Trisomy 21

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Introduction

Chromosome- trisomy.jpg
Trisomy 21 newborn
Nuchal Translucency[1]

International Classification of Diseases (ICD-10) - Q90 Down's syndrome (ICD-11 beta) - LC20.1 Complete trisomy 21


Down syndrome or trisomy 21 is caused by nondisjunction of chromosome 21 in a parent who is chromosomally normal and is one of the most common chromosomal aneuploidy abnormalities in liveborn children. The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.


Down Syndrome is the historic name used for this condition identified by Down, J.L.H. in a 1866 paper[2] where he described the "phenotypic features that includes mental retardation and characteristic facies".


Aneuploidy is the term used to describe any abnormal number of chromosomes either an increase or decrease in total number. This can occur during gamete development or following fertilisation during early rounds of mitosis.


Recent attention has focussed on screening for Down's syndrome (mainly in terms of cost and efficiency) during fetal life with over 350 articles in the medical literature in just the past five years. There is also a high correlation of increased genetic risk with maternal age. To help understand these changes with age, you need to study the development of the ovary and the long process of meiosis that commences in the early oocyte.


Australian - Department of Health[3]

"9.3 Screening tests in the first trimester - Offering the genetic screening test to all women in the first trimester — regardless of maternal age — is recommended in the United Kingdom (NICE 2008), the United States (ACOG 2007) and Australia (HGSA & RANZCOG 2007)."
"Combined test (nuchal translucency thickness, free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A),"
Genetic Links: genetic abnormalities | Genetic risk maternal age | Trisomy 21 | Trisomy 18 | Trisomy 13 | Trisomy X | Monosomy | Fragile X | Williams | Alagille | Philadelphia chromosome | mitochondria | hydatidiform mole | epigenetics | Prenatal Diagnosis | Neonatal Diagnosis | meiosis | mitosis | International Classification of Diseases | genetics


Diagnosis Links: Prenatal Diagnosis | Pregnancy Test | Amniocentesis | Chorionic villus sampling | Ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Non-Invasive Prenatal Testing | Fetal Cells in Maternal Blood | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Genome Sequencing | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Classification of Diseases | Category:Neonatal Diagnosis

