Skip to main content
SpringerLink
Log in

Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

We examined the association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error. We analyzed data from two population-based, case–control studies: Atlanta Down Syndrome Project (1989–1999) and National Down Syndrome Project (2001–2004). Cases were live born infants with trisomy 21 and controls were infants without trisomy 21 delivered in the same geographical regions. We enrolled 1,215 of 1,881 eligible case families and 1,375 of 2,293 controls. We report four primary findings. First, the significant association between advanced maternal age and chromosome 21 nondisjunction was restricted to meiotic errors in the egg; the association was not observed in sperm or in post-zygotic mitotic errors. Second, advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII). For example, compared to mothers of controls, mothers of infants with trisomy 21 due to MI nondisjunction were 8.5 times more likely to be ≥40 years old than 20–24 years old at the birth of the index case (95% CI = 5.6–12.9). Where nondisjunction occurred in MII, mothers were 15.1 times more likely to be ≥40 years (95% CI = 8.4–27.3). Third, the ratio of MI to MII errors differed by maternal age. The ratio was lower among women <19 years of age and those ≥40 years (2.1, 2.3, respectively) and higher in the middle age group (3.6). Lastly, we found no effect of grand-maternal age on the risk for maternal nondisjunction. This study emphasizes the complex association between advanced maternal age and nondisjunction of chromosome 21 during oogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Aagesen L, Grinsted J, Mikkelsen M (1984) Advanced grandmaternal age on the mother’s side—a risk of giving rise to trisomy 21. Ann Hum Genet 48:297–301

    Article  PubMed  CAS  Google Scholar 

  • Antonarakis SE, Avramopoulos D, Blouin JL, Talbot CC Jr, Schinzel AA (1993) Mitotic errors in somatic cells cause trisomy 21 in about 4.5% of cases and are not associated with advanced maternal age. Nature Genet 3:146–150

    Article  PubMed  CAS  Google Scholar 

  • Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F, Pangalos C, Raoul O, Slaugenhaupt SA, Hafez M (1992) The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms. Am J Hum Gen 50:544–550

    CAS  Google Scholar 

  • Battaglia DE, Goodwin P, Klein NA, Soules MR (1996) Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Human Reprod 11:2217–2222

    CAS  Google Scholar 

  • Book JA, Fraccaro M, Lindsten J (1959) Cytogenetical observations in Mongolism. Acta Paediatr 48:453–468

    Article  PubMed  CAS  Google Scholar 

  • Canfield MA, Honein MA, Yuskiv N, Xing J, Mai CT, Collins JS, Devine O, Petrini J, Ramadhani TA, Hobbs CA, Kirby RS (2006) National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001. Birth Defects Res A Clin Mol Teratol 76:747–756

    Article  PubMed  CAS  Google Scholar 

  • Carothers AD, Castilla EE, Dutra MG, Hook EB (2001) Search for ethnic, geographic, and other factors in the epidemiology of Down syndrome in South America: analysis of data from the ECLAMC project, 1967–1997. Am J Med Genet 103:149–156

    Article  PubMed  CAS  Google Scholar 

  • Correa-Villasenor A, Cragan J, Kucik J, O’Leary L, Siffel C, Williams L (2003) The metropolitan Atlanta congenital defects program: 35 years of birth defects surveillance at the centers for disease control and prevention. Birth Defects Res A Clin Mol Teratol 67:617–624

    Article  PubMed  CAS  Google Scholar 

  • de Bruin JP, Dorland M, Spek ER, Posthuma G, van Heaften M, Looman CW, Te Velde ER (2004) Age-related changes in the ultrastructure of the resting follicle pool in human ovaries. Biol Reprod 70:419–424

    Google Scholar 

  • Eichenlaub-Ritter U, Boll I (1989) Nocodazole sensitivity, age-related aneuploidy, and alterations in the cell cycle during maturation of mouse oocytes. Cytogenet Cell Genet 52:170–176

