Trisomy 21 Evaluation: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Angelika Buczynska.

Trisomy 21 (T21), also known as Down syndrome, is one of the most frequently occurring chromosomal aberrations, appearing in 1 in 319 to 1 in 1000 live births. The most frequently diagnosed duplication of chromosome 21 as a result of the abnormal nondisjunction of chromosomes occurs in an estimated 95% of cases, and the remaining 5% are associated with translocation and somatic mosaicism. T21 patients struggle with physical and mental disabilities and many others comorbidities, such as heart defects, thyroid disease, leukemia, cancers, Alzheimer’s disease, and others.

  • trisomy 21
  • metabolomics
  • genomics
  • prenatal screening

1. Introduction

Trisomy 21 (T21), also known as Down syndrome, is one of the most frequently occurring chromosomal aberrations, appearing in 1 in 319 to 1 in 1000 live births [1]. The most frequently diagnosed duplication of chromosome 21 as a result of the abnormal nondisjunction of chromosomes occurs in an estimated 95% of cases, and the remaining 5% are associated with translocation and somatic mosaicism [1,2,3][1][2][3]. T21 patients struggle with physical and mental disabilities and many others comorbidities, such as heart defects, thyroid disease, leukemia, cancers, Alzheimer’s disease, and others [1,3,4,5][1][3][4][5]. The clinical manifestation of an additional chromosome 21 determines the well-recognized phenotype, which includes an altered facial appearance (flatness of the bridge of the nose, midfacial hypoplasia, and a tendency to protrude the tongue) and musculoskeletal features (inflammatory arthritis, scoliosis, and patellar instability) [1,3,6][1][3][6].

The prenatal screening for T21 is currently based on noninvasive methods, which enable the estimation of the risk of its occurrence, and invasive techniques, mainly used to verify the presence of chromosomal aberrations. Serum screening and ultrasound are used to identify women whose pregnancies are at a high risk of chromosomal abnormalities. Positive screening results can lead to the need to undergo invasive procedures, such as amniocentesis or chronic villus sampling (CVS), where the 21-trisomic karyotype can be confirmed. CVS involves the aspiration of placental tissue, and amniocentesis involves the collection of amniotic fluid. Although invasive techniques are characterized by high diagnostic specificity, they are also associated with a 1% risk of miscarriage [6,7][6][7]. On the other hand, material collected using invasive techniques, such as amniotic fluid, is still useful for research [8]. The breakthrough moment in prenatal diagnosis was the development of noninvasive cell-free fetal DNA (cffDNA) evaluation; however, its high cost has limited the introduction of this test into routine management. There has been significant development of diagnostic tools for prenatal diagnosis, but the number of patients undergoing invasive tests remains constant [7,8][7][8]. Therefore, it is still important to find a cost-effective and noninvasive screening method for biomarker discovery characterized by high sensitivity and specificity, which would provide certain benefits, subsequently leading to the evaluation of novel medical targets. In this case, the application of novel biochemical screening markers, determined using specific novel techniques, may lead to a reduction in unnecessary invasive procedures [9].

Clearly, there is still a need to evaluate the insufficiencies in metabolic pathways involved in the patomechanism of T21. Bioinformatics has enabled comprehensive multi-omics and clinical data integration for insightful interpretation. In thiRes review, we earchers outline the considerations of omics methods are applied to experimental design and general frameworks for the integration of omics data in T21 research, along with analytic strategies, and speculate about future multi-omics approaches. Information about T21 prenatal screening received with use of advanced technology, with a particular emphasis on the evaluation of novel screening biomarkers and the discovery of potential novel medical targets, was collected. We hope that this studThis entry will also provide novel insights to improve the management of complications related to the genetic, metabolomic, and proteomic disturbances observed in T21 development, while also providing possible insights into the role of prenatal screening.

2. Current Recommendation for Down Syndrome Screening

The screening for T21 is currently based on noninvasive methods using serum biomarkers and ultrasound examination. First-trimester aneuploidy screening is performed during the 11th to 13th weeks of gestation and includes the measurement of nuchal translucency by ultrasound and maternal serum-free beta-human chorionic gonadotrophin (βhCG) and pregnancy-associated plasma protein A (PAPP-A) [15][10].