Some Recent Findings

Bivalent separation into univalents precedes age-related meiosis I errors in oocytes[4]
Polo-like kinase 4 centriole duplication activity
Polo-like kinase 4 centriole duplication activity[5]
  • Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human Female Meiosis[6] "Meiosis is the cellular program that underlies gamete formation. For this program, crossovers between homologous chromosomes play an essential mechanical role to ensure regular segregation. We present a detailed study of crossover formation in human male and female meiosis, enabled by modeling analysis. Results suggest that recombination in the two sexes proceeds analogously and efficiently through most stages. However, specifically in female (but not male), ∼25% of the intermediates that should mature into crossover products actually fail to do so. Further, this "female-specific crossover maturation inefficiency" is inferred to make major contributions to the high level of chromosome mis-segregation and resultant aneuploidy that uniquely afflicts human female oocytes (e.g., giving Down syndrome). Additionally, crossover levels on different chromosomes in the same nucleus tend to co-vary, an effect attributable to global per-nucleus modulation of chromatin loop size. Maturation inefficiency could potentially reflect an evolutionary advantage of increased aneuploidy for human females."
  • Widespread domain-like perturbations of DNA methylation in whole blood of Down syndrome neonates[7] "Down syndrome (DS) is the most frequent genetic cause of intellectual disability. Despite the fact that more than 50 years have passed since the discovery of its genetic aberrations, the exact pathogenesis of the DS phenotype has remained largely unexplained. It was recently hypothesized that the DS pathogenesis involves complex (epi)genetic, molecular and cellular determinants. To date, many reports have addressed epigenetic aberrations associated with DS at different developmental stages/ages and tissue types, but to our best knowledge not in DS newborns. We analyzed blood samples obtained from ten newborns with DS and five age-matched non-trisomic newborns. Epigenetic profiles were obtained from extracted DNA using the Illumina Infinium 450K array. Since aberrant blood cell distribution is known to be present in DS, we applied two distinct models: with and without correction for estimated blood cell distribution. ... In this study, we found methylation profile differences between DS newborns and controls reflecting a systematically affected epigenetic profile. The observed chromosome 21 dosage effect suggests the involvement of affected essential regulatory factors/regions or altered expression of chromatin modeling enzymes located on chromosome 21."
  • Transcriptome analysis of genetically matched human induced pluripotent stem cells disomic or trisomic for chromosome 21 [8] "Trisomy of chromosome 21, the genetic cause of Down syndrome, has the potential to alter expression of genes on chromosome 21, as well as other locations throughout the genome. These transcriptome changes are likely to underlie the Down syndrome clinical phenotypes. We have employed RNA-seq to undertake an in-depth analysis of transcriptome changes resulting from trisomy of chromosome 21, using induced pluripotent stem cells (iPSCs) derived from a single individual with Down syndrome. ...Unexpectedly, the trisomic iPSCs we characterized expressed higher levels of neuronal transcripts than control disomic iPSCs, and readily differentiated into cortical neurons, in contrast to another reported study. Comparison of our transcriptome data with similar studies of trisomic iPSCs suggests that trisomy of chromosome 21 may not intrinsically limit neuronal differentiation, but instead may interfere with the maintenance of pluripotency."
  • Trisomy 21 consistently activates the interferon response[9] "Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition."
  • Uptake, outcomes, and costs of implementing non-invasive prenatal testing (NIPT) for Down's syndrome into UK NHS maternity care[10] "Eight maternity units across the United Kingdom between 1 November 2013 and 28 February 2015. All pregnant women with a current Down's syndrome risk on screening of at least 1/1000. NIPT was prospectively offered to 3175 pregnant women. In 934 women with a Down's syndrome risk greater than 1/150, 695 (74.4%) chose NIPT, 166 (17.8%) chose invasive testing, and 73 (7.8%) declined further testing. Of 2241 women with risks between 1/151 and 1/1000, 1799 (80.3%) chose NIPT. Of 71 pregnancies with a confirmed diagnosis of Down's syndrome, 13/42 (31%) with the diagnosis after NIPT and 2/29 (7%) after direct invasive testing continued, resulting in 12 live births. ...Implementation of NIPT as a contingent test within a public sector Down's syndrome screening programme can improve quality of care, choices for women, and overall performance within the current budget. As some women use NIPT for information only, the Down's syndrome live birth rate may not change significantly. Future research should consider NIPT uptake and informed decision making outside of a research setting." | Non-Invasive Prenatal Testing United Kingdom Statistics
  • Bivalent separation into univalents precedes age-related meiosis I errors in oocytes[4] "The frequency of chromosome segregation errors during meiosis I (MI) in oocytes increases with age. The two-hit model suggests that errors are caused by the combination of a first hit that creates susceptible crossover configurations and a second hit comprising an age-related reduction in chromosome cohesion. This model predicts an age-related increase in univalents, but direct evidence of this phenomenon as a major cause of segregation errors has been lacking. Here, we provide the first live analysis of single chromosomes undergoing segregation errors during MI in the oocytes of naturally aged mice. Chromosome tracking reveals that 80% of the errors are preceded by bivalent separation into univalents. The set of the univalents is biased towards balanced and unbalanced predivision of sister chromatids during MI. Moreover, we find univalents predisposed to predivision in human oocytes. This study defines premature bivalent separation into univalents as the primary defect responsible for age-related aneuploidy."
Past papers  
  • Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome[11] "Down syndrome (DS) is the most frequent genetic cause of intellectual disability, and altered GABAergic transmission through Cl(-)-permeable GABAA receptors (GABAARs) contributes considerably to learning and memory deficits in DS mouse models. However, the efficacy of GABAergic transmission has never been directly assessed in DS. Here GABAAR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABAAR-driven Cl(-) currents (ECl) was shifted toward more positive potentials in the hippocampi of adult DS mice. Accordingly, hippocampal expression of the cation Cl(-) cotransporter NKCC1 was increased in both trisomic mice and individuals with DS. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and hippocampus-dependent memory in adult DS mice. Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS."
  • Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos[12] "By screening day-3 embryos during in vitro fertilization cycles, we identified an association between aneuploidy of putative mitotic origin and linked genetic variants on chromosome 4 of maternal genomes. This associated region contains a candidate gene, Polo-like kinase 4 (PLK4), that plays a well-characterized role in centriole duplication and has the ability to alter mitotic fidelity upon minor dysregulation. Mothers with the high-risk genotypes contributed fewer embryos for testing at day 5, suggesting that their embryos are less likely to survive to blastocyst formation. The associated region coincides with a signature of a selective sweep in ancient humans, suggesting that the causal variant was either the target of selection or hitchhiked to substantial frequency."
  • Domains of genome-wide gene expression dysregulation in Down’s syndrome "A comparison of identical human twins, only one of whom has Down's syndrome, reveals a genome-wide flattening of gene-expression levels in the affected individual. These results indicate that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes." Nature Published online 16 April 2014
  • DNA sequencing versus standard prenatal aneuploidy screening[13] "In high-risk pregnant women, noninvasive prenatal testing with the use of massively parallel sequencing of maternal plasma cell-free DNA (cfDNA testing) accurately detects fetal autosomal aneuploidy. Its performance in low-risk women is unclear. ...In a general obstetrical population, prenatal testing with the use of cfDNA had significantly lower false positive rates and higher positive predictive values for detection of trisomies 21 and 18 than standard screening. (Funded by Illumina; ClinicalTrials.gov number, NCT01663350.)."
  • Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the US National Down Syndrome Project[14] "Both a lack of maternal folic acid supplementation and the presence of genetic variants that reduce enzyme activity in folate pathway genes have been linked to meiotic nondisjunction of chromosome 21; however, the findings in this area of research have been inconsistent. To better understand these inconsistencies, we asked whether maternal use of a folic acid-containing supplement before conception reduces risk for chromosome 21 nondisjunction. ...These data suggest that lack of folic acid supplementation may be associated specifically with MII errors in the aging oocyte. If confirmed, these results could account for inconsistencies among previous studies, as each study sample may vary by maternal age structure and proportion of meiotic errors." Folic Acid
  • Introduction of first trimester combined test increases uptake of Down's syndrome screening[15] "Addition of the earlier first trimester combined test has increased uptake of antenatal screening for Down's syndrome in women of all ages. This is most likely due to the advantages this test gives women such as earlier decision making, earlier further invasive diagnostic testing and earlier termination, if necessary."
  • Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study.[16] "Multiplexed maternal plasma DNA sequencing analysis could be used to rule out fetal trisomy 21 among high risk pregnancies. If referrals for amniocentesis or chorionic villus sampling were based on the sequencing test results, about 98% of the invasive diagnostic procedures could be avoided."
  • Non-invasive prenatal detection of trisomy 21 using tandem single nucleotide polymorphisms[17] "We outline a novel, rapid, highly sensitive, and targeted approach to non-invasively detect fetal T21 using maternal plasma DNA. ...a targeted approach, based on calculation of Haplotype Ratios from tandem SNP sequences combined with a sensitive and quantitative DNA measurement technology can be used to accurately detect fetal T21 in maternal plasma when sufficient fetal DNA is present in maternal plasma."
More recent papers  
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Search term: Trisomy 21

