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#190685 TRISOMY
21
Alternative
titles; symbols
DOWN SYNDROME
DOWN SYNDROME CHROMOSOME REGION, INCLUDED; DCR,
INCLUDED
DOWN SYNDROME CRITICAL REGION, INCLUDED; DSCR,
INCLUDED
table OF
CONTENTS
Gene Map Locus: 21q22.3
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TEXT
-
DESCRIPTION
- A number sign (#) is used with this entry
because it concerns a chromosomal aberration and
many genes are involved in the phenotype.
Down syndrome, the most frequent form of
mental retardation caused by a microscopically
demonstrable chromosomal aberration, is
characterized by well-defined and distinctive
phenotypic features and natural history. It is
caused by triplicate state (trisomy) of all or a
critical portion of chromosome 21.
-
CLINICAL
FEATURES
- Trisomy 21 (Lejeune
et al., 1959), one of the most common
chromosomal abnormalities in liveborn children,
causes Down syndrome (Down,
1866), a particular combination of
phenotypic features that includes mental
retardation and characteristic facies.
It has long been recognized that the risk of
having a child with trisomy 21 increases with
maternal age (Penrose,
1933). For example, the risk of having a
liveborn with Down syndrome at maternal age 30
is 1 in 1,000 and at maternal age 40 is 9 in
1,000 (Hook, 1982;
Hook et al.,
1983).
Individuals with Down syndrome often have
specific major congenital malformations such as
those of the heart (30-40% in some studies),
particularly the atrioventricular canal, and of
the gastrointestinal tract, such as duodenal
stenosis or atresia, imperforate anus, and
Hirschsprung disease (142623).
Some of these clinical features have been
incorporated into the preliminary phenotypic
maps of chromosome 21 developed by Korenberg
(1993), Korenberg et
al. (1992), and Delabar
et al. (1993).
Leukemia (both ALL and AML) and leukemoid
reactions show increased incidence in Down
syndrome (Fong and
Brodeur, 1987; Robinson,
1992). Estimates of the relative risk have
ranged from 10 to 20 times higher than the
normal population; in particular, acute
megakaryocytic leukemia occurs 200 to 400 times
more frequently in the Down syndrome than in the
chromosomally normal population (Zipursky
et al., 1987). Transient leukemoid reactions
have been reported repeatedly in the neonatal
period, and this phenotype has been tentatively
mapped to the proximal long arm of chromosome 21
(Niikawa et al.,
1991).
Ninety percent of all Down syndrome patients
have a significant hearing loss, usually of the
conductive type (Mazzoni
et al., 1994).
For additional defects and phenotypic
characteristics, see Epstein
(1989).
Patients with Down syndrome develop the
neuropathologic hallmarks of Alzheimer disease
at a much earlier age than individuals with
Alzheimer disease without trisomy 21 (Wisniewski
et al., 1985). Characteristic senile plaques
and neurofibrillary tangles are present in the
brain of all individuals with Down syndrome over
the age of 40 years (Wisniewski
et al., 1985). It is not known if the
triplication of the amyloid precursor protein
gene (APP; 104760)
is the cause of this phenomenon. Several
mutations in the APP gene have been described in
families with early-onset Alzheimer disease
without trisomy 21 (e.g., Goate
et al., 1991).
CYTOGENETICS
- Most individuals (95%) with trisomy 21 have
3 free copies of chromosome 21; in about 5% of
patients, 1 copy is translocated to another
acrocentric chromosome, most often chromosome 14
or 21 (Thuline and
Pueschel, 1982; Hook,
1982). In 2 to 4% of cases with free trisomy
21 there is recognizable mosaicism for a
trisomic and a normal cell line (Mikkelsen,
1977).
-
Origin of Free Trisomy 21
The availability of highly informative DNA
markers has allowed the parental origin of the
extra chromosome 21 and the meiotic/mitotic
origin to be determined. More than 400 families
have been studied (Antonarakis et al., 1991,
1992; Antonarakis,
1993; Sherman et al., 1991,
1992) and the results
are as follows : 1) Errors in meiosis that lead
to trisomy 21 are overwhelmingly of maternal
origin; only about 5% occur during
spermatogenesis. 2) Most errors in maternal
meiosis occur in meiosis I and the mean maternal
age associated with these is 32 years (the mean
maternal age of the general population is
approximately 27 years). Thus, meiosis I errors
account for 76 to 80% of maternal meiotic errors
and 67 to 73% of all instances of free trisomy
21. 3) Maternal meiosis II errors constitute 20
to 24% of maternal errors and 18 to 20% of all
cases of free trisomy 21. The mean maternal age
is also advanced and is 31.4 in one study and
34.1 in another. 4) In rare families in which
there is paternal nondisjunction, most of the
errors occur in meiosis II. The mean maternal
and paternal ages are similar to the mean
reproductive age in western societies. 5) In 5%
of trisomic individuals the supernumerary
chromosome 21 appears to result from an error in
mitosis. In these cases there is no advanced
maternal age and there is no preference for
which chromosome 21 is duplicated in the mitotic
error.
