to Article dE revision

Acta Pediatr Mex. 2016 Sep; 37 (5): 289-296.

Genomics Down syndrome

Diaz-Cuéllar S 1, Yokoyama-Rebollar E two, Of the Castillo-Ruiz V 3

Summary

Down syndrome is the most common chromosomal disorder of the human being,
with a frequency of 1 in 650 live births. Clinical manifestations are highly variable
and depend largely par- you of the presence of various factors such as genetic
mosaicism, variables changes in copy number variants or single nucleotide. The
identification of these variants has become a central topic of research since it is
essential for understanding the molecular mechanisms underlying this disease.

KEYWORDS: Down syndrome, trisomy 21, Hsa21, genomics.

1 Third-year medical resident. Department of Human

Genetics.
two Doctor of medical sciences. Medical seconded from the
Acta Pediatr Mex. 2016 Sep; 37 (5): 289-296.
Department of Human Genetics.
3 Medical geneticist. Head of the Depart- ment of Human

Genomics of Down syndrome. Genetics. National Institute of Pediatrics, Mexico.

Diaz-Cuéllar S 1, Yokoyama-Rebollar E two, Of the Castillo-Ruiz V 3

Abstract

Down syndrome is the MOST common chromosomal abnormality in humans with a

13 June 2016
frequency of 1 in 650 live births. Clinical manifestations tions are highly varying and Correspondence
depend Largely on the Presence of various genetic factors as mosaicism, copy number Dra. Emiy Yokoyama-Rebollar
2016; 37 (5): 289-296. Received: May 27, 2016 Accepted:
variants single nucleotide changes or variants. The identification of These variants have eyr75@hotmail.com.
Become a topic of research center, since it is essential for understanding the molecular Castillo- Genomics Down syndrome. Acta Pediatr Mex.
Mechanisms underlying esta disease. This article should be cited as
Diaz-Cuéllar S, Yokoyama-Rebollar E, Ruiz V. From the

KEYWORDS: Down syndrome; trisomy 21; Hsa 21; genomics

www.actapediatrica.org.mx
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 Acta Pediatric Mexico 2016 September; 37 (5)

INTRODUCTION The World Health Organization estimates a worldwide

Down syndrome is the most common chromosomal
abnormality and the leading cause of intellectual disability
worldwide. In most cases the cause is an extra copy of
chromosome 21 ( human chromosome 21 - Hsa21). It
encompasses a complex set of diseases that involve
virtually all organ systems. The most prevalent and
distinctive alterations are difficulty learning, craniofacial
dysmorphism, hypothyroidism, congenital heart disease,
gastrointestinal disorders and leukemias. It is estimated to
be the cause of 1 in every 150 abortions in the first quarter
and 8% of congenital anomalies in Europe. 1.2
prevalence of 1 in 1,000 live births; However, these figures
vary, reflecting the prevalence depends on socio-cultural
variations, such as access to prenatal diagnosis and legal
termination of pregnancy. 5 In Mexico, the Ministry of Health
estimates a prevalence of 1 in 650 live births; 6 but the 2010
report of the Registry and Epidemiological Surveillance of
External Congenital Malformations (RYVEMCE) estimated
a rate of 14.32 per 10,000 live births: 1 in 698. 7

Diagnosis is clinical and confirmed by cytogenetics.

It was described by John Langdon Down in 1866, in its
proposed classification of patients with intellectual
disabilities. 3 He teamed up for the first time with a
chromosomal abnormality in 1959 when Lejeune, Gautier
and Turpin described 5 boys and 4 girls with intellectual
disabilities and 47 chromosomes in cultured fibroblasts, a
small acrocentric being extra chromosome. The authors
proposed that the origin of the extra chromosome was
probably due to a lack of disjunction, therefore this was
the reason why the frequency of the disease increased
with maternal age. 4
Pattern observable physical characteristics ( Gestalt) is
highly suggestive and systemic alterations. However, not
all changes are present in each affected individual. In
newborns diagnosis may be difficult; However, ten
characteristics are highly prevalent. Hall, 1966, 48 affected
newborns analyzed and found 100% had 4 or more and
89% had characteristics 6 or more. Since then, these
characteristics are used to evaluate all live newborn,
known as Hall criteria 8 ( Table 1).