Deana J Hussamy, Christina L Herrera, Diane M Twickler, Donald D Mcintire, Jodi S Dashe Number of Risk Factors in Down Syndrome Pregnancies. Am J Perinatol: 2018; PubMed 30016823

Miguel Galeote, Elena Checa, Eugenia Sebastián, Mª Auxiliadora Robles-Bello The acquisition of different classes of words in Spanish children with Down syndrome. J Commun Disord: 2018, 75;57-71 PubMed 30016759

Carla L Pennella, Jorge G Rossi, Edgardo M Baialardo, Cristina N Alonso, Myriam R Guitter, Cristian G Sánchez La Rosa, Natalia C Millán, Elizabeth M Alfaro, Pedro A Zubizarreta, María S Felice Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome. [Leucemia linfoblástica aguda en niños con síndrome de Down: análisis comparativo con pacientes sin síndrome de Down.] Arch Argent Pediatr: 2018, 116(4);e500-e507 PubMed 30016023

Paolo Versacci, Duccio Di Carlo, Maria C Digilio, Bruno Marino Cardiovascular disease in Down syndrome. Curr. Opin. Pediatr.: 2018; PubMed 30015688

Amal Isaiah, Edgar Kiss, Patrick Olomu, Korgun Koral, Ron B Mitchell Characterization of upper airway obstruction using cine MRI in children with residual obstructive sleep apnea after adenotonsillectomy. Sleep Med.: 2017, 50;79-86 PubMed 30015255

Trisomy 21 (Down Syndrome) Karyotypes

Trisomy 21 Male Karyotype Trisomy 21 Female Karyotype
Trisomy 21 Male Karyotype
Trisomy 21 Female Karyotype


The normal human karyotypes contain 22 pairs of autosomal chromosomes and one pair of sex chromosomes. The karyotype is the characteristic chromosome complement as identified by staining and can only be identified during cell division when chromosomes are folded. The chromosomes when organised as an image in sequence are called a karyogram or idiogram.

International Classification of Diseases

The International Classification of Diseases (ICD) World Health Organization's classification used worldwide as the standard diagnostic tool for epidemiology, health management and clinical purposes. This includes the analysis of the general health situation of population groups. It is used to monitor the incidence and prevalence of diseases and other health problems. Within this classification "congenital malformations, deformations and chromosomal abnormalities" are (Q00-Q99) but excludes "inborn errors of metabolism" (E70-E90).

Chromosomal abnormalities, not elsewhere classified (Q90-Q99)

  • Q90 Down's syndrome
    • Q90.0 Trisomy 21, meiotic nondisjunction
    • Q90.1 Trisomy 21, mosaicism (mitotic nondisjunction)
    • Q90.2 Trisomy 21, translocation
    • Q90.9 Down's syndrome, unspecified Trisomy 21 NOS


ICD-10

History

John Langdon Down (1828 – 1896)
  • 1866 - British physician John Langdon Down was first to describe the syndrome he described as Mongoloid idiocy.[2]
  • 1959 - French geneticist Jerome Lejeune discovered the chromosome abnormality.[18]
  • 1961 - The Lancet letter to the editor proposed that the name Down's Syndrome. (see reprint Am J Hum Genet. 1961.[19])
Letter To The Editor (1961)  
Reprinted from Lancet, Vol. 1: 775 (Apr. 8) 1961.[19])

Mongolism

It has long been recognized that the terms “mongolian idiocy”, “mongolism”, “mongoloid”, etc., as applied to a specific type of mental deficiency have misleading connotations. The occurrence of this anomaly among Europeans and their descendents is not related to the segregation of genes derived from Asians; its appearance among members of Asian populations suggests such ambiguous designations as, “mongol Mongoloid” ; and the increasing participation of Chinese and Japanese investigators in the study of the condition imposes on them the use of an embarrassing term. We urge, therefore, that the expressions which imply a racial aspect of the condition be no longer used.


