathway. Biol Reprod 2008;78(4):667–672. DOI: 10.1095/biolreprod.107.066019.
  28. Hawley RS, Frazier JA, Rasooly R. Separation anxiety: The etiology of nondisjunction in flies and people. Hum Mol Genet 1994;3(9): 1521–1528. DOI: 10.1093/hmg/3.9.1521.
  29. Goutas A, Outskouni Z, Papathanasiou I, et al. The establishment of mitotic errors-driven senescence depends on autophagy. Redox Biol 2023;62:102701. DOI: 10.1016/j.redox.2023.102701.
  30. Wolstenholme J, Angell RR. Maternal age and trisomy: A unifying mechanism of formation. Chromosoma 2000;109(7):435–438. DOI: 10.1007/s004120000088.
  31. MacLennan M, Crichton JH, Playfoot CJ, et al. Oocyte development, meiosis and aneuploidy. Semin Cell Dev Biol 2015;45:68–76. DOI: 10.1016/j.semcdb.2015.10.005.
  32. Pelleri MC, Locatelli C, Mattina T, et al. Partial trisomy 21 with or without highly restricted Down syndrome critical region (HR-DSCR): Report of two new cases and reanalysis of the genotype-phenotype association. BMC Med Genomics 2022;15(1):266. DOI: 10.1186/s12920-022-01422-6.
  33. Papavassiliou P, Charalsawadi C, Rafferty K, et al. Mosaicism for trisomy 21: A review. Am J Med Genet A 2015;167A(1):26–39. DOI: 10.1002/ajmg.a.36861.
  34. Papavassiliou P, York TP, Gursoy N, et al. The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues. Am J Med Genet A 2009;149A(4):573–583. DOI: 10.1002/ajmg.a.32729.
  35. Sanchez–Pavon E, Mendoza H, Garcia–Ferreyra J. Trisomy 21 and assisted reproductive technologies: A review. JBRA Assist Reprod 2022;26(1):129–1241. DOI: 10.5935/1518-0557.20210047.
  36. Hulten MA, Jonasson J, Nordgren A, et al. Germinal and somatic trisomy 21 mosaicism: How common is it, what are the implications for individual carriers and how does it come about? Curr Genomics 2010;11(6):409–419. DOI: 10.2174/138920210793176056.
  37. Munne S, Wells D. Detection of mosaicism at blastocyst stage with the use of high-resolution next-generation sequencing. Fertil Steril 2017;107(5):1085–1091. DOI: 10.1016/j.fertnstert.2017.03.024.
  38. Taylor TH, Gitlin SA, Patrick JL, et al. The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans. Hum Reprod Update 2014;20(4):571–581. DOI: 10.1093/humupd/dmu016.
  39. Pangalos C, Avramopoulos D, Blouin JL, et al. Understanding the mechanism(s) of mosaic trisomy 21 by using DNA polymorphism analysis. Am J Hum Genet 1994;54(3):473–4781. PMID: 8116616.
  40. Chen CP, Liou JD, Chern SR, et al. Prenatal diagnosis of maternal uniparental disomy 21 in association with low-level mosaic trisomy 21 at amniocentesis in a pregnancy associated with intrauterine growth restriction and a favorable outcome. Taiwan J Obstet Gynecol 2022;61(1):146–149. DOI: 10.1016/j.tjog.2021.11.025.
  41. Bandyopadhyay R, McCaskill C, Knox–Du Bois C, et al. Mosaicism in a patient with Down syndrome reveals post-fertilization formation of a Robertsonian translocation and isochromosome. Am J Med Genet A 2003;116A(2):159–163. DOI: 10.1002/ajmg.a.10113.
  42. Petersen MB, Adelsberger PA, Schinzel AA, et al. Down syndrome due to de novo Robertsonian translocation t(14q;21q): DNA polymorphism analysis suggests that the origin of the extra 21q is maternal. Am J Hum Genet 1991;49(3):529–536. PMID: 1831959.
  43. Shaffer LG, Agan N, Goldberg JD, et al. American College of Medical Genetics statement of diagnostic testing for uniparental disomy. Genet Med 2001;3(3):206–211. DOI: 10.1097/00125817-200105000-00011.
  44. Iourov IY, Vorsanova SG, Yurov YB. Chromosomal mosaicism goes global. Mol Cytogenet 2008;1:26. DOI: 10.1186/1755-8166-1-26.
  45. Namba A, Nishiyama M, Weiser JJ, et al. Prenatal diagnosis of complex rearrangement of chromosome 21: The significance of interphase and metaphase fluorescence in situ hybridization and comparative genomic hybridization. Clin Case Rep 2013;1(2):50–53. DOI: 10.1002/ccr3.22.
  46. Witters I, Devriendt K, Legius E, et al. Rapid prenatal diagnosis of trisomy 21 in 5049 consecutive uncultured amniotic fluid samples by fluorescence in situ hybridisation (FISH). Prenat Diagn 2002;22(1): 29–33. DOI: 10.1002/pd.225.
  47. Davies AF, Barber L, Murer–Orlando M, et al. FISH detection of trisomy 21 in interphase by the simultaneous use of two differentially labelled cosmid contigs. J Med Genet 1994;31(9):679–685. DOI: 10.1136/jmg.31.9.679.
  48. Beverstock GC, Hansson K, Helderman–van den Enden AT, et al. A near false-negative finding of mosaic trisomy 21: A cautionary tale. Prenat Diagn 1998;18(7):742–746. PMID: 9706658.
  49. Li J, Kalev–Zylinska ML. Advances in molecular characterization of myeloid proliferations associated with Down syndrome. Front Genet 2022;13:891214. DOI: 10.3389/fgene.2022.891214.
  50. Livy A, Lye S, Jagdish CK, et al. Evaluation of quality of DNA extracted from buccal swabs for microarray based genotyping. Indian J Clin Biochem 2012;27(1):28–33. DOI: 10.1007/s12291-011-0154-y.
  51. Singh AK, Olsen MF, Lavik LAS et al. Detecting copy-number variation in next generation sequencing data from diagnostic gene panels. BMC Med Genomics 2021;14(1):214. DOI: 10.1186/s12920-021- 01059-x.
  52. Qin D. Next-generation sequencing and its clinical application. Cancer Biol Med 2019;16(1):4–10. DOI: 10.20892/j.issn.2095-3941.2018. 0055.
  53. 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.
  54. Rambo–Martin BL, Mulle JG, Cutler DJ, et al. Analysis of copy-number variants on chromosome 21 in Down syndrome-associated congenital heart defects. G3 (Bethesda) 2018;8(1):105–111. DOI: 10.1534/g3.117. 300366.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.