Table 1. Hall criteria

Characteristic %

flat facial profile 90

Down syndrome is due to a complete trisomy or partial
Moro reflex decreased 85
trisomy Hsa21 including the critical region 21q22.3. 95%
of cases are due to a complete or regular trisomy; about hypotonia 80

3% due to mosaicism, an impaired patients have normal hypermobility 80

cells and cells together with an extra Hsa21; less than 2% Redundant neck skin 80

is caused by an unbalanced translocation; ie, a karyotype Fissures upward slanting palpebral 80

with 46 chromosomes, but one of them, usually Hip dysplasia 70
chromosome 14, contains the extra material chromosomal Clinodactyly of the fifth finger 60
Hsa21.
pinnae dysplastic 60

Transverse palmar crease Four. Five

Hall B. Clin Pediatr.1966; 5 (1): 4-12.

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Diaz-Cuéllar S et to the. Genomics Down syndrome
In the 50s of the last century only 47% of live births with
Down syndrome survive one year; this figure increased to
over 90% in 1983 to 80 and 1997 life expectancy rose
from 25 to 49 years. Risk factors influencing survival are
black mother, congenital heart disease, heart no major
defects and prematurity. Predictors of survival did not
differ in patients with Down syndrome compared with
patients with intellectual disabilities in general. 9
Morbidity of patients with Down involves medical costs 12
syndrome to 13 times higher compared to the general
population during the first four years of life, especially
patients with congenital heart disease with the highest
mortality and who are estimated to require 5 to 7 times
more medical care than patients with Down syndrome
without congenital heart disease. 10
Other frequent causes of hospitalization are complications
of leukemia, respiratory, hypothyroidism and dementia;
respiratory cause even increased mortality. eleven
The history of a child with translocation de novo It does not
represent an increased risk and recurrence must only
relationship with maternal age. However, if the parent
carries a Robertsonian translocation risk is 3 to 5%; if the
mother is the carrier the risk increases 10 to 15%. The
situation is different when a parent carries a translocation
21:21, because the risk of recurrence is 100%.
CLINICAL AND ITS association with
GENOMICS
Although some characteristics of patients with Down
syndrome are constant there is great phenotypic
variability. Diverse studies
in mice and humans they have attempted to identify
sensitive genes dose explaining individually each of the
clinical data. Initially a region of the Hsa21 delimited called
critical region Down syndrome; however, other studies
have determined different regionesque also contribute to
the phenotype. 12
neurological manifestations
Developing
Patients acquire development milestones belatedly both
the motor area and the language. The average IQ in
patients with Down syndrome is 35 to 70 points. 13 Studies
in mice have suggested that defects in neurogenesis,
synaptic transmission and cell signaling pathways could
contribute to the problem of development through
excessive inhibition of neurotransmission. 14
Studies in patients with partial trisomy of Hsa21 have
suggested various regions of the Hsa21 contributing to
this intellectual disabilities; fifteen However, studies in mice did
not confirm these findings. 16
There are several genes in the critical region of Down
syndrome. The Gen DYRK1A ( 21q22.13) expressed in the
developing nervous system and the adult, its function is
the inhibition of cell proliferation and neuronal
differentiation promoting premature. Studies in mice
overexpressing Dyrk1a showed serious problems of
learning and spatial memory defects. 17 Similarly, the gene SIM2
( 21q22.13) orthologous to the gene Drosophila single
minded, is a transcription factor and principal regulator of
development; It is also expressed in the developing
human brain and in transgenic mice overexpressing Sim2,
They have shown mild problems learning and memory
problems. 18 Accession molecule
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 Acta Pediatric Mexico
sion of Down syndrome ( DSCAM, 21q22.2) it is expressed
in neuronal dendrites and contributes to synaptic plasticity;
however, it inhibits the branching of dendrites when
overexpressed in neurons of the hippocampus in vitro
and mice with three copies of Dscam. 19 Another gene
associated with mental retardation is Kcnj6 (GIRK2, 21q22.1), locomotor defects caused failure vesicle recycling at the
which it has been overexpressed in mouse hippocampus. twenty neuromuscular junction, suggesting that these three
There are also genes outside the critical region of Down
syndrome they have been associated with neurological
phenotype of patients with Down syndrome. The
synaptojanin1 ( SYNJ1, 21q22.2) is a protein, forming
vesicles in neuronal synapses, which plays an important
role in neurotransmission dephosphorylating
phosphatidylinositol bisphosphate altered in a mouse model
with Down syndrome who had problems with learning and
memory, which is normalized to the reduce gene dose Synj1
from three to two. twenty-one
Finally, analysis of segmental trisomies confirmed the
important role of amyloid precursor protein ( APP, 21q21.3)
as inhibitors of the metabolites of this protein in a mouse
model, improved learning and memory, suggesting that