Some of the signers of this letter are inclined to replace the term “mongolism” by such designations as “Langdon-Down anomaly”, or “Down’s syndrome or anomaly” or “congenital acromicria”. Several other signers believe that this is an appropriate time to introduce the term “trisomy 21 anomaly” which would include cases of simple trisomy as well as translocations. It is hoped that agreement on a specific phrase will soon cr_vstalize if once the term “mongolism” has been abandoned.

GORDON ALLEN (Bethesda, M d., USA)

C. E. BENDA (Waverly, Mass., USA)

J. A. Bṏṏk (Uppsala, Sweden)

C. O. CARTER (London, England)

C. E. FORD (Harwell, England)

E. H. Y. Chu (Oak Ridge, Tenn., USA)

E. HANHART (Ancona, Switzerland)

GEORGE JERVIS (Letchworth Village, New York, USA)

W. LANGDON-DoWN (Normansfield, England)

J. LEJEUNE (Paris, France)

H1deo NISHIMURA (Kyoto, Japan)

J. OSTER (Randers, Denmark)

L. S. PENROSE (London, England)

P. E. POLANI (London, England)

Edith L. Potter (Chicago, 121., USA)

CURT STERN (Berkeley, Calif, USA)

R. TURPIN (Paris, France)

J. WARKANY (Cincinnati, Ohio, USA)

HERMAN YANNET (Southberry, Conn., USA)

Associated Congenital Abnormalities

Human idiogram-chromosome 21.jpg
  • neurological (mental retardation)
  • characteristic facies
  • heart (atrioventricular canal)
  • gastrointestinal tract (duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease)
  • leukemia - Acute lymphocytic (lymphoblastic) leukemia (ALL) and Acute megakaryocytic leukemia (AML). AML occurs 200 to 400 times more frequently in Down syndrome.
  • hearing loss (90% of all patients) - usually of the conductive type. (More? Hearing Abnormalities)
  • musculoskeletal (limb abnormalities, hypotonia, joint hypermobility, ligamentous laxity, spine anomolies, scoliosis) - include bony anomalies of the cervical spine (produce atlanto-occipital and cervical instability), scoliosis, hip instability, slipped capital femoral epiphysis, patellar instability, and foot deformities.[20]

Heart Defects

Congenital heart defects are common (40 to 50%) in Down’s babies and are a common cause of postnatal death.

Approximately 30 to 40% have complete atrioventricular septal defects (early diagnosis generally allows corrective surgery to be performed).


A Korean study[21] of data from 2005-2006 showed a prevalence of trisomy 21 of 4.4 per 10,000 total births (1.5% of all birth defects). Of the 394 trisomy infants 56.9% (224) had heart defects.

Heart Abnormal: Tutorial Abnormalities | atrial septal defects | double outlet right ventricle | hypoplastic left heart | patent ductus arteriosus‎ | transposition of the great vessels | Tetralogy of Fallot | ventricular septal defects | coarctation of the aorta | Category ASD | Category PDA | Category ToF | Category VSD | ICD10 - Cardiovascular | ICD11
| Cardiovascular Abnormalities | Cardiovascular Development | Cardiac Tutorial | Lecture - Heart

Limb Defects

Trisomy 21 hand features
  • Hand - features short and broad hands, clinodactyly (curving of the fifth finger, little finger) with a single flexion crease (20%), hyperextensible finger joints.
  • Foot - space between the great toe (big) and the second toe is increased.
  • Hip - acquired hip dislocation (6%).

Other musculoskeletal effects include bony anomalies of the cervical spine (produce atlanto-occipital and cervical instability), scoliosis, hip instability, slipped capital femoral epiphysis, patellar instability, and foot deformities.[22]


Links: Limb Abnormalities | Musculoskeletal System Development

Neural Defects

Down syndrome cell adhesion molecule (DSCAM, 21q22.2) is a member of the immunoglobulin superfamily and a class of neural cell adhesion molecules. There are several models[23] that suggest that it is required for early neural development and that over-expression may be associated with the mental retardation seen in Trisomy 21.


Links: OMIM 602523

Australian Clinical Practice Guidelines

The 2018 Australian Clinical Practice Guidelines - Pregnancy Care[24] recommends a combined first trimester test comprising both:

  • ultrasound measurement of fetal nuchal translucency thickness between GA 11 weeks and 13 weeks 6 days gestation (when the fetus has a crown-rump length of 45–84 mm)
  • maternal plasma testing of pregnancy-associated placental protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (b-hCG) between GA 9 weeks and 13 weeks, 6 days gestation.


