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Introduction
A rare chromosome variant of trisomy 21 is the "mirror" (reverse
tandems) duplication of chromosome 21. Several cases have been described in the
literature (Warkany and Soukup 1963; Zellweger et al. 1963; Lejeune et al.
1965; Richards et al. 1965; Cohen and Davidson 1967; Garson et al. 1970;
Kadotani et al. 1970; Sachdeva et al. 1971; Vogel 1972; Bartsch-Sandhoff and
Schade 1973; Niebuhr 197; Schuh et al. 1974; Hagemeijer and Smit 1977; Harvey
1977; Berg et al. 1980; Cantu et al. 1980; Turleau et al. 1980.
In theory, there are two possible mechanisms for the formation of this
chromosomal rearrangement: (1) a telomeric fusion of two chromosomes 21,
without loss of chromosomal material, and (2) a reciprocal translocation or
exchange between the long arms of chromosome 21 (or sister chromatids). In both
cases the deletion or inactivation of one of the two centromeres is necessary
for the stability of the derived chro-mosome. Although the precision of the
cytogenetic analysis of these chromosomes is limited, in some cases there is
apparently little loss of chromosomal material (Turleau et al. 1980), while in
others the duplication might be partial, resulting from breakage in the 21q22.3
region, leading to partial monosomy of distal 21q22.3 (Cantu et al.1980). This
cytogenetic heterogeneity could account for the clinical variability described
in the literature (Niebuhr 1974). The purpose of the present study was to
perform the molecular analysis of three cases of trisomy 21 with a mirror
duplication of chromosome 21, in order to (1) study the chromosome
rearrangement, i.e., determine possible loss of chromosomal material and
localize regional breakpoints, and (2) clarify possible genotype-phenotype
correlations not only with regard to Down syndrome but also with regard to
clinical features observed in cases of partial or possibly complete monosomy 21
(reviewed in Korenberg et al. 1991).
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Subjects and MethodsHaut
Clinical Data
1. Case TY (Greece).
- This girl was born in 1980. She was the first child of healthy
parents and was born when her father and mother were, respectively, 26 and 25
years old. Birthweight was 2,250 g (<3d percentile), height was 47 cm
(<10th), and head circumference was 31 cm (<3d percentile). At birth the
phenotypic evaluation revealed a typical Down syndrome phenotype, although both
ears were large with unfolded helix and without crux cymbae (fig. 1). There was
no joint hyperflexibility, the tonus was moderately decreased with a diastasis
recti, and there was livedo reticularis (marble skin). The findings of the
clinical analysis at time of birth are shown in table 1. The child was
reexamined at age 9 years (fig. 1 b and table 1). The subject displayed
features of typical Down syndrome phenotype, with the exception of ear shape,
absence of short neck, and teeth which were normal. No Brushfield spots were
present, but the irides were dark. The subject suffered from hyperme-tropia
Psychological and mental evaluation was performed at the age of 10
years 8 mo, by both the WISC-K and Griffith mental development scales. Her
overall performance was low. On the WISC-K test, the verbal score was 50, the
performance score was 60, and the full-scale score was 50. On the Griffith
mental development scale, mental age was 6.4 years, and general quotient was
60.
 Fig. 1 - Patient TY at age 1 mo (a) and at age 9 years
(b)
2. Case LI (Belgium).
- This boy was born in 1986. He was the first child of healthy
parents. At the time of birth of the child, the father was 31 years old, and
the mother was 37 years old. Birthweight was 2,660 g (<10th percentile),
height was 48 cm (<10th percentile), and head circumference was 32 cm
(<3d percentile). At birth the child had features of Down phenotype (fig. 2
and table 1), as well as a murmur accompanied by a discrete cyanosis when she
was fed. A tetralogy of Fallot, with subvalvular obstruction, was diagnosed,
and a surgical correction was attempted.
 Fig. 2 - Patient LI
at age 15 d
3. Case AL (France).
- This girl was born in 1963. The case was published by Lejeune et
al. (1965). Birthweight was 2,430 g (<3d percentile), height was 46 cm
(<3d percentile), and head circumference was 32 cm (<3d percentile). An
initial examination at 16 mo revealed a typical Down syndrome phenotype (table
1) with a heart systolic murmur. The auscultation data and the absence of ECG
modifications suggested a small ventricular septal defect (Roger disease),
which was well tolerated. The IQ (Brunet-Lezine test) was 52. From the age of 6
years, the cardiac auscultation became normal. For this study, the patient was
reexamined at the age of 27 years (fig. 3 and table 1). Height was 137 cm,
weight was 57 kg, and cranial circumference was 49 cm. The IQ (Binet-Simon
test) was 35. The following features were observed: blepharitis conjunctivitis,
keratitis, strabisms (operated), severe myopia (-14.5 diopters on both eyes),
furrowed tongue, rough voice, and hypothyroidism diagnosed at age 23 years and
treated with thyroid hormone. An Epstein-Barr virus-transformed lym-phoblastoid
cell line was established.