Lately, the second-trimester screening for T21 has been primarily assigned to lower levels of maternal serum alpha fetoprotein (MSAFP) and unconjugated estriol with elevated βhCG and inhibin a concentrations. An increased concentration of MSAFP was associated with open spina bifida in the fetus [16][11]. The most reliable serum biomarkers—βhCG, alpha-fetoprotein (AFP), unconjugated estriol (E3), and PAPP-A—were associated with 5–10% rates of false positives ( Table 1 ) [2,7,17,18,19][2][7][12][13][14].

Table 1. Biochemical prenatal screening markers [10,20,21,22,23,24][15][16][17][18][19][20].
Pregnancy Period Ultrasound Biochemical Test Sensitivity Specificity
First trimester

(11–13 weeks)		 + (NT) PAPP-A and free βhCG 85–90% 82–87%
Second trimester (18–24 weeks) + βhCG + uE3 + AFP + inhibin A 69–92% 81–96%
First or second trimester + PAPP-A, AFP, uE3, total hCG 88% 90–95%
First or second trimester + PAPP-A, inhibin A, AFP, uE3, free βhCG/total hCG 85% 90–95%

In the last decade, the first-trimester prenatal screening replaced the performance of second-trimester measurements. It was proved that first-trimester prenatal screening biochemical tests, when combined with the ultrasound marker of fetal NT thickness, are more reliable, thus detecting more than 90% of the cases [15,25][10][21].

Due to the rapid development of promising untargeted omics evaluations using advanced technology for the comprehensive comparative analysis of genomes, knowledge of the metabolome and proteasome could enhance the diagnostic use of prenatal screening. These methods are characterized by high sensitivity, specificity, and reproducibility. Moreover, these studies enable the dissemination of knowledge about the disturbances of metabolic pathways involved in T21 development, which could reveal unanticipated metabolic perturbations and lead to the discovery of novel medical targets. The detection of fetal cells and fetal DNA circulating in maternal blood has increased the role of prenatal screening [26,27][22][23]. The progressive integration of different omics methods in T21 pathogenesis could elucidate potential causative changes that lead to this disease or determine the treatment targets that could be studied in further clinical trials.

3. Prenatal Genetic Diagnosis of Down Syndrome

In order to avoid invasive prenatal procedures, there is a need for new T21 biomarkers that have high sensitivity and specificity. Thus, genetic tests could be implemented for noninvasive T21 screening panels. Since the presence of fetal DNA in maternal plasma and serum was established by Lo et al. in 1997 using genome sequencing techniques, rapid progress has been observed in prenatal genetic testing [23][19]. Gene identification is important for understanding the pathophysiology of diseases and improving diagnosis, prevention, and treatment. The complete sequencing of chromosome 21 provided a basis for the identification of candidate genes for T21 phenotype manifestations. The mechanisms by which an extra copy of chromosome 21 produces the phenotypes of T21 are complex. Next-generation sequencing (NGS) technology is not limited to gene chip technology, so the identification of novel genes is less time-consuming and expensive. Moreover, post-data analysis has been improved by the establishment of huge public data repositories.

NGS technology facilitates a high detection rate and a low percentage of false positive T21 results [24][20]. There are several genes located on chromosome 21 associated with T21 phenotypes. The genes that have been implicated in T21 development include Cu/Zn superoxide dismutase (SOD1), amyloid precursor protein (APP), Ets-2 transcription factors, Down syndrome critical region 1 (DSCR1) stress-inducible factor, beta-site APP cleaving enzyme (BACE), and S100 [33,34][24][25]. The Down syndrome critical region (DSCR) is a chromosome 21 segment purported to contain genes responsible for many features of T21 [35][26]. The DSCR hypothesis predicts that genes in this region are sufficient to produce T21 phenotypes. Studies should evaluate the association of DSCR with T21 diagnosis. The involvement of other genes can be elucidated with advances in omics methods. Sequencing methods are characterized by higher accuracy than chromosome analysis and can detect gene variation effectively. Moreover, this type of prenatal screening is not dependent on gestational age [25][21]. Compared with traditional first-generation sequencing technology, the sequencing of the human genome initiated the discovery of the T21 patomechanism, leading to a growing understanding of the genetic determinants of this disease, resulting in noninvasive prenatal screening (NIPT) [24][20].