American College of Obstetricians and Gynecologists Recommendations

The following ACOG recommendations[25] (January 2007) are based on good and consistent scientific evidence:

  • First-trimester screening using both nuchal translucency (NT), an ultrasound exam that measures the thickness at the back of the neck of the fetus, and a blood test is an effective screening test in the general population and is more effective than NT alone.
  • Women found to be at increased risk of having a baby with Down syndrome with first-trimester screening should be offered genetic counseling and the option of CVS or mid-trimester amniocentesis.
  • Specific training, standardization, use of appropriate ultrasound equipment, and ongoing quality assessment are important to achieve optimal NT measurement for Down syndrome risk assessment, and this procedure should be limited to centers and individuals meeting this criteria.
  • Neural tube defect screening should be offered in the mid-trimester to women who elect only first-trimester screening for Down syndrome.

Prevalence

Abnormalities from USA Nationwide Inpatient Sample database (1998 to 2008)[26]

Prevalence is measure of the proportion of a population that are disease cases at a point in time. Generally used to measure only relatively stable conditions, not suitable for acute disorders. Listed below are some sample data from different world regions.

  • Ireland county Galway (1981 to 2000) overall prevalence rate was 26.8/10,000 live births for the full period (decade 1991-2000 29.8/10,000; 1981-1990 24.1/10,000).[27]
  • USA Atlanta (1990-1993) 8.4/10,000 live births excluding terminations and 8.8/10,000 including terminations; (1994-1999) 10.1/10,000 excluding terminations and 15.3/10,000 including terminations.[28]

Down's syndrome Screening

Screening Strategies

Nuchal translucency 11, 12, 13 weeks[1]
Ultrasound nuchal translucency[29]
  Procedure   Detection Rate
First trimester screening (10 to 14 weeks):

  Maternal age

  Nuchal translucency measurement by ultrasound

  First trimester double test (PAPP-A, HCG)

  First trimester combined test (nuchal translucency, PAPP-A, HCG)

 

  32%

  74%

  63%

  86%

Second trimester screening (15 to 19 weeks):

  Maternal age

  Second trimester double test (AFP, HCG)

  Triple test (AFP, HCG, uE3)

  Quadruple test (AFP, HCG, uE3, inhibin A)

  Integrated test (first trimester: nuchal translucency, PAPP-A; second trimester: quadruple test)

 

  32%

  60%

  68%

  79%

  95%

Prenatal diagnosis:

  Amniocentesis (15 weeks)

  Chorionic villus sampling (11-14 weeks)

 

  100%

  100%

Table data from United Kingdom[30]

AFP = alpha fetoprotein, HCG = human chorionic gonadotrophin, PAPP-A = pregnancy associated plasma protein A, uE3 = unconjugated oestriol.

Termination (UK): Surgical dilatation, evacuation (11 to 13 weeks), Medical with mifepristone (14 weeks)

Termination strategies and regulations differ from country to country.

See also the UK report: Serum, Urine and Ultrasound Screening Study (SURUSS) 1996-2003 published 2006.[31]


Links: Alpha-Fetoprotein | Pregnancy-associated plasma protein-A

Second Trimester Ultrasound

Some ultrasound markers have been identified as indicating further testing, but by themselves are not entirely diagnostic. Increased nuchal fold and structural malformation have in some studies been shown to have the highest correlation.[32]

  • increased nuchal fold thickness (≥ 6 mm)
  • structural fetal malformation
  • cardiac hyperechogenic focus
  • mild ventriculomegaly
  • choroid plexus cysts
  • uni- or bilateral renal pyelectasis
  • intestinal hyperechogenicity
  • single umbilical artery
  • short femur and humerus length
  • hand/foot alterations
  • congenital heart disease


Links: Ultrasound

Maternal Blood Screening

There have now been reported several non-invasive tests based upon collection and analysis of maternal blood.

  • Germany, Austria and Switzerland - PrenaTest detects only trisomy 21 and can be carried out at gestational age 12 to 14 weeks.[33] In Germany, about 50,000 people have Down’s syndrome that is currently detected in one in 800 pregnancies.
  • South Korea - The phosphodiesterases gene, PDE9A, located on chromosome 21q22.3, is completely methylated in blood (M-PDE9A) and unmethylated in the placenta (U-PDE9A). Therefore, we estimated the accuracy of non-invasive fetal DS detection during the first trimester of pregnancy using this tissue-specific epigenetic characteristic of PDE9A. "Our findings suggest that U-PDE9A level and the unmethylation index of PDE9A may be useful biomarkers for non-invasive fetal DS detection during the first trimester of pregnancy, regardless of fetal gender."[34]

AMH - A study has shown that maternal blood antimullerian hormone (AMH) levels do not predict fetal aneuploidy[35] "Maternal AMH does not appear to be a marker of fetal aneuploidy in ongoing pregnancies. Contrary to previous reports, we found a significant decline in maternal AMH levels with advancing gestational age."