the dose triple gene
APP It could be causing neurological phenotype in
patients with Down syndrome. 22
Motor control and hypotonia
Neonates with Down syndrome commonly have hypotonia
and most motor disturbances. The findings in humans and
in mouse models have shown a reduced number of
granular neurons in the cerebellum. 2. 3 This reduced
cerebellar neurogenesis may be due to faulty signaling
sonic hedgehog ( SHH) precursor neurons, caused by high
levels of APP. 24 Another gene mentioned is the DYRK1A, whichregion contains the gene ETS2 (ETS2, 21q22.2) whose
also it is proposed as a candidate gene for motor deficits
in these patients.
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2016 September; 37 (5)
Another theory are defects in synapse morphology and
formation of synaptic vesicles at the neuromuscular
junction. Strengthening this theory, the overexpression of
genes
ITSN1 ( 21q22.1), SYNJ1 ( 21q22.2) and DSCR1
(21q22.12) in transgenic flies counterparts Drosophila, and
genes, along with DYRK1A and APP, They are sensitive
candidate genes causing dose-engine defects in patients
with Down syndrome. 25
Alzheimer disease
Patients with Down syndrome are characterized by
Alzheimer's at an early age and the eventual onset of
dementia. A major candidate gene is the aforementioned
APP, since its proteolysis generates amyloid β
(TO- β) the main component of amyloid plaques in brains of
patients with Alzheimer's disease mutations and
duplications whose type have been linked to early onset of
the disease. 26 Another involved gene, also already
mentioned, is the
DYRK1A, whose product has been shown phosphorylate
APP protein. A mouse model overexpressing Dyrk1a shows
high levels of phospho-APP and A β. 27
craniofacial features
Microcephaly, flat occiput, brachycephaly, small face and
jaw of small size are characteristics of Down syndrome.
Mouse model studies have revealed a pattern of
craniofacial abnormalities like these, and even a region
responsible for these characteristics will be delimited. 28 This
overexpression showed an association with skeletal
abnormalities observed in patients with Down syndrome. 29
Diaz-Cuéllar S et to the. Genomics Down syndrome
Hemato-oncological disorders
hematologic
Patients with Down syndrome are at increased risk of
developing leukemia (relative risk of 18) and particularly
megakaryoblastic leukemia has a much higher relative risk
(500). 30
It is noteworthy that 10 to 20% of patients with Down
syndrome develop a call transient leukemia, also known
as transient myeloproliferative disorder or abnormal
transient myelopoiesis. This is an almost exclusively
leukemia newborns with Down syndrome, which is often
accompanied by mutations in the gene transcription factor
hematopoietic GATA1 ( Xp11.23) and although usually
resolves spontaneously at 3 months of age 20% of
patients recovered from a megakaryoblastic transient
leukemia develop leukemia in the first 4 years of life and is
always accompanied by somatic mutations in GATA1, indicating
congenital heart Disease
that mutations in this gene could be an event in utero
and megakaryoblastic leukemia blasts can involve
persistent transient subclones cell leukemia because
additional mutations. 31 In addition, human studies with
different partial trisomy 21 identified a 8.35 Mb region in
Hsa21, involving genes RUNX1 ( 21q22.3), ERG
(21q22.2) and ETS2 ( 21q22.3) as candidates for the
development of megakaryoblastic leukemia in Down
syndrome. Particularly, the transcription factor RUNX1 It is
involved in megakaryopoiesis and maintenance of
hematopoietic stem cells. 12
solid tumors
The risk for solid tumors is lower in patients with Down
syndrome. heterozygous mice
for mutations in the gene APC (APC, 5q22.2) crossed with
trisomic models 33 genes with homology to human genes
in Hsa21, they showed a clear reduction in tumor
incidence in trisomic offspring compared with euploid
progeny. The Gen ETS2 (ETS2,
21q22.3), included in this region, inhibited tumor growth
when expressed in three copies, conversely, when
reduced to a copy, resulting in increased rate of tumors. 32
Recently it has been postulated that a decrease in
angiogenesis may prevent the growth of tumors in Down
syndrome. In this context, DSCR1 It has shown to inhibit
angiogenesis induced by vascular endothelial growth
factor. Other genes that have decreased angiogenesis in
mouse models include ADAMTS1, Erg, Jam2 and Pttg1ip. 33
About 50% of patients with Down syndrome have
congenital heart disease. 8 One of the largest
population-based studies frequently were complete
atrioventricular canal defects, ventricular septal defect,
atrial septal defect, tetralogy of Fallot and persistence of
the ductus arteriosus. 3. 4
Mexican population data indicate a prevalence of
congenital heart diseases (Down syndrome) 58%;
However, in contrast to reports worldwide complete
atrioventricular canal shows a much lower frequency than
the interventricular and interatrial communications ( Table
2). 35 In 2008, the National Down Syndrome Project of
United States of America found that Hispanic descent
confers an odds ratio of 0.48 for complete atrioventricular
canal. 36
Genomic mechanisms involved in this variability are still
widely discussed. Because of its high frequency,
compared to
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 Acta Pediatric Mexico 2016 September; 37 (5)