One of the most limiting factors in cbDNA procedure is to isolate the rare fetal cell from maternal circulation. Fingerprinting by short tandem repeat analysis, fetal cell enrichment, and staining, cell sorting based on physical characteristics, antigens, and proteins have been proposed as useful methods to obtain information regarding the cellular origin [44][27]. Recently, automated fetal nRBC and extravillous trophoblast capture systems have been validated in the genetic diagnosis [45,46][28][29]. Nevertheless, insufficient clinical trials able to provide evidence demonstrating a robustness of cbDNA and its diagnostic value in fetal aneuploidy diagnosis still restrain its clinical implementation [47][30].

Altered RNA expression is observable for many but not all of the genes mapped on chromosome 21 and for a larger number of genes located on other chromosomes. Epigenetics refers to the regulation of gene expression through microRNA synthesis, DNA methylation, and histone modification processes. Data in the literature suggest that DNA methylation, as a mechanism regulating gene expression, plays an important role in the pathogenesis of T21 [48,49][31][32]. DNA methylation is a chemical modification of the fifth carbon of a cytosine base to form 5-methylcytosine (5-mc) catalyzed by DNA methyltransferases. Studying the baseline epigenetic effects on chromosome 21 is a useful approach for evaluating novel therapies. Studies focused on the epigenome-wide evaluation of T21 have identified 1052 differentially methylated regions associated with this disease, including significant hypermethylation regions of RUNX family transcription factor 1 (RUNX1) and Fli-1 proto-oncogene (FLI1), the main regulators of hematopoiesis [48][31]. Furthermore, it was proved that reduced neuron-restrictive silencer factor/RE1-silencing transcription factor (NRSF/REST) expression with the simultaneous upregulation of DYRK1A (mapped on chromosome 21q22.13) and protocadherin gamma cluster (PCDHG) gene expression observed during early T21 development may contribute to insufficient neural circuit formation in the developing brain. The upregulation of DNMT3L (on chromosome 21q22.4) could additionally lead to de novo methylation during neurodevelopment, resulting in DNMT3A and DNMT3B downregulation in the brains of T21 fetuses [50][33]. The epigenetic signature of T21 is mainly enriched in genes responsible for hematopoiesis, morphogenesis, and development, and the regulation of the chromatin structure in neurons [51][34]. This observation may provide useful novel biomarkers for T21 brain development and potential novel medical targets for prenatal therapeutic interventions.

4. Proteomics and Down Syndrome Screening

The proteome describes the protein component expressed in cells and tissues. By using proteomic techniques, isoforms and protein post-translational variants can also be evaluated. In addition, post-translational modifications such as phosphorylation, ubiquitination (which modulates protein activity and mediates signal transduction), and proteolytic cleavage can be determined. Current proteomics use MS with LC-MS-MS and matrix-assisted laser desorption/ionization (MALDI) equipment [67][35]. The MALDI method is based on an ionization technique that uses a laser energy-absorbing matrix to create ions from large molecules with minimal fragmentation.

Proteomics could also enable the detection of novel and more affordable T21 biomarkers [68,69][36][37]. Accordingly, Charkiewicz et al. suggested that imbalance in the level of circulating proteins in maternal blood can stimulate an immune response producing autoantibodies. In this study, 190 amniocenteses were performed, and 10 patients with confirmed fetal Down syndrome (15th–18th weeks of gestation) were found. Statistical analysis of the expression of 9000 autoantibodies in T21 pregnancies, revealed using a protein microarray, which allows for the simultaneous determination of 9000 proteins per sample, showed that the expression of 213 autoantibodies was significantly different when compared with that in euploid pregnancies. Moreover, this panel could potentially be used in prenatal T21 screening, based on the specification of the predictive value (specificity and sensitivity) equal to 100%, 0% classification errors, and 0% cross-validation errors [70][38].