Novel Screening Strategies

There are several additional suggested screening 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.

  • Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors[36] "To report the performance of massively parallel sequencing (MPS) based prenatal noninvasive fetal trisomy test based on cell-free DNA sequencing from maternal plasma in a routine clinical setting in China. One hundred ninety cases were classified as positive, including 143 cases of trisomy 21 and 47 cases of trisomy 18. With the karyotyping results and the feedback of fetal outcome data, we observed one false positive case of trisomy 21, one false positive case of trisomy 18 and no false negative cases, indicating 100% sensitivity and 99.96% specificity for the detection of trisomies 21 and 18. Our large-scale multicenter study proved that the MPS-based test is of high sensitivity and specificity in detecting fetal trisomies 21 and 18. The introduction of this screening test into a routine clinical setting could avoid about 98% of invasive prenatal diagnostic procedures."
  • ADAM12-S as a maternal serum marker.<ref>First trimester screening for trisomy 21 in gestational week 8-10 by ADAM12-S as a maternal serum marker.[37]
    • " The data show moderately decreased levels of ADAM12-S in cases of fetal aneuploidy in gestational weeks 8-11. However, including ADAM12-S in the routine risk does not improve the performance of first trimester screening for fetal trisomy 21."
  • Nasal bone measurement[38]
  • Jugular lymphatic sacs in the first trimester of pregnancy[39]
  • First-trimester combined screening for trisomy 21 with the double test taken before a gestational age of 10 weeks[40]

Detection using Tandem Single Nucleotide Polymorphisms

Trisomy 21 detection using tandem single nucleotide polymorphisms.jpg

Trisomy 21 detection using tandem single nucleotide polymorphisms[17]

DNA obtained from maternal buccal swab represent maternal germinal DNA. Tandem Single Nucleotide Polymorphism (SNP) sequences on chromosome 21 are amplified by Multiplexed Linear Amplification (MLA) followed by High-Fidelity Polymerase Chain Reaction (HiFi PCR) and Cycling Temperature Capillary Electrophoresis (CTCE) analysis. DNA obtained from maternal plasma represents a mixture of fetal and maternal DNA. Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by MLA followed by High-Fidelity PCR (HiFi PCR) and CTCE analysis. CTCE analysis is followed by Tandem SNP evaluation to check for informativeness. Results with 3 peaks are subjected to Haplotype Ratio (HR) analysis.

Terms

  • Buccal swab is a simple technique used to collect cheek cells from inside your mouth.
  • Cycling Temperature Capillary Electrophoresis is a molecular biology technique for detecting DNA variation by DNA sequencing.
  • Haplotype is a genetic term for a combination of alleles (DNA sequences) at different places (loci) on the chromosome that are transmitted together.
  • Polymerase Chain Reaction is a molecular biology technique for amplifying, making many copies of, a short sequence of DNA.
  • Single Nucleotide Polymorphism is a genetic term for a variation in single nucleotide in a DNA sequence differing between individuals or paired chromosomes in an individual.

Screening By Country

  • Spain - all pregnant women aged 35 years and older are offered genetic examination through invasive testing in order to detect fetal trisomy 21 cases
  • Canada - all pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies in addition to a second trimester ultrasound for dating, assessment of fetal anatomy, and detection of multiples. (see detailed recommendations[15])

Meiosis I and Meiosis II

A recent study[41] has analysed two large USA studies (1,215 of 1,881 eligible case families and 1,375 of 2,293 controls) the Atlanta Down Syndrome Project (1989-1999) and National Down Syndrome Project (2001-2004), looking for an association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error.

Four key findings:

  1. Significant association between advanced maternal age and chromosome 21 nondisjunction was restricted to meiotic errors in the oocyte. The association was not observed in sperm or in post-zygotic mitotic errors.
  2. Advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII).
  3. The ratio of MI to MII errors differed by maternal age. (ratio lower among young and older women and higher in the middle age group).
  4. No effect of grand-maternal age on the risk for maternal nondisjunction.


Links: Cell Division - Meiosis

Aneuploidy

Ploidy refers to the chromosomal genetic content of cells and there are a range of terms used to describe variations that may occur:

  • Euploidy normal, means having the complete chromosome sets (n, 2n, 3n). Aneuploidy is one of the three main classes of numerical chromosomal abnormalities:
  • Aneuploidy are chromosome mutations in which chromosome number is abnormal (increased or reduced), nondisjunction in meiosis or mitosis (anaphase of meiosis I, sister chromatids fail to disjoin at either meiosis II or at mitosis) is the cause of most aneuploids.
  • Polyploidy includes triploidy, usually due to two sperm fertilizing a single egg.
  • Mixoploidy includes mosaicism, where there are two or more genetically different cell lines in an individual.