Warren et al.
(1987) and Sherman et
al. (1991) have described an association
between trisomy 21 and reduced recombination in
meioses. A significant proportion (at least 30%)
of maternal meiosis I nondisjunctions of
chromosome 21 is associated with failure to
recombine. It is not known whether the paucity
of recombination is related to maternal age;
moreover, the mechanism of recombination failure
(asynapsis vs abnormalities during or after
synapsis) is as yet unclear.
-
Origin of Translocation trisomy
21
All de novo t(14;21) trisomies studied have
originated in maternal germ cells (Petersen
et al., 1991; Shaffer
et al., 1992). The mean maternal age was
29.2 years. In de novo t(21;21) Down syndrome
the situation is different (Grasso
et al., 1989; Antonarakis
et al., 1990; Shaffer
et al., 1992). In most cases (14 out of 17)
the t(21;21) is an isochromosome (dup21q) rather
than the result of a Robertsonian translocation
caused by a fusion between 2 heterologous
chromatids. About half were of paternal and half
of maternal origin. In the 3 de novo t(21;21)
true Robertsonian trisomy 21 cases, the extra
chromosome 21 was maternal.
-
MAPPING
-
-
Down Syndrome Critical Region
Mapping of the chromosomal region that, if
triplicated, results in the phenotypic
characteristics of Down syndrome has been
facilitated by the use of DNA samples from
individuals who have partial trisomy 21 with or
without features of the Down syndrome phenotype
(Rahmani et al.,
1989; McCormick et
al., 1989; Korenberg
et al., 1990; Delabar
et al., 1993; Korenberg,
1993). Although detailed analysis of these
DNAs is still under way, an area of
approximately 5 Mb between loci D21S58 and
D21S42 has been identified that is associated
with mental retardation and most of the facial
features of the syndrome. In particular, a
subregion that includes D21S55 and MX1
(interferon-induced protein p78; 147150),
the latter being located in band 21q22.3, has
been associated with mental retardation and
several morphologic features, including oblique
eye fissure, epicanthus, flat nasal bridge,
protruding tongue, short broad hands,
clinodactyly of the fifth finger, gap between
first and second toes, hypotonia, short stature,
Brushfield spots, and characteristic
dermatoglyphics (Delabar
et al., 1993). Additional phenotypic
characteristics may map outside the minimum
critical region (symbolized DCR). Material from
other rare patients who have features of Down
syndrome but no visible chromosomal abnormality
may help to narrow down the critical region. In
several such studies, however, no triplicated
region has been identified (McCormick
et al., 1989; Delabar
et al., 1993). It is possible that these
patients do not have any chromosome 21
abnormality and their phenotype is a phenocopy
of Down syndrome.
Fuentes et al.
(1995) cloned a gene (DSCR1; 602917)
from the Down syndrome critical region that is
highly expressed in brain and heart, and
suggested it as a candidate for involvement in
the pathogenesis of DS, in particular mental
retardation and/or cardiac defects.
-
PATHOGENESIS
- As a first step in identifying the genes
responsible for individual features of Down
syndrome and their pathophysiology, Korenberg
et al. (1994) established a panel of cell
lines derived from 16 individuals with Down
syndrome caused by duplication of small regions
of chromosome 21. The molecular breakpoints were
determined using fluorescence in situ
hybridization and Southern blot dosage analysis
of 32 markers unique to chromosome 21. Combining
this information with detailed clinical
evaluations of the subjects, Korenberg
et al. (1994) constructed a 'phenotypic map'
that included 25 features and assigned regions
of 2 to 20 Mb as likely to contain the genes
responsible. This study provided evidence for a
significant contribution of genes outside the
D21S55 region to the DS phenotypes, including
the facies, microcephaly, short stature,
hypotonia, abnormal dermatoglyphics, and mental
retardation. The results strongly suggest that
DS is a contiguous gene syndrome and make it
unlikely that a single DS chromosomal region is
responsible for most of the DS phenotypic
features.
