2/6/2023 - Technology and Innovation

Genomic analysis of Down Syndrome

By pablo ortega

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Learning Down Syndrome

Down syndrome is a suffering in which the patient has an extra chromosome. The normal is to have 23 pairs of chromosomes, i.e. 46 chromosomes in total, in patients with Down syndrome there is a third repetition of chromosome 21. This is known as trisomy, so Down syndrome is also known as trisomy 21. This extra copy changes the way the body and brain of the baby develops, which can cause both mental and physical problems. [12]

Types of Down Syndrome

There are three types of Down syndrome. Generally one cannot distinguish between one type and the other without observing chromosomes because physical characteristics and behaviors are similar: [1,3]
  • Trisomy 21: Most people with Down syndrome have trisomy 21. With this type of Down syndrome, each cell of the body has three separate copies of chromosome 21. [1,3]
  • Translocation Down Syndrome: It happens when there is a part or an extra full 21 chromosome present, but connected or “translocated” to a different chromosome instead of being on a separate 21 chromosome, this represents a minority of patients. [1,3]
  • Down syndrome with mosaicism: For patients with Down syndrome with mosaicism, some of the cells have 3 copies of chromosome 21, but others have the typical two copies of chromosome 21. These patients may have the same characteristics as other patients with Down syndrome. However, they may have less disease characteristics due to the presence of some cells with the normal amount of chromosomes. [1,3]

Common problems

Many people with Down syndrome have typical facial traits and no other major birth defect. However, others may have one or more major birth defects or other medical problems. Some of the most common health problems among children with Down syndrome are: [1,3]
  • Hearing loss.
  • Apnea of obstructive sleep.
  • Ear infections.
  • Eye diseases, such as cataracts, and eye problems that require glasses.
  • Heart defects present from birth.


There are two types of basic tests available to detect Down syndrome during pregnancy. The detection tests are one of the types, and the diagnostic tests are the other. [1]

Detection tests

Detection tests usually include a combination of blood tests, which measure the amount of various substances in the mother's blood (e.g., alfafetoprotein test in the maternal serum or MS-AFP, triple detection or cuádruple detection) and ultrasonography, which creates an image of the baby. In the ultrasound, one of the things the technician observes is the liquid that is behind the baby's neck. The presence of extra fluid in this region may indicate that there is a genetic problem. [1, 4]Another relatively new test is the detection of certain chromosome problems, including Down syndrome, analyzes the mother's blood in order to detect the small pieces of the baby's DNA in gestation circulating through the mother's blood. This test is recommended for women who are more likely to have a pregnancy affected by Down syndrome. This test is usually performed in the first quarter. [1, 4]

Diagnostic tests

Diagnostic tests are usually done to confirm the diagnosis of Down syndrome after positive results have been obtained in a detection test. Types of diagnostic tests include: [1, 4]
  • The sampling of corianic hair, which examines material from the placenta.
  • Amniocentesis, which examines amniotic fluid.
  • Cordocentesis, also called percutaneous blood sample of the umbilical cord, which examines the blood of the umbilical cord.
But these are not the only available evidence, as the technology develops, it is possible to use new methods for detection and diagnosis of genetic diseases. One of these new techniques is based on the use of comparative genomic hybridization platforms in microarrays (aCGH). A tool that initially developed for the detection of genomic changes in cancer has revolutionized the field of cytogenetics. The methodology is based on the cohibition of the DNA that is being worked and the DNA-control, both marked with different fluorochromes to a solid support that contains immobilized DNA fragments, called probes. The hybridization competition is the key factor that allows observing the gains or losses of genetic material in the patient's sample in relation to control. This tool has largely supported the diagnosis of genetic alterations such as Down syndrome. [4]

Genomic analysis

What this third copy ends up provoking at the genetic level is an overexpression of genes, creating an imbalance in the way they act to achieve the normal development and functioning of cells and the organism as a whole. [2.3] In recent decades, research has been dedicated to understanding the molecular bases by which overexpression of these genes causes the phenotypic alterations proper to the syndrome. To this end, they were based on the following principles: [2]
  • The specific genes of chromosome 21 will show effects due to the gene dose, i.e. when there are 3 copies of a gene instead of only 2, there will be an increase of up to 50% in the levels of RNA and protein derived from each gene. [2]
  • Some of these increases will cause disturbances in the pathways and cellular processes in which the producers of these genes intervene.
  • Disorders can form a chain affecting cellular processes not directly linked to chromosome 21, these induce anomalies in the development of various organs, tissues and systems of the organism. [2]
One of the main differences that separates Down syndrome from the rest of other forms of intellectual disability, is that, in itself, there is no anomalous function of the gene or lack in function, but, trisomy 21 only produces excess copies, it is an increase in activity of approximately 1.5 times more in each chromosome gene. The problem is that this increase extends to a long number of genes, which in itself increases the probability of being involved multiple pathways and functional networks in which the products of these genes intervene, which contribute to cellular activity. [2]Sequence of chromosome 21: The partial sequence of chromosome 21 was published in 2000 as part of the research of the Human Genome Project. What was shown in chromosome was a composition of 33.5 million pb of DNA on his long arm and 285 thousand on his short arm. In this publication, the existence of 225 genes, later and more accurate investigations increased the number of genes to 364. [2.3]Among the genes that fall within chromosome 21 are 7 RNA processing genes, 4 genes involved in the proteosome pathway, 7 in monocarbonate metabolism and methylation, 14 which encode for MAP-kinase and calcium/calcineurine pathway. Another 14 genes that encode for transcription factors, 8 genes responsible for cell adhesion and union and 14 genes involved in generating energy in mitochondria and the metabolism of reactive oxygen species, among others. Of those mentioned, everyone has an important role and can cause serious diseases. As mentioned on several occasions, although there is no “incorrect” expression of these genes, overexpression can be equal to responsible for causing problems, balancing the important balance of cellular processes [2,4]