    Article  PubMed  CAS  Google Scholar 

  • Eichenlaub-Ritter U, Vogt E, Yin H, Gosden R (2004) Spindles, mitochondria and redox potential in ageing oocytes. Reprod Biomed Online 8:45–58

    PubMed  CAS  Google Scholar 

  • Ford CE, Jones KW, Miller OJ, Mittwoch U, Penrose LS, Ridler M, Shapiro A (1959) The chromosomes in a patient showing both Mongolism and the Klinefelter syndrome. Lancet 1:709–710

    Article  PubMed  CAS  Google Scholar 

  • Freeman SB, Allen EG, Oxford-Wright CL, Tinker SW, Druschel C, Hobbs CA, O’Leary LA, Romitti PA, Royle MH, Torfs CP, Sherman SL (2007) The National Down Syndrome Project: design and implementation. Public Health Rep 122:62–72

    PubMed  Google Scholar 

  • Freeman SB, Yang Q, Allran K, Taft LF, Sherman SL (2000) Women with a reduced ovarian complement may have an increased risk for a child with Down syndrome. Am J Hum Genet 66:1680–1683

    Article  PubMed  CAS  Google Scholar 

  • Gaulden ME (1992) Maternal age effect: the enigma of Down syndrome and other trisomic conditions. Mutat Res 296:69–88

    PubMed  CAS  Google Scholar 

  • Gomez D, Solsona E, Guitart M, Baena N, Gabau E, Egozcue J, Caballin MR (2000) Origin of trisomy 21 in Down syndrome cases from a Spanish population registry. Ann Genet 43:23–28

    PubMed  CAS  Google Scholar 

  • Greenberg RC (1963) Two factors influencing the births of Mongols to younger mothers. Med Off 109:62–64

    Google Scholar 

  • Hamatani T, Falco G, Carter MG, Akutsu H, Stagg CA, Sharov AA, Dudekula DB, VanBuren V, Ko MS (2004) Age-associated alteration of gene expression patterns in mouse oocytes. Human Mol Genet 13:2263–2278

    Article  CAS  Google Scholar 

  • Hassold T, Chiu D (1985) Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum Genet 70:11–17

    Article  PubMed  CAS  Google Scholar 

  • Hassold T, Hunt P (2001) To err (meiotically) is human: the genesis of human aneuploidy. Nature Rev Genet 2:280–291

    Article  CAS  PubMed  Google Scholar 

  • Hodges CA, Ilagan A, Jennings D, Keri R, Nilson J, Hunt PA (2002) Experimental evidence that changes in oocyte growth influence meiotic chromosome segregation. Hum Reprod 17:1171–1180

    Article  PubMed  CAS  Google Scholar 

  • Hodges CA, Revenkova E, Jessberger R, Hassold TJ, Hunt PA (2005) SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat Genet 37:1351–1355

    Article  PubMed  CAS  Google Scholar 

  • Jacobs PA, Baikie AG, Court Brown WM, Strong JA (1959) The somatic chromosomes in Mongolism. Lancet 1:710

    Article  PubMed  CAS  Google Scholar 

  • Lamb NE, Freeman SB, Savage-Austin A, Pettay D, Taft L, Hersey J, Gu Y, Shen J, Saker D, May KM, Avramopoulos D, Petersen MB, Hallberg A, Mikkelsen M, Hassold TJ, Sherman SL (1996) Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II. Nature Genet 14:400–405

    Article  PubMed  CAS  Google Scholar 

  • Lamb NE, Yu K, Shaffer J, Feingold E, Sherman SL (2005) Association between maternal age and meiotic recombination for trisomy 21. Am J Hum Genet 76:91–99

    Article  PubMed  CAS  Google Scholar 

  • Lejeune J (1959) Le Mongolism. Premier exemple d’aberration autosomique humaine. Annals of Genetics 1:41–49

    Google Scholar 

  • LeMaire-Adkins R, Radke K, Hunt PA (1997) Lack of checkpoint control at the metaphase/anaphase transition: a mechanism of meiotic nondisjunction in mammalian females. J Cell Biol 139:1611–1619