-
POPULATION
GENETICS
- The frequency of trisomy 21 in the
population is 1 in 650 to 1,000 live births
(Hook, 1982).
-
SEE ALSO
- Rex and Preus
(1982)
REFERENCES
- 1. Antonarakis, S.
E. :
- Human chromosome 21: genome mapping
and exploration circa 1993. Trends
Genet. 9: 142-148, 1993.
PubMed ID : 8516850
- 2. Antonarakis, S.
E.; Adelsberger, P. A.; Petersen, M. B.;
Binkert, F.; Schinzel, A. A. :
- Analysis of DNA polymorphism
suggests that most de novo dup(21q) chromosomes
in patients with Down syndrome are
isochromosomes and not translocations.
Am. J. Hum. Genet. 47: 968-972,
1990.
PubMed ID : 1978562
- 3. Antonarakis, S.
E.; Lewis, J. G.; Adelsberger, P. A.; Petersen,
M. B.; Schinzel, A. A.; Binkert, F.; Schmid, W.;
Pangalos, C.; Raoul, O.; Chakravarti, A.; Hafez,
M.; Cohen, M. M.; Roulston, D.; Schwartz, S.;
Mikkelsen, M.; Tranebjaerg, L.; Greenberg, F.;
Hoar, D. I.; Rudd, N. L.; Warren, A. C.;
Metaxotou, C.; Bartsocas, C.; Down Syndrome
Collaborative Group :
- Parental origin of the extra
chromosome in trisomy 21 using DNA polymorphism
analysis. New Eng. J. Med.
324: 872-876, 1991.
PubMed ID : 1825697
- 4. Antonarakis, S.
E.; Petersen, M. B.; McInnis, M. G.;
Adelsberger, P. A.; Schinzel, A. A.; Binkert,
F.; Pangalos, C.; Raoul, O.; Slaugenhaupt, S.
A.; Hafez, M.; Cohen, M. M.; Roulson, D.;
Schwartz, S.; Mikkelsen, M.; Tranebjaerg, L.;
Greenberg, F.; Hoar, D. I.; Rudd, N. L.; Warren,
A. C.; Metaxotou, C.; Bartsocas, C.;
Chakravarti, A. :
- The meiotic stage of nondisjunction
in trisomy 21: determination using DNA
polymorphisms. Am. J. Hum.
Genet. 50: 544-550, 1992.
PubMed ID : 1347192
- 5. Delabar, J. M.;
Theophile, D.; Rahmani, Z.; Chettouh, Z.;
Blouin, J. L.; Prieur, M.; Noel, B.; Sinet, P.
M. :
- Molecular mapping of twenty-four
features of Down syndrome on chromosome
21. Europ. J. Hum. Genet. 1:
114-124, 1993.
- 6. Down, J. L. H.
:
- Observations on an ethnic
classification of idiots. London
Hosp. Clin. Lect. Rep. 3: 259 only, 1866.
- 7. Epstein, C. J.
:
- Down syndrome, trisomy
21.In: Scriver, C. R.; Beaudet, A. L.;
Sly, W. S.; Valle, D. :
- Metabolic Basis of Inherited
Disease. New York: McGraw-Hill (pub.)
1989. Pp. 291-326.
- 8. Fong, C.-T.;
Brodeur, G. M. :
- Down's syndrome and leukemia:
epidemiology, genetics, cytogenetics and
mechanisms of leukemogenesis.
Cancer Genet. Cytogenet. 28: 55-76,
1987.
PubMed ID : 2955886
- 9. Fuentes, J.-J.;
Pritchard, M. A.; Planas, A. M.; Bosch, A.;
Ferrer, I.; Estivill, X. :
- A new human gene from the Down
syndrome critical region encodes a proline-rich
protein highly expressed in fetal brain and
heart. Hum. Molec. Genet. 4:
1935-1944, 1995.
PubMed ID : 8595418
- 10. Goate, A.;
Chartier-Harlin, M. C.; Mullan, M.; Brown, J.;
Crawford, F.; Fidayi, L.; Giuffra, L.; Haynes,
A.; Irvine, N.; James, L.; Mant, R.; Newton, P.;
Rooke, K.; Roques, P.; Talbot, C.;
Pericak-Vance, M.; Roses, A.; Williamson, R.;
Rorsov, M.; Owen, M.; Hardy, J. :
- Segregation of a missense mutation
in the amyloid precursor protein gene with
familial Alzheimer disease.