Clinical manifestations

There are several genes in the critical region of Down syndrome, one of the most important and that usually appears and different affections is the gene DYRK1A (21q22.13), expressed in the developing nervous system and during adultity. Its main function is based on inhibiting cell proliferation, in addition to promoting premature neuronal differentiation. Some studies, in mice, have demonstrated that the overexpression of this gene causes serious learning problems, such as defects in spatial memory. Another gene whose expression affects the same areas is the gene SIM2, a transcription factor and main development regulator. The syndrome adhesion molecule (DSCAM, 21q22.2) is expressed mainly in neuronal dendrites and contributes to synaptic plasticity, the theme is that when it is expressed, it inhibits the branching of the neuronal dendrites of the hippocampus. [3]But there are also genes outside the critical region, such as the gene (SYNJ1, 21q22.2) encoding for a vesicle-forming protein in neuronal synapse and plays an important role in neurotransmission, whose overexpression once again causes problems in the area of memory and learning. Along with these problems, patients with Down syndrome are also more prone to early development of Alzheimer. This is due to overexpression of the gene APP, whose proteolysis generates amyloid β, which is the main component of amyloid plates in brains of Alzheimer's patients and whose mutations of type duplications have a strong relationship with early onset. [3]In addition to the disorders of the nervous system, one of the clearest signs of Down syndrome are observed in the craneofacial characteristics, where microcephaly, flat occipital, brachicephaly, small face is observed, among others. Studies in mice have revealed a craneofacial pattern of abnormalities similar to those mentioned, even if a responsible candidate of these characteristics was obtained. It is the region that contains the gene ETS2 (21q22.2) whose overexpression showed an association with these skeletal changes. [3]Outside of the multiple sufferings caused by overexpression of genes, there are also certain beneficial things that have been found. One is that the risk for developing solid tumors is lower in patients with Down syndrome. This was observed in modified mice, where trisomal mice showed a clear reduction in the frequency of tumors. Also here is involved the gene ETS2, since it inhibits the growth of tumors when expressed in 3 copies, and when expressed in only 2 copies, the rate of tumors increased. Recently, it was also postulated that a decrease in angiogenesis could prevent the growth of tumors in the overexpression of genes like DSCR1 which demonstrated inhibit angiogenesis induced by the endothelial bascle growth factor. Other genes that decreased angiogenesis in mouse models include ADAMTS1, ERG, JAM2 and PTT G1IP. [3]The study of all genes involved in Down syndrome and how its overexpression affects the different cellular processes remains a central theme of discussion that offers great challenges to overcome. It is not known clearly that so far these effects come and that other genes are sensitive to the doses involved in the phenotype of these patients. Something that is clear is that several of these clinical manifestations are multifactorial, that is, that there is not a single gene responsible for its presentation, but are mainly the interactions between the different genes, which is one of the factors that most complexity brings to the underlying physiopathology of this disease. [1,2,3,4]


  1. CDC, Information on Down syndrome, [Internet], CDC, 2020, [consulted September 14, 2022], available at: https://www.cdc.gov/ncbddd/spanish/birthdefects/downsyndrome.html
  2. Ibero-American Foundation Down21, The chromosome 21, [Internet], Down21, 2005, [consulted September 14, 2022], available at: https://www.down21. org/basic information/76-that-es-el-syndrome-de-down/133-el-chromosome-21. html
  3. Díaz Cuellar S, Yokoyama Rebollar And, Del Castillo Rui V., Genomic of Down syndrome, Acta pediatr. Méx, [Internet], 2016, [consulted September 14, 2022], 37(5), available at: https://www.scielo. org.mx/scielo. php?script=sci_arttext&pid=S0186-23912016000500289
  4. Palaces Verdu M.G., Pérez Jurado L.A., New methodologies in the study of genetic diseases and their indications, Ped. Int., [Internet], 2014, [consulted on September 14, 2022], pp. 515-528, available in: https://cdn.pediatriaintegral. es/wp-content/uploads/2014/xviii08/02/515-528.pdf

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pablo ortega

pablo ortega

Hello, I am Pablo Ortega Ferron, a Biotechnology undergraduate student at Anáhuac University, currently developing my graduation project focused on observing the different effects that type 2 diabetes mellitus has on memory and learning. I have a special interest in clinical research, mainly focused on medical biotechnology and genetic topics.


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