Proteomics can also be used to determine disturbed metabolic pathways. Many studies have reported the overexpression of several plasma proteins as a result of trisomy 21 development [74,75,76,77][39][40][41][42]. In evaluating duplicated chromosome 21 genes, several antiangiogenic factor genes were mapped. These gene abnormalities were the basis for subsequent research in the field of disturbed protein expression, resulting in specific changes in T21 pregnancy proteinograms. Several proteins have been shown to be differentially expressed in T21 maternal serum [68,78][36][43]. A study by Kolialexi et al., using Western blotting, found that the plasma transthyretin (THY), ceruloplasmin (CERU), afamin (AFAM), alpha-1-microglobulin (AMBP), apolipoprotein E (APOE) , serum amyloid P-component (SAMP), and histidine-rich glycoprotein (HRG) concentrations were upregulated, with a simultaneous decreased concentration of clusterin (CLUS) [79][44]. In this study, pPlasma obtained from eight women carrying DS fetuses and twelve with non-DS fetuses was analyzed using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Three proteins (AFAM, CERU, and TTHY) are involved in carrying factors, such as fat-soluble vitamin E, copper, a thyroid hormone, thyroxine (T4), and retinol-binding protein bound to retinol. These results were also associated with poor pregnancy outcomes [80][45]. These proteins are necessary for proper hormone synthesis, antioxidant defense, and cell development. CLUS, an acute phase protein, is involved in diseases related to oxidative stress [81][46]. In this case, the disturbed protein profile observed in the maternal compartment resulting from T21 pregnancy could be related to the many comorbidities observed in T21 fetuses [79,82,83][44][47][48].

In summary, the application of proteomic technologies to the evaluation of biological compartments creates novel possibilities for elucidating the patomechanism and discovering novel drug targets and early disease markers. At the same time, proteomic results showing how sets of proteins interact with environmental factors are constantly changing [85][49]. Furthermore, the concentrations of many proteins depend on their locations in biological compartments and the phase of the cell cycle, which can also be interrupted by many diseases [68,69][36][37]. However, the extensive software required for utilizing proteomic data and the need for highly proficient technicians substantially increase the cost. Moreover, quality control has not yet been developed, so the clinical requirements are not met [86][50]. It should be emphasized that proteomics has already contributed to significant progress being made in determining insufficient biological pathways in T21 aneuploidy.