    Article  PubMed  CAS  Google Scholar 

  • Malini SS, Ramachandra NB (2006) Influence of advanced age of maternal grandmothers on Down syndrome. BMC Med Genet 7:4

    Google Scholar 

  • Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML (2005) Births: final data for 2003. Natl Vital Stat Rep 54(2):1–116

    Google Scholar 

  • Mikkelsen M, Hallberg A, Poulsen H, Frantzen M, Hansen J, Petersen MB (1995) Epidemiology study of Down’s syndrome in Denmark, including family studies of chromosomes and DNA markers. Develop Brain Dysfunct 8:4–12

    Google Scholar 

  • Muller F, Rebiffe M, Taillandier A, Oury JF, Mornet E (2000) Parental origin of the extra chromosome in prenatally diagnosed fetal trisomy 21. Hum Genet 106:340–344

    Article  PubMed  CAS  Google Scholar 

  • Mutton D, Alberman E, Hook EB (1996) Cytogenetic and epidemiological findings in Down syndrome, England and Wales 1989 to 1993. National Down syndrome Cytogenetic Register and the Association of Clinical Cytogeneticists. J Med Genet 33:387–394

    Article  PubMed  CAS  Google Scholar 

  • Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, Masse N, Sherman SL (2008) New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet 4:e1000033

    Article  PubMed  CAS  Google Scholar 

  • Pan H, Ma P, Zhu W, Schultz RM (2008) Age-associated increase in aneuploidy and changes in gene expression in mouse eggs. Dev Biol 316:397–407

    Article  PubMed  CAS  Google Scholar 

  • Papp Z, Varadi E, Szabo Z (1977) Grandmaternal age at birth of parents of children with trisomy 21. Hum Genet 39:221–224

    Article  PubMed  CAS  Google Scholar 

  • Pellestor F, Anahory T, Hamamah S (2005) Effect of maternal age on the frequency of cytogenetic abnormalities in human oocytes. Cytogenet Genome Res 111:206–212

    Article  PubMed  CAS  Google Scholar 

  • Pellestor F, Andreo B, Arnal F, Humeau C, Demaille J (2002) Mechanisms of non-disjunction in human female meiosis: the co-existence of two modes of malsegregation evidenced by the karyotyping of 1397 in-vitro unfertilized oocytes. Hum Reprod 17:2134–2145

    Article  PubMed  Google Scholar 

  • Pellestor F, Andreo B, Arnal F, Humeau C, Demaille J (2003) Maternal aging and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes. Hum Genet 112:195–203

    PubMed  Google Scholar 

  • Penrose LS (1933) The relative effects of paternal and maternal age in Mongolism. J Genet 27:219–224

    Article  Google Scholar 

  • Penrose LS (1934) The relative aetiological importance of birth order and maternal age in Mongolism. Proc R Soc B Biol Sci 115:431–450

    Article  Google Scholar 

  • Penrose LS (1964) Genetical aspects of mental deficiency. Proceedings of the international Copenhagen congress on the scientific study of mental retardation, pp 165–172

  • Petersen MB, Antonarakis SE, Hassold TJ, Freeman SB, Sherman SL, Avramopoulos D, Mikkelsen M (1993) Paternal nondisjunction in trisomy 21: excess of male patients. Human Mol Genet 2:1691–1695

    Article  CAS  Google Scholar 

  • Richards BW (1970) Observations on mosaic parents of mongol propositi. J Ment Defic Res 14:342–346

    PubMed  CAS  Google Scholar 

  • Schon EA, Kim SH, Ferreira JC, Magalhaes P, Grace M, Warburton D, Gross SJ (2000) Chromosomal non-disjunction in human oocytes: is there a mitochondrial connection? Hum Reprod 15(Suppl 2):160–172

    PubMed  Google Scholar 

  • Sherman SL, Freeman SB, Allen EG, Lamb NE (2005) Risk factors for nondisjunction of trisomy 21. Cytogenet Genome Res 111:273–280