Table 2. Reported prevalence of congenital heart disease globally and in complete atrioventricular canal in patients with Down
Mexico syndrome. 38

Type of heart disease % World% Mexico

Among variants in copy number of chromosome 21
atrioventricular canal 37 8
associated with disease are some involving duplications of
communication intervertricular 31 22 the gene regulatory regions RIPK4 ( 21q22.2), which it has
septal fifteen 24 been associated with epithelial morphogenesis (RR: 2.29)
Tetralogy of Fallot 5 0.6 and the gene ZBTB21 involved in the regulation of the
Patent ductus arteriosus signaling pathway Wnt / beta-catenin via required for
4 twenty-one
cardiac differentiation of embryonic cells (RR: 1.84). In

Irving C et to the. Arch Dis Child.2012 Apr; 97 (4): 326-30; Rubens J et to the.
addition, we have identified copy number variants on
Rev Esp Cardiol.2003 Sep.56 (9): 894-9. chromosome 21 outside, especially regions previously
associated with non-syndromic congenital heart disease.
This affects the genes group cilioma, which is a critical
individuals without Down syndrome and variable clinical
component of the atrioventricular septation 39 ( Table 3).
spectrum, congenital heart disease have been used as a
model in search
loci risk pathogenic mutations, and gene dose variation in
copy number variations (CNVs for short English)
explaining this complex etiopathogenesis of the phenotype
of Down syndrome. 37 Finally, it is important to note that despite these advances
there are still various manifestations frequent clinical in
patients with Down syndrome who do not yet have a
correlation with specific genes, such as ophthalmological
Analysis in humans with different trisomies, 21 partial, led
disorders, audiological, hypothyroidism, dermatological
to the identification of a region
disorders, genitourinary as cryptorchidism, hypospadias ,
1.77 Mb containing 10 genes. Of these, DSCAM
kidney malformations and immune dysregulation
(21q22.2) is the only expressed in the developing heart, so
associated with recurrent infections.
it was proposed as a candidate gene; this analysis rule
genes previously identified as candidates, including DIRK1A

and COL6A1 ( 21q22.3) genes highly expressed in the

atrioventricular endocardial cushions to level in fetuses Table 3. Number of rare variants copies associated with congenital heart
with Down syndrome. (12) Unfortunately, no heart defects disease in Down syndrome

found in mice models trisomic for 33 genes, including DSCAM.

locus Number variants genes
copies identified

2p21 Duplication (584.5kb) LINC01121,

SRBD1, RKCE
Outside the Hsa21, mutations in CRELD1 2q12.3 Duplication (784.7kb) LIMS1
(3p25.3) have been associated with complete 2q13 Deletion (583.3-559.3kb) MIR4267
atrioventricular canal in the general population and has
8p23.1 Deletion (79.1kb) XKR5, DEFB1
been postulated association with the defect in patients with
8p23.1 Duplication CTSB, DEFB134,
Down syndrome. Other studies have shown that (251-524.7kb) DEFB136,
polymorphisms in genes DEFB135

SLC19A1 ( 21q22.3) and MTHFR ( 1p36.3) involved in folate 15q13.3 Duplication (514kb) CHRNA7

pathway, they are associated with 22q11.21 Deletion (957.8kb) PPM1F, TOP3B

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Diaz-Cuéllar S et to the. Genomics Down syndrome
CONCLUSIONS
The study of genes implicated in Down syndrome
continues to be a central theme, providing major
challenges for analysis. The information obtained so far
has not allowed clarify exactly dose responsive genes
involved in the phenotype of these patients, which could
be explained by the effect of multiple genes involved and
the complex interaction between them. Furthermore, many
of the clinical manifestations of patients with Down
syndrome behave as multifactorial entities, where there is
one involved causative gene, but a group of genes that
interact with the environment, which gives high complexity
to the underlying pathophysiology of this disease.
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