Methodology

There were 39 Down's syndrome individuals in the study (24 males and 15 girls), ranging in age from
5 to 18. The sample was thoroughly examined for prenatal diagnostic procedures ranging from
karyotyping to rapid molecular methods such as MLPA, FISH, QF-PCR, PSQ, NGS, and non-invasive
prenatal diagnosis, including MLPA, FISH, QF-PCR, PSQ, NGS, and non-invasive prenatal diagnosis,
including MLPA, FISH, QF-PCR, PSQ, NGS, and non-invasive prenatal diagnosis.

Hypothesis

Gene dosage imbalance occurs when the dosage or amount of Hsa21 genes is elevated, leading to
increased gene proliferation."

"It also includes the possibility of different genes being linked to different Down syndrome
symptoms."

Given that Hsa21 contains five miRNA genes, bioinformatic annotation predicted that Ts21 would
cause these miRNAs' gene dosage to be overexpressed. This notion was first tested in fibroblasts
from a person with DS and their monozygotic twin who was unaffected. The study used twins so that
changes in gene expression could be explained only by Hsa21 supernumeraries rather than
polymorphism variability elsewhere in the genome. Importantly, our studies demonstrated that miR-
155 was more abundantly expressed in the fibroblasts isolated from the DS individual compared to
the unaffected twin; the expression levels of the other four Hsa21-derived miRNAs were not found.

To confirm these findings, MiRNA expression profile studies were performed utilising RNA from
control and DS foetal hippocampus tissues. When hippocampal specimens from people with DS were
compared to controls, 10 were found to be overexpressed and 22 were found to be underexpressed
by at least 50% in hippocampus specimens from people with DS. Importantly, the profile tests
revealed that among the five Hsa21-derived miRNAs, miR-99a, let-7c, and miR-155 were
overexpressed. The values of miR-125b-2 were ambiguous, and miR-802 was not identified. Finally,
when total RNA isolated from human prefrontal cortex specimens from foetuses, infants/children,
adolescents, and adults with DS was compared to age- and sex-matched control brain specimens,
qPCR revealed that all five Hsa21-derived miRNAs were overexpressed by at least 50% in prefrontal
cortex samples at all ages examined.

5. DOWN'S SYNDROME RESEARCH PROBLEMS-

Genetic science has yet to overcome the following problems:

• Downs syndrome can be inherited in some rare cases.

• In roughly 5% of cases, various chromosomal translocations produce Downs syndrome.

• There is currently no recognised cause for Down syndrome.

• Non-disjunction occurs when the two copies of chromosome 21 do not separate during egg
formation, resulting in two copies of the chromosome in the egg. When this egg is fertilised, three
copies of chromosome 21 are found in each of the baby's cells. The cause of this non-disjunction is
still unknown.

• The chances of having a baby with Down syndrome increase as the mother's age increases; yet,
over half of all Down syndrome babies are born to mothers under the age of 35, simply because
more young women are having children.

• Down syndrome is unaffected by race, country, financial status, religion, or what the mother or
father performed during pregnancy.

• There is no link between incest and Down syndrome development.

• Two to four percent of the population has mosaic translocation. Down syndrome (mDs) is a genetic
disorder in which some cells, but not all, have an extra copy of the 21st chromosome, but the
remainder of the cells are unaffected. Translocation occurs when a part of chromosome 21 gets
linked to another chromosome during cell division.

In hereditary Translocation Down syndrome, one of the parents inherits an extra chromosome 21.
(which affects one to two percent of all people with Down syndrome).

CONCLUSION

The most common cause of DS babies is the presence of an extra copy of chromosome 21, leading in
trisomy. Two more possibilities are Robertsonian translocation and isochromosome or ring
chromosome. The term isochromosome refers to a phenomenon in which two long arms of a
chromosome split together during egg sperm development rather than the long and short arms
splitting apart. Trisomy 21 (karyotype 47, XX, + 21 for females and 47, XY, + 21 for males) is caused
by the failure of chromosome 21 to split during egg or sperm development. In Robertsonian
translocation, the long arm of chromosome 21 is joined to another chromosome, which occurs in
just 2-4 percent of cases (generally chromosome 14).
After conception or during cell division, mosaicism is concerned with mistakes or mis divisions. As a
result, people with mosaic DS have two cell lineages that contribute to Mosaicism patients' tissues
and organs (one with the normal number of chromosomes, and other one with an extra number 21).

Corelation between genetics and phenotype.

The Gene Dosage Imbalance Hypothesis states that DS patients have a higher dosage or copy
number of genes on Hsa 21, which could contribute to an increase in gene expression. This approach
has been expanded to include the possibility that certain genes or subsets of genes influence
different DS features. A genetic imbalance is formed by a non-specific dosage of a number of
trisomic genes, according to the amplified developmental instability theory, which has a significant
impact on the expression and regulation of numerous genes across the genome. The crucial zone
theory was also included to the list of hypotheses. Only one or a few small chromosomal regions,
known as "Down syndrome critical regions" (DSCR), a region of 3.8-6.5 Mb on 21q21.22 with roughly
30 genes, were found to be responsible for the bulk of DS symptoms in patients with partial trisomy
for Hsa21. A 1.6 to 2.5 Mb area was previously thought to be sufficient to induce the DS phenotype.
Hsa 21 sequencing was a significant step forward in DS research, allowing researchers to get a better
grasp of the disease's genotype-phenotype connections as well as more precise characterizations of
DSCR regions. A "critical region" inside 21q22 was assumed to be the origin of several DS symptoms,
including craniofacial deformities, congenital cardiac malformations of the endocardial cushions,
clinodactyly of the fifth finger, and mental retardation. Down syndrome cell adhesion molecule
(DSCAM), a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK1A) and calcineurin 1
(RCAN1) regulator, has been proposed to play a critical role in the developing brain and has also
been identified as a candidate gene for the increased risk of CHD in DS individuals. The disruption of
these systems may play a role in the neurocognitive phenotype of DS. DSCAM is required for
neuronal differentiation, axon guidance, and the development of neural networks. Based on a
thorough examination of human and DS mouse studies, it is obvious that no single gene or gene
region is sufficient to cause all DS symptoms. Alternatively, a number of important locations or genes
are likely to play a role in a certain phenotypic or phenotypic combination associated with DS.

DS or Trisomy 21, the most common chromosomal aberration in live-born infants, is connected to a
number of congenital disorders. To better understand the link between phenotype and genotype,
several ideas have been offered. A "critical region" inside 21q22 was assumed to be the origin of
several DS symptoms, including craniofacial deformities, congenital heart malformations of the
endocardial cushions, clinodactyly of the fifth finger, mental retardation, and other features. The
goal of this study is to determine which genes, such as APP, BACE2, PICALM, APOE, GATA 1, JAK 2,
CRELD 1, and DSCAM, are linked to DS symptoms. The procedures utilised in the prenatal diagnosis
of Down syndrome are also covered in detail in this article. In the mid-1990s, FISH, a quick
aneuploidy test that can be conducted on uncultured amniocytes, was launched. In recent years,
MLPA and QF-PCR have been added to the list of rapid aneuploidy detection procedures. One of the
other techniques is to use NGS for cell-free foetal DNA screening in maternal plasma. Other
technologies for aneuploidy diagnosis, aside from FISH, MLPA, and QF-PCR, are not commercialised
due to their high operating costs, labor-intensive process, and challenging data interpretation.