    Article  PubMed  CAS  Google Scholar 

  • Steuerwald NM, Bermudez MG, Wells D, Munne S, Cohen J (2007) Maternal age-related differential global expression profiles observed in human oocytes. Reprod Biomed Online 14:700–708

    Article  PubMed  CAS  Google Scholar 

  • Steuerwald NM, Steuerwald MD, Mailhes JB (2005) Post-ovulatory aging of mouse oocytes leads to decreased MAD2 transcripts and increased frequencies of premature centromere separation and anaphase. Mol Hum Reprod 11:623–630

    Article  PubMed  CAS  Google Scholar 

  • Stoller A, Collmann RD (1969) Grandmaternal age at birth of mothers of children with Down’s syndrome (ONGOLISM). J Ment Defic Res 13:201–205

    Google Scholar 

  • van Montfrans JM, van Hooff MH, Martens F, Lambalk CB (2002) Basal FSH, estradiol and inhibin B concentrations in women with a previous Down’s syndrome affected pregnancy. Human Reprod 17:44–47

    Article  Google Scholar 

  • Vogt E, Kirsch-Volders M, Parry J, Eichenlaub-Ritter U (2008) Spindle formation, chromosome segregation and the spindle checkpoint in mammalian oocytes and susceptibility to meiotic error. Mutat Res 651:14–29

    PubMed  CAS  Google Scholar 

  • Warburton D (2005) Biological aging and the etiology of aneuploidy. Cytogenet Genome Res 111:266–272

    Article  PubMed  CAS  Google Scholar 

  • Yang Q, Sherman SL, Hassold TJ, Allran K, Taft L, Pettay D, Khoury MJ, Erickson JD, Freeman SB (1999) Risk factors for trisomy 21: maternal cigarette smoking and oral contraceptive use in a population-based case–control study. Genet Med 1:80–88

    Article  PubMed  CAS  Google Scholar 

  • Yoon PW, Freeman SB, Sherman SL, Taft LF, Gu Y, Pettay D, Flanders WD, Khoury MJ, Hassold TJ (1996) Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study. Am J Hum Genet 58:628–633

    PubMed  CAS  Google Scholar 

  • Yusuf RZ, Naeem R (2004) Cytogenetic abnormalities in products of conception: a relationship revisited. Am J Reprod Immunol 52:88–96

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the many families nationwide whose participation has made this study possible. In addition, we want to thank all personnel at each NDSP site and their associated birth surveillance teams who made this project a success. Lastly, we would like to thank Larry Edmonds and Dr. Paula Yoon who shared their experience with the National Birth Defects Prevention Study. Their help was invaluable. This work was supported by NIH R01 HD38979 and by the technical assistance of the General Clinical Research Center at Emory University (NIH/NCRR M01 RR00039).

Author information

Authors and Affiliations

  1. Department of Human Genetics, Emory University, 2165 North Decatur Rd, Decatur, Atlanta, GA, 30030, USA

    Emily Graves Allen, Sallie B. Freeman & Stephanie L. Sherman

  2. New York State Department of Health , Troy, NY, USA

    Charlotte Druschel

  3. Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Charlotte A. Hobbs

  4. Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USA

    Leslie A. O’Leary

  5. Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA

    Paul A. Romitti

  6. New Jersey Department of Health and Senior Services, Trenton, NJ, USA

    Marjorie H. Royle

  7. Birth Defects Studies, Public Health Institute, Emeryville, CA, USA

    Claudine P. Torfs

Authors
  1. Emily Graves Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sallie B. Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charlotte Druschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charlotte A. Hobbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leslie A. O’Leary
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul A. Romitti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marjorie H. Royle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Claudine P. Torfs
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephanie L. Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emily Graves Allen.

Additional information

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Allen, E.G., Freeman, S.B., Druschel, C. et al. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum Genet 125, 41–52 (2009). https://doi.org/10.1007/s00439-008-0603-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-008-0603-8

Keywords

Search

Navigation