Nature 349: 704-706, 1991.
PubMed ID : 1671712
- 11. Grasso, M.;
Giovannucci, M. L.; Pierluigi, M.; Tavellini,
F.; Perroni, L.; Dagna-Bricarelli, F. :
- Isochromosome, not translocation in
trisomy 21q21q. Hum. Genet.
84: 63-65, 1989.
PubMed ID : 2532615
- 12. Hook, E. B.;
Cross, P. K.; Schreinemachers, D. M. :
- Chromosomal abnormality rates at
amniocentesis and in live-born infants.
J.A.M.A. 249: 2034-2038, 1983.
PubMed ID : 6220164
- 13. Hook, E. G.
:
- Epidemiology of Down
syndrome.In: Pueschel, S. M.; Rynders,
J. E. :
- Down Syndrome. Advances in
Biomedicine and the Behavioral
Sciences. Cambridge: Ware Press (pub.)
1982. Pp. 11 only.
- 14. Korenberg, J.;
Bradley, C.; Disteche, C. :
- Down syndrome: molecular mapping of
congenital heart disease and duodenal
stenosis. Am. J. Hum. Genet.
50: 294-302, 1992.
PubMed ID : 1531166
- 15. Korenberg, J.;
Kawashima, H.; Pulst, S.; Ikeuchi, T.;
Ogasawara, N.; Yamamoto, K.; Schonberg, S.;
Kojis, T.; Allen, L.; Magenis, E.; Ikawa, H.;
Taniguchi, N.; Epstein, C. :
- Molecular definition of the region
of chromosome 21 that causes features of the
Down syndrome phenotype. Am. J.
Hum. Genet. 47: 236-246, 1990.
PubMed ID : 2143053
- 16. Korenberg, J.
R. :
- Toward a molecular understanding of
Down syndrome.In: Epstein, C. J. :
- The Phenotypic Man. Prog. Clin.
Biol. Res.. 384 1993. Pp. 87-115.
- 17. Korenberg, J.
R.; Chen, X.-N.; Schipper, R.; Sun, Z.; Gonsky,
R.; Gerwehr, S.; Carpenter, N.; Daumer, C.;
Dignan, P.; Disteche, C.; Graham, J. M., Jr.;
Hugdins, L.; McGillivray, B.; Miyazaki, K.;
Ogasawara, N.; Park, J. P.; Pagon, R.; Pueschel,
S.; Sack, G.; Say, B.; Schuffenhauer, S.;
Soukup, S.; Yamanaka, T. :
- Down syndrome phenotypes: the
consequences of chromosomal imbalance.
Proc. Nat. Acad. Sci. 91: 4997-5001,
1994.
PubMed ID : 8197171
- 18. Lejeune, J.;
Gautier, M.; Turpin, R. :
- Etude des chromosomes somatiques de
neuf enfants mongoliens. C. R.
Acad. Sci. 248: 1721-1722, 1959.
- 19. Mazzoni, D. S.;
Ackley, R. S.; Nash, D. J. :
- Abnormal pinna type and hearing loss
correlations in Down's syndrome. J.
Intellect. Disabil. Res. 38: 549-560,
1994.
PubMed ID : 7881226
- 20. McCormick, M.;
Schinzel, A.; Petersen, M.; Stetten, G.;
Driscoll, D.; Cantu, E.; Tranebjaerg, L.;
Mikkelsen, M.; Watkins, P.; Antonarakis, S.
:
- Molecular genetic approach to the
characterization of the Down syndrome region of
chromosome 21. Genomics 5:
325-331, 1989.
PubMed ID : 2529205
- 21. Mikkelsen, M.
:
- Down's syndrome cytogenetic
epidemiology. Hereditas 86:
45-59, 1977.
PubMed ID : 143464
- 22. Niikawa, N.;
Deng, H. X.; Abe, K.; Harada, N.; Okada, T.;
Tsuchiya, H.; Akaboshi, I.; Matsuda, I.;
Fukushima, Y.; Kaneko, Y. :
- Possible mapping of the gene for
transient myeloproliferative syndrome at
21q11.2. Hum. Genet. 87:
561-566, 1991.
PubMed ID : 1680787
- 23. Penrose, L. S.