References

  1. Sherman, S.L.; Allen, E.G.; Bean, L.H.; Freeman, S.B. Epidemiology of Down syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 2007, 13, 221–227.
  2. Malone, F. First-Trimester Sonographic Screening for Down Syndrome*1. Obstet. Gynecol. 2003, 102, 1066–1079.
  3. Asim, A.; Kumar, A.; Muthuswamy, S.; Jain, S.; Agarwal, S. Down syndrome: An insight of the disease. J. Biomed. Sci. 2015, 22, 41.
  4. Silverman, W. Down syndrome: Cognitive phenotype. Ment. Retard. Dev. Disabil. Res. Rev. 2007, 13, 228–236.
  5. Foley, C.; Killeen, O.G. Musculoskeletal anomalies in children with Down syndrome: An observational study. Arch. Dis. Child. 2019, 104, 482–487.
  6. Zbucka-Kretowska, M.; Charkiewicz, K.; Goscik, J.; Wolczynski, S.; Laudanski, P. Maternal plasma angiogenic and inflammatory factor profiling in foetal Down syndrome. PLoS ONE 2017, 12, e0189762.
  7. Alldred, S.K.; Deeks, J.J.; Guo, B.; Neilson, J.P.; Alfirevic, Z. Second trimester serum tests for Down’s Syndrome screening. Cochrane Database Syst. Rev. 2012, 2012, cd009925.
  8. Bianchi, D.W. Gene expression analysis of amniotic fluid: New biomarkers and novel antenatal treatments. Clin. Biochem. 2011, 44, 448–450.
  9. Buczyńska, A.; Sidorkiewicz, I.; Ławicki, S.; Krętowski, A.; Zbucka-Krętowska, M. The Significance of Apolipoprotein E Measurement in the Screening of Fetal Down Syndrome. J. Clin. Med. 2020, 9, 3995.
  10. Nicolaides, K.H. Screening for fetal aneuploidies at 11 to 13 weeks. Prenat. Diagn. 2011, 31, 7–15.
  11. Kitchen, F.L.; Jack, B.W. Prenatal Screening; StatPearls Publishing: Treasure Island, FL, USA, 2021.
  12. Wald, N.J.; Watt, H.C.; Hackshaw, A.K. Integrated screening for Down’s syndrome based on tests performed during the first and second trimesters. N. Engl. J. Med. 1999, 341, 461–467.
  13. Sparks, A.B.; Wang, E.T.; Struble, C.A.; Barrett, W.; Stokowski, R.; Mcbride, C.; Zahn, J.; Lee, K.; Shen, N.; Doshi, J.; et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat. Diagn. 2012, 32, 3–9.
  14. Cuckle, H. Biochemical screening for Down syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 2000, 92, 97–101.
  15. Hutton, B.; Salanti, G.; Caldwell, D.M.; Chaimani, A.; Schmid, C.H.; Cameron, C.; Ioannidis, J.P.A.; Straus, S.; Thorlund, K.; Jansen, J.P.; et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Ann. Intern. Med. 2015, 162, 777–784.
  16. Wiseman, F.K.; Alford, K.A.; Tybulewicz, V.L.J.; Fisher, E.M.C. Down syndrome-Recent progress and future prospects. Hum. Mol. Genet. 2009, 18, R75–R83.
  17. Salman, M.S. Systematic review of the effect of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome. Eur. J. Paediatr. Neurol. 2002, 6, 213–219.
  18. Gardiner, K.J. Pharmacological approaches to improving cognitive function in down syndrome: Current status and considerations. Drug Des. Devel. Ther. 2014, 9, 103–125.
  19. KH, N. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am. J. Obstet. Gynecol. 2004, 191, 45–67.
  20. KH, N. A model for a new pyramid of prenatal care based on the 11 to 13 weeks’ assessment. Prenat. Diagn. 2011, 31, 3–6.
  21. Durković, J.; Ubavić, M.; Durković, M.; Kis, T. Prenatal screening markers for down syndrome: Sensitivity, specificity, positive and negative expected value method. J. Med. Biochem. 2018, 37, 62–66.
