Talk:Trisomy 21

Novel Screening Strategies

There are several additional suggested screeening stratagies currently at various stages of development. These techniques should be seen as at the research stage olny until data, a clinical concensus and a recommendation has been made.

• Odibo AO, Sehdev H, Stamilio DM, Macones GA. OC053: The efficiency of second-trimester nasal bone (NB) hypoplasia as a Down syndrome marker in low versus high-risk groups. Ultrasound Obstet Gynecol. 2008 Aug 11;32(3):259-260. PMID: 18697081
• van Heesch PN, Struijk PC, Brandenburg H, Steegers EA, Wildschut HI. Jugular lymphatic sacs in the first trimester of pregnancy: the prevalence and the potential value in screening for chromosomal abnormalities. J Perinat Med. 2008 Aug 6. PMID: 18681837
• Calda P, Belosovicova-Viskova H, Valtrova H, Svabik K, Manasova S, Zizka Z, Brestak M, Nekovarova K. OC052: Ultrasound at 20-22 weeks of pregnancy increases the rate of detection of Down syndrome above that of combined first-trimester screening alone. Ultrasound Obstet Gynecol. 2008 Aug 11;32(3):259. PMID: 18697054
• Kirkegaard I, Petersen OB, Uldbjerg N, Turring N. Improved performance of first-trimester combined screening for trisomy 21 with the double test taken before a gestational age of 10 weeks. Prenat Diagn. 2008 Aug 1. PMID: 18677711

Novel Screening Strategies

There are several additional suggested screeening stratagies currently at various stages of development. These techniques should be seen as at the research stage only until data, a clinical concensus and a recommendation has been made.

• Jugular lymphatic sacs in the first trimester of pregnancy
• First-trimester combined screening for trisomy 21 with the double test taken before a gestational age of 10 weeks

• The National Down Syndrome Project: Design and Implementation http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1802119/

Some Recent Findings

• Screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart rate, free beta-hCG and pregnancy-associated plasma protein-A. Kagan KO, Wright D, Valencia C, Maiz N, Nicolaides KH. Hum Reprod. 2008 Sep;23(9):1968-75. Epub 2008 Jun 10. PMID: 18544579

• Down syndrome—recent progress and future prospects Frances K. Wiseman, Kate A. Alford, Victor L.J. Tybulewicz, and Elizabeth M.C. Fisher Hum Mol Genet. 2009 April 15; 18(R1): R75–R83. doi: 10.1093/hmg/ddp010. PMCID: PMC2657943

• Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice. Leland S, Nagarajan P, Polyzos A, Thomas S, Samaan G, Donnell R, Marchetti F, Venkatachalam S. Proc Natl Acad Sci U S A. 2009 Jul 17. PMID: 19617567

"Aneuploidy, the most common chromosomal abnormality at birth and the main ascertained cause of pregnancy loss in humans, originates primarily from chromosome segregation errors during oogenesis. Here, we report that heterozygosity for a mutation in the mitotic checkpoint kinase gene, Bub1, induces aneuploidy in female germ cells of mice and that the effect increases with advancing maternal age."

Impact of trisomy on fertility and meiosis in male mice

Hum Reprod. 2007 Feb;22(2):468-76. Epub 2006 Oct 17. Davisson M, Akeson E, Schmidt C, Harris B, Farley J, Handel MA.

The Jackson Laboratory, Bar Harbor, ME 04609, USA. muriel.davisson@jax.org Abstract BACKGROUND: Chromosomal abnormalities frequently are associated with impairment or arrest of spermatogenesis in mammals but are compatible with fertility in female carriers of the same anomaly. In the case of trisomy, mice have extra genomic DNA as well as the chromosomal abnormality, usually present as an extra, unpaired chromosome. Thus, impairment of spermatogenesis in trisomic males could be due to the presence of extra genomic material (i.e. triplicated genes) or due to the chromosomal abnormality and presence of an unpaired chromosome in meiosis.

METHODS: In this study, fertility and chromosomal pairing configurations during meiotic prophase were analysed in male mice trisomic for different segments of the genome. Four have an extra segmental or tertiary trisomic chromosome--Ts(17(16))65Dn, Ts(10(16))232Dn, Ts(12(17))4Rk and Ts(4(17))2Lws--and one has the triplicated segment attached to another chromosome--Ts(16C-tel)1Cje. Ts(17(16))65Dn and Ts(16C-tel)1Cje have similar gene content triplication and differ primarily in whether the extra DNA is in an extra chromosome or not.

RESULTS: The presence of an intact extra chromosome, rather than trisomy per se, is associated with male sterility. Additionally, sterility is correlated with a high frequency of association of the unpaired chromosome with the XY body, which contains the largely unpaired X and Y chromosomes.

CONCLUSIONS: Intact extra chromosomes disrupt spermatogenesis, and unpaired chromosomes establish a unique chromatin territory within meiotic nuclei.

PMID: 17050550

Trisomy 21 enhances human fetal erythro-megakaryocytic development

Chou ST, Opalinska JB, Yao Y, Fernandes MA, Kalota A, Brooks JS, Choi JK, Gewirtz AM, Danet-Desnoyers GA, Nemiroff RL, Weiss MJ. Blood. 2008 Dec 1;112(12):4503-6. PMID: 18812473

"Children with Down syndrome exhibit 2 related hematopoietic diseases: transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AMKL). Both exhibit clonal expansion of blasts with biphenotypic erythroid and megakaryocytic features and contain somatic GATA1 mutations. ...Our findings indicate that trisomy 21 itself is associated with cell-autonomous expansion of erythro-megakaryocytic progenitors. This may predispose to TMD and AMKL by increasing the pool of cells susceptible to malignant transformation through acquired mutations in GATA1 and other cooperating genes."

Kirkegaard I, Petersen OB, Uldbjerg N, T√∏rring N. Abstract Improved performance of first-trimester combined screening for trisomy 21 with the double test taken before a gestational age of 10 weeks.Prenat Diagn. 2008 Aug 1. [Epub ahead of print]

Breathnach FM, Malone FD. Screening for aneuploidy in first and second trimesters: is there an optimal paradigm? Curr Opin Obstet Gynecol. 2007 Apr;19(2):176-82.

"Screening strategies for aneuploidy continue to evolve, with the most recent evidence favouring a contingent sequential approach."

American College of Obstetricians and Gynecologists New Recommendations for Down Syndrome Call for Screening of All Pregnant Women (January 2, 2007) (More? [#ACOGrecommendations ACOG Screening Recommendations])

"This new recommendation says that the maternal age of 35 should no longer be used by itself as a cut-off to determine who is offered screening versus who is offered invasive diagnostic testing"

Akiyama T, Nagata M, Aoki F. Inadequate histone deacetylation during oocyte meiosis causes aneuploidy and embryo death in mice. Proc Natl Acad Sci U S A. 2006 May 1;

"It was recently reported that histones are globally deacetylated in mammalian oocytes during meiosis but not mitosis. ... The high incidence of aneuploidy in the embryos of older females may be due to inadequate meiotic histone deacetylation."

Prenatal Diagnosis

Chitty LS, Kagan KO, Molina FS, Waters JJ, Nicolaides KH. Fetal nuchal translucency scan and early prenatal diagnosis of chromosomal abnormalities by rapid aneuploidy screening: observational study. BMJ. 2006 Feb 13