Links: Abnormal Development - Genetic

Trisomy 21 Growth Charts

Data from this paper "describes an approach for generating subpopulation-specific growth charts meeting requirements for implementation into Electronic health record (EHR) systems, using as an example weights for children with Down syndrome. Gender-specific growth curves were generated from 2358 weight values obtained from 331 patients with Down syndrome from July 2001 until March 2005. The project generated printable curves and computable data tables formatted according to growth chart standards set forth by the Centers for Disease Control and Prevention to facilitate implementation into EHR systems."[42]

Growth curve for boys with Trisomy 21 (Down syndrome).jpg Growth curve for girls with Trisomy 21 (Down syndrome).jpg
Links: Growth Charts

Mouse Model

The following are some recent articles using the Ts65Dn and Ts1Cje mouse models.

Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome.[43]

"Down syndrome (DS) is the most frequent genetic disorder leading to intellectual disabilities and is caused by three copies of human chromosome 21. Mouse models are widely used to better understand the physiopathology in DS or to test new therapeutic approaches. The older and the most widely used mouse models are the trisomic Ts65Dn and the Ts1Cje mice. They display deficits similar to those observed in DS people, such as those in behavior and cognition or in neuronal abnormalities. The Ts65Dn model is currently used for further therapeutic assessment of candidate drugs."

Gene expression profiling in a mouse model identifies fetal liver- and placenta-derived potential biomarkers for Down Syndrome screening.[44]

"Placenta and fetal liver at 15.5 days gestation were analyzed by microarray profiling. We confirmed increased expression of genes located at the trisomic chromosomal region. Overall, between the two genotypes more differentially expressed genes were found in fetal liver than in placenta. Furthermore, the fetal liver data are in line with the hematological aberrations found in humans with Down Syndrome as well as Ts1Cje mice. Together, we found 25 targets that are predicted (by Gene Ontology, UniProt, or the Human Plasma Proteome project) to be detectable in human serum."


Gene Network Disruptions and Neurogenesis Defects in the Adult Ts1Cje Mouse Model of Down Syndrome[45]

"We have shown that trisomy affects a number of elements of adult neurogenesis likely to result in a progressive pathogenesis and consequently providing the potential for the development of therapies to slow progression of, or even ameliorate the neuronal deficits suffered by DS individuals."

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Journals

NCBI Bookshelf

Reviews

Greaney J, Wei Z & Homer H. (2017). Regulation of chromosome segregation in oocytes and the cellular basis for female meiotic errors. Hum. Reprod. Update , , . PMID: 29244163 DOI.

Dent KM & Carey JC. (2006). Breaking difficult news in a newborn setting: Down syndrome as a paradigm. Am J Med Genet C Semin Med Genet , 142C, 173-9. PMID: 17048355

Antonarakis SE & Epstein CJ. (2006). The challenge of Down syndrome. Trends Mol Med , 12, 473-9. PMID: 16935027 DOI.

Benn PA. (2002). Advances in prenatal screening for Down syndrome: II first trimester testing, integrated testing, and future directions. Clin. Chim. Acta , 324, 1-11. PMID: 12204419

Maymon R & Jauniaux E. (2002). Down's syndrome screening in pregnancies after assisted reproductive techniques: an update. Reprod. Biomed. Online , 4, 285-93. PMID: 12709282

Souter VL & Nyberg DA. (2001). Sonographic screening for fetal aneuploidy: first trimester. J Ultrasound Med , 20, 775-90. PMID: 11444737

Jackson M & Rose NC. (1998). Diagnosis and management of fetal nuchal translucency. Semin Roentgenol , 33, 333-8. PMID: 9800243

Menéndez M. (2005). Down syndrome, Alzheimer's disease and seizures. Brain Dev. , 27, 246-52. PMID: 15862185 DOI.

FitzPatrick DR. (2005). Transcriptional consequences of autosomal trisomy: primary gene dosage with complex downstream effects. Trends Genet. , 21, 249-53. PMID: 15851056 DOI.

Articles

Zelazowski MJ, Sandoval M, Paniker L, Hamilton HM, Han J, Gribbell MA, Kang R & Cole F. (2017). Age-Dependent Alterations in Meiotic Recombination Cause Chromosome Segregation Errors in Spermatocytes. Cell , 171, 601-614.e13. PMID: 28942922 DOI.

Wang S, Kleckner N & Zhang L. (2017). Crossover maturation inefficiency and aneuploidy in human female meiosis. Cell Cycle , 16, 1017-1019. PMID: 28471715 DOI.

Ren H, Ferguson K, Kirkpatrick G, Vinning T, Chow V & Ma S. (2016). Altered Crossover Distribution and Frequency in Spermatocytes of Infertile Men with Azoospermia. PLoS ONE , 11, e0156817. PMID: 27273078 DOI.

Lee A & Kiessling AA. (2017). Early human embryos are naturally aneuploid-can that be corrected?. J. Assist. Reprod. Genet. , 34, 15-21. PMID: 27900612 DOI.

Jones KT. (2008). Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age. Hum. Reprod. Update , 14, 143-58. PMID: 18084010 DOI.