  22. Norton, M.E.; Jacobsson, B.; Swamy, G.K.; Laurent, L.C.; Ranzini, A.C.; Brar, H.; Tomlinson, M.W.; Pereira, L.; Spitz, J.L.; Hollemon, D.; et al. Cell-free DNA analysis for noninvasive examination of trisomy. N. Engl. J. Med. 2015, 372, 1589–1597.
  23. Badeau, M.; Lindsay, C.; Blais, J.; Nshimyumukiza, L.; Takwoingi, Y.; Langlois, S.; Légaré, F.; Giguère, Y.; Turgeon, A.F.; Witteman, W.; et al. Genomics-based non-invasive prenatal testing for detection of fetal chromosomal aneuploidy in pregnant women. Cochrane Database Syst. Rev. 2017, 2017, CD011767.
  24. Sánchez, O.; Domínguez, C.; Ruiz, A.; Ribera, I.; Alijotas, J.; Cabero, L.; Carreras, E.; Llurba, E. Angiogenic Gene Expression in Down Syndrome Fetal Hearts. Fetal Diagn. Ther. 2016, 40, 21–27.
  25. Antonarakis, S.E.; Skotko, B.G.; Rafii, M.S.; Strydom, A.; Pape, S.E.; Bianchi, D.W.; Sherman, S.L.; Reeves, R.H. Down syndrome. Nat. Rev. Dis. Prim. 2020, 6, 9.
  26. Olson, L.E.; Richtsmeier, J.T.; Leszl, J.; Reeves, R.H. A chromosome 21 critical region does not cause specific down syndrome phenotypes. Science 2004, 306, 687–690.
  27. Rezaei, M.; Winter, M.; Zander-Fox, D.; Whitehead, C.; Liebelt, J.; Warkiani, M.E.; Hardy, T.; Thierry, B. A Reappraisal of Circulating Fetal Cell Noninvasive Prenatal Testing. Trends Biotechnol. 2019, 37, 632–644.
  28. Ma, G.-C.; Lin, W.-H.; Huang, C.-E.; Chang, T.-Y.; Liu, J.-Y.; Yang, Y.-J.; Lee, M.-H.; Wu, W.-J.; Chang, Y.-S.; Chen, M. A Silicon-based Coral-like Nanostructured Microfluidics to Isolate Rare Cells in Human Circulation: Validation by SK-BR-3 Cancer Cell Line and Its Utility in Circulating Fetal Nucleated Red Blood Cells. Micromachines 2019, 10, 132.
  29. Huang, C.-E.; Ma, G.-C.; Jou, H.-J.; Lin, W.-H.; Lee, D.-J.; Lin, Y.-S.; Ginsberg, N.A.; Chen, H.-F.; Chang, F.M.-C.; Chen, M. Noninvasive prenatal diagnosis of fetal aneuploidy by circulating fetal nucleated red blood cells and extravillous trophoblasts using silicon-based nanostructured microfluidics. Mol. Cytogenet. 2017, 10, 44.
  30. Cayrefourcq, L.; Vincent, M.-C.; Pierredon, S.; Moutou, C.; Imbert-Bouteille, M.; Haquet, E.; Puechberty, J.; Willems, M.; Liautard-Haag, C.; Molinari, N.; et al. Single Circulating Fetal Trophoblastic Cells Eligible for Non Invasive Prenatal Diagnosis: The Exception Rather than the Rule. Sci. Rep. 2020, 10, 9861.
  31. Muskens, I.S.; Li, S.; Jackson, T.; Elliot, N.; Hansen, H.M.; Myint, S.S.; Pandey, P.; Schraw, J.M.; Roy, R.; Anguiano, J.; et al. The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis. Nat. Commun. 2021, 12, 821.
  32. Lim, J.H.; Kang, Y.J.; Lee, B.Y.; Han, Y.J.; Chung, J.H.; Kim, M.Y.; Kim, M.H.; Kim, J.W.; Cho, Y.H.; Ryu, H.M. Epigenome-wide base-resolution profiling of DNA methylation in chorionic villi of fetuses with down syndrome by methyl-capture sequencing. Clin. Epigenet. 2019, 11, 180.
  33. Lu, J.; Shee, V. Genetic and Epigenetic Mechanisms in Down Syndrome Brain. In Down Syndrome; InTech: London, UK, 2013.
  34. Bacalini, M.G.; Gentilini, D.; Boattini, A.; Giampieri, E.; Pirazzini, C.; Giuliani, C.; Fontanesi, E.; Scurti, M.; Remondini, D.; Capri, M.; et al. Identification of a DNA methylation signature in blood cells from persons with down syndrome. Aging 2015, 7, 82–96.
  35. Aslam, B.; Basit, M.; Nisar, M.A.; Khurshid, M.; Rasool, M.H. Proteomics: Technologies and their applications. J. Chromatogr. Sci. 2017, 55, 182–196.