:
- The relative effects of paternal and
maternal age in mongolism. J.
Genet. 27: 219 only, 1933.
- 24. Petersen, M.
B.; Adelsberger, P. A.; Schinzel, A. A.;
Binkert, F.; Hinkel, G. K.; Antonarakis, S. E.
:
- Down syndrome due to de novo
Robertsonian translocation t14;21: DNA
polymorphism analysis suggests that the origin
of the extra 21q is maternal. Am.
J. Hum. Genet. 49: 529-536, 1991.
PubMed ID : 1831959
- 25. Rahmani, Z.;
Blouin, J.; Creau-Goldberg, N.; Watkins, P.;
Mattei, J.; Poissonnier, M.; Prieur, M.;
Chettouh, Z.; Nicole, A.; Aurias, A.; Sinet, P.;
Delabar, J. :
- Critical role of D21S55 region on
chromosome 21 in the pathogenesis of Down
syndrome. Proc. Nat. Acad.
Sci. 86: 5958-5962, 1989.
PubMed ID : 2527368
- 26. Rex, A. P.;
Preus, M. :
- A diagnostic index for Down
syndrome. J. Pediatr. 100:
903-906, 1982.
PubMed ID : 6211531
- 27. Robinson, L. L.
:
- Down syndrome and leukemia.
Leukemia 6: 5-7, 1992.
PubMed ID : 1532221
- 28. Shaffer, L. G.;
Jackson-Cook, C. K.; Stasiowski, B. A.; Spence,
J. E.; Brown, J. A. :
- Parental origin determination in 30
de novo Robertsonian translocations.
Am. J. Med. Genet. 43: 957-963,
1992.
PubMed ID : 1357969
- 29. Sherman, S. L.;
Freeman, S. B.; Grantham, M.; Peters, J.;
Jacobs, P. A.; Kurnit, D. M.; Uchida, I.;
Petersen, M. B.; Mikkelsen, M.; Hassold, T. J.
:
- Non-disjunction of trisomy 21:
comparison of centromere maps resulting from
maternal meiosis I and II non-disjunction.
(Abstract) Am. J. Hum. Genet.
51 (suppl.): A24 only, 1992.
- 30. Sherman, S. L.;
Takaesu, N.; Freeman, S. B.; Grantham, M.;
Phillips, C.; Blackston, R. D.; Jacobs, P. A.;
Cockwell, A. E. :
- Association between reduced
recombination and nondisjunction.
Am. J. Hum. Genet. 49: 608-620,
1991.
PubMed ID : 1831960
- 31. Thuline, H. C.;
Pueschel, S. M. :
- Cytogenetics in Down
syndrome.In: Pueschel, S. M.; Rynders,
J. E. :
- Down Syndrome. Advances in
Biomedicine and the Behavioral
Sciences. Cambridge: Ware Press (pub.)
1982. Pp. 133 only.
- 32. Warren, A. C.;
Chakravarti, A.; Wong, C.; Slaugenhaupt, S. A.;
Halloran, S. L.; Watkins, P. C.; Metaxotou, C.;
Antonarakis, S. E. :
- Evidence for reduced recombination
on the nondisjoined chromosomes 21 in Down
syndrome. Science 237:
652-654, 1987.
PubMed ID : 2955519
- 33. Wisniewski, K.
E.; Wisniewski, H. M.; Wen, G. Y. :
- Occurrence of neuropathological
changes and dementia of Alzheimer's disease in
Down's syndrome. Ann. Neurol.
17: 278-282, 1985.
PubMed ID : 3158266
- 34. Zipursky, A.;
Peeters, M.; Poon, A. :
- Megakaryoblastic leukemia and Down
syndrome--A review.In: McCoy, E. E.;
Epstein, C. J. :
- Oncology and Immunology of Down
Syndrome. New York: Alan R. Liss (pub.)
1987. Pp. 33-56.
CLINICAL
SYNOPSIS
View
Clinical Synopsis Entry
Rebekah S. Rasooly - updated : 8/2/1998
Orest Hurko - updated : 8/11/1995
Victor A. McKusick : 7/21/1994
EDIT HISTORY
terry : 5/20/1999
alopez : 8/2/1998
terry : 11/7/1997
alopez : 7/10/1997
terry : 7/9/1997
mark : 7/8/1997
mark : 9/13/1996
mimadm : 6/7/1995
pfoster : 2/14/1995
carol : 9/19/1994
davew : 7/21/1994
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