Van Riper M. (2007). Families of children with Down syndrome: responding to "a change in plans" with resilience. J Pediatr Nurs , 22, 116-28. PMID: 17382849 DOI.

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ & D'Alton ME. (2005). First-trimester or second-trimester screening, or both, for Down's syndrome. N. Engl. J. Med. , 353, 2001-11. PMID: 16282175 DOI.

Gilbert RE, Augood C, Gupta R, Ades AE, Logan S, Sculpher M & van Der Meulen JH. (2001). Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies. BMJ , 323, 423-5. PMID: 11520837

Down JLH. Observations on an ethnic classification of idiots. (1866) London Hospital Reports, 3:259-262.

Associated Neurological

Menéndez M. (2005). Down syndrome, Alzheimer's disease and seizures. Brain Dev. , 27, 246-52. PMID: 15862185 DOI.

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ & D'Alton ME. (2005). First-trimester or second-trimester screening, or both, for Down's syndrome. N. Engl. J. Med. , 353, 2001-11. PMID: 16282175 DOI.

Hook EB, Cross PK & Schreinemachers DM. (1983). Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA , 249, 2034-8. PMID: 6220164

Schreinemachers DM, Cross PK & Hook EB. (1982). Rates of trisomies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in live births. Hum. Genet. , 61, 318-24. PMID: 6891368

Books

Note: books are listed for educational and information purposes only and does not suggest a commercial product endorsement.

OMIM

Search PubMed

Search PubMed Now: Trisomy 21 | Down Syndrome | aneuploidy |

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

Australia

The Royal Hospital for Women (2014) Trisomy 21 Screening, Including Non-Invasive Prenatal Testing (Nipt) PDF

International

Australian Support

  • The Australian Down Syndrome Association Inc c/o - Down Syndrome Association of NSW IncPO Box 2356 (31 O'Connell Street)North Parramtta NSW 2151 AustraliaTel. 02 9683 4333 Fax. 02 9683 420E-mail:dsansw@hartingdale.com.au
  • The ACT Down Syndrome Association P.O. Box 717Mawson ACT 2607Tel: 06 290 1984 Fax: 06 286 4475Email: ehoek@pcug.org.au
  • The Down Syndrome Association of QueenslandP.O. Box 1293Milton Queensland 4064

Terms

  • alpha-fetoprotein - (AFP) A serum fetal glycoprotein produced by both the yolk sac and fetal liver. The presence of the protein in maternal blood is the basis of a test for genetic or developmental problems in the fetus. Low levels of AFP normally occur in the blood of a pregnant woman, high levels may indicate neural tube defects (spina bifida, anencephaly). (More? Alpha-Fetoprotein Test)
  • alpha-fetoprotein test (APF test) A prenatal test to measure the amount of a fetal protein in the mother's blood (or amniotic fluid). Abnormal amounts of the protein may indicate genetic or developmental problems in the fetus. Serum alpha-fetoprotein (AFP) is a fetal glycoprotein produced by the yolk sac and fetal liver. Low levels of AFP normally occur in the blood of a pregnant woman, high levels may indicate neural tube defects (spina bifida, anencephaly). (More? Alpha-Fetoprotein Test)
  • aneuploidy - Term used to describe an abnormal number of chromosomes mainly (90%) due to chromosome malsegregation mechanisms in maternal meiosis I. (More? Prenatal Diagnosis | Abnormal Development - Genetic | Cell Division - Meiosis)
  • Down Syndrome - The historic name used for trisomy 21, named after the original identifier Down, J.L.H. in a 1866 paper (cited above).
  • karyotype - (Greek, karyon = kernel or nucleus + typos = stamp) Term used to describe the chromosomal (genetic) makeup (complement) of a cell. (More? Abnormal Development - Genetic)
  • nuchal - neck, anatomically refers to the neck region.
  • nuchal translucency - (fetal nuchal-translucency thickness) An initial diagnostic ultrasound measurement in the fetal neck region carried out by trans-abdominal ultrasound at gestational age GA 10–14 weeks. Fetal sagittal section scan at a magnification that the fetus occupied at least 75% of the image. Measured is the maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine.
  • single umbilical artery - (SUA) Placental cord with only a single placental artery (normally paired). This abnormality can be detected by ultrasound (colour flow imaging of the fetal pelvis) and is used as an indicator for further prenatal diagnostic testing for chromosomal abnormalities and other systemic defects. (More? Prenatal Diagnosis | Ultrasound)
  • trimester - Clinical term used to describe and divide human pregnancy period (9 months) into three equal parts of about three calendar months. The first trimester corresponds approximately to embryonic development (week 1 to 8) of organogenesis and early fetal. The second and third trimester correspond to the fetal period of growth in size (second trimester) and weight (third trimester), as well as continued differentiation of existing organs and tissues. (More? Timeline human development)
  • triple markers - alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol.


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Cite this page: Hill, M.A. (2018, July 18) Embryology Trisomy 21. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Trisomy_21

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