  36. Kang, Y.; Dong, X.; Zhou, Q.; Zhang, Y.; Cheng, Y.; Hu, R.; Su, C.; Jin, H.; Liu, X.; Ma, D.; et al. Identification of novel candidate maternal serum protein markers for Down syndrome by integrated proteomic and bioinformatic analysis. Prenat. Diagn. 2012, 32, 284–292.
  37. López Uriarte, G.A.; Burciaga Flores, C.H.; Torres de la Cruz, V.M.; Medina Aguado, M.M.; Gómez Puente, V.M.; Romero Gutiérrez, L.N.; Martínez de Villarreal, L.E. Proteomic profile of serum of pregnant women carring a fetus with Down syndrome using nano uplc Q-tof ms/ms technology. J. Matern. Neonatal Med. 2018, 31, 1483–1489.
  38. Charkiewicz, K.; Zbucka-Kretowska, M.; Goscik, J.; Wolczynski, S.; Lemancewicz, A.; Laudanski, P. Brief communication: Maternal plasma autoantibodies screening in fetal down syndrome. J. Immunol. Res. 2016, 2016, 9362169.
  39. Karaca, E.; Aykut, A.; Ertürk, B.; Durmaz, B.; Güler, A.; Büke, B.; Yeniel, A.Ö.; Ergenoğlu, A.M.; Özkınay, F.; Özeren, M.; et al. Microrna expression profile in the prenatal amniotic fluid samples of pregnant women with down syndrome. Balkan Med. J. 2018, 35, 163–166.
  40. Ahlfors, H.; Anyanwu, N.; Pakanavicius, E.; Dinischiotu, N.; Lana-Elola, E.; Watson-Scales, S.; Tosh, J.; Wiseman, F.; Briscoe, J.; Page, K.; et al. Gene expression dysregulation domains are not a specific feature of Down syndrome. Nat. Commun. 2019, 10, 2489.
  41. Lana-Elola, E.; Watson-Scales, S.D.; Fisher, E.M.C.; Tybulewicz, V.L.J. Down syndrome: Searching for the genetic culprits. DMM Dis. Model. Mech. 2011, 4, 586–595.
  42. Hernandez, D.; Fisher, E.M.C. Down syndrome genetics: Unravelling a multifactorial disorder. Hum. Mol. Genet. 1996, 5, 1411–1416.
  43. Galambos, C.; Minic, A.D.; Bush, D.; Nguyen, D.; Dodson, B.; Seedorf, G.; Abman, S.H. Increased lung expression of anti-angiogenic factors in Down syndrome: Potential role in abnormal lung vascular growth and the risk for pulmonary hypertension. PLoS ONE 2016, 11, e0159005.
  44. Kolialexi, A.; Tsangaris, G.T.; Papantoniou, N.; Anagnostopoulos, A.K.; Vougas, K.K.; Bagiokos, V.; Antsaklis, A.; Mavrou, A. Application of proteomics for the identification of differentially expressed protein markers for Down syndrome in maternal plasma. Prenat. Diagn. 2008, 28, 691–698.
  45. Anagnostopoulos, A.; Th Tsangaris, G. Serum amyloid-p (SAP), a potential biomarker for Down syndrome fetuses prevention in maternal plasma. EPMA J. 2014, 5, A98.
  46. Stoltzner, S.E.; Grenfell, T.J.; Mori, C.; Wisniewski, K.E.; Wisniewski, T.M.; Selkoe, D.J.; Lemere, C.A. Temporal accrual of complement proteins in amyloid plaques in Down’s syndrome with Alzheimer’s disease. Am. J. Pathol. 2000, 156, 489–499.
  47. Kim, J.; Basak, J.M.; Holtzman, D.M. The Role of Apolipoprotein E in Alzheimer’s Disease. Neuron 2009, 63, 287–303.
  48. Sui, W.; Gan, Q.; Gong, W.W.; Wei, X.; Ou, M.; Tang, D.; Jing, H.; Lin, H.; Zhang, Y.; Dai, Y. Verification of foetal Down syndrome biomarker proteins in maternal plasma and applications in prenatal screening for Down syndrome. Transl. Med. Commun. 2018, 3, 9.
  49. Tyers, M.; Mann, M. From genomics to proteomics. Nature 2003, 422, 193–197.
  50. Betzen, C.; Alhamdani, M.S.S.; Lueong, S.; Schröder, C.; Stang, A.; Hoheisel, J.D. Clinical proteomics: Promises, challenges and limitations of affinity arrays. PROTEOMICS—Clin. Appl. 2015, 9, 342–347.
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