 Fig. 3 - Patient AL at age 27
years
Table I. - Clinical Manifestations of Down Syndrome in
Patients TY, LI, and AL
|
TY |
LI |
AL |
Birth |
Age 9 years |
Age 15 d r |
Age 16 mo |
Age 26 years |
Jackson's checklist: |
Brachycephaly(a) | + | id |
+ | + | id |
Oblique eye
fissure(a) | + | id | + | + | id |
Epicanthic eye
fold | + | id | + | + | id |
Blepharitis,
conjunctivitis | ND | + | ND | ND | + |
Brushfield spots (iris color) | -
(darks) | id | - | + | + |
Nystagmus | - | id | - | - | - |
Flat nasal
bridge(a) | + | id | + | + | + |
Mouth permanently
open | - | - | - | ND | - |
Abnormal teeth
| | - | | | + |
Protruding tongue
(macroglossia) | - | - | + | ND | - |
Furrowed tongue
| | + | | | + |
High-arched
palate | + | id | - | + | id |
Narrow
palates(a) | + | id | - | + | id |
Folded ear (right,
left)(a) | -,- | id | -,+ | -,- | id |
Short
neck(a) | + | - | + | + | - |
Loose skin of neck
(newborn) | ND | | - | ND | |
Short and broad
hands | + | id | + | + | id |
Short fifth finger (right, left)
| +,+ | id | -,- | -,- | id |
Incurved fifth finger (right,
left)(a) | +,+ | id | -,- | -,- | id |
Transverse palmar crease (right,
left) | -,- | id | -,- | -,+ | id |
Gap between first and second toes (right,
left)(a) | +,+ | id | +,+ | +,+ | id |
Congenital heart defect
(type) | - | id | + (Fallot) | +
(VSD(b)) | ND |
Murmur | - | id | + | + | - |
Joint
hyperflexibility | - | id | - | + | - |
Muscular
hypotonia(a) | + | - | + | + | + |
Total
| 12 | 12 | 12 | 15 | 14 |
Other features: |
Mental retardation (i.e., IQ score)
[test] | | 60 [G], 50 [W] | | 51 [BL] | 35
[BS] |
Short stature (height in m) [percentile] | -(0.47)
[<10th] | +(1.2) [<3d] | -(0.48) [<10th] | +(0.69)
[<3d] | +(1.37) [<3d] |
Head circumference (percentile) | 31 cm
(<3d) | 50,5 cm (<50th) | 32 cm
(<3d) | ND | 49 cm (<3d) |
Ophthalmological
defect | | Hypermetropia | | Strabism,
myopia | id |
Dermatoglyphics: |
Palmar t" (right,
left) | +,+ | id | -,- | +,+ | id |
Hypothenar ulnar loop (right,
left) | +,+ | id | -,- | +,+ | id |
High Cummins index > 30 (right,
left) | -,- | id | +,- | +,- | id |
Visceral abnormality (other than heart
defect) | - | id | - | - | id |
Leukemia | - | - | - | - | - |
Alzheimer
disease | | - | | | - |
NOTE. - id = idem; and ND = not determined.
(a) Discriminating signs under age 2 years (Jackson et al. 1976). (b)
Ventricular septal defect. (c) G = Griffith mental development scale; W =
WISC-K test; BL. = Brunet-Lezine test; and BS - Binet-Simon test. |
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Cytogenetic Analysis
Seventy-two-hour lymphocyte culture was performed in all cases.
Standard banding techniques - i.e., RHG and GTG, C and NOR, and RTBG (high
resolution R-banding) - were performed. In all three cases the karyotypic
analysis showed a mirror duplication of chromosome 21:46,XX, or XY, -21, + psu
dic(21)t(21;21)(q22.3;q22.3). Two centromeres at both ends of the rearranged
chromosomes were revealed, by the C-banding technique, with apparent
inactivation of one of the two centromeres. The duplicated chromosome had
stalks in both arms and satellites visualized by the NOR technique (fig. 4).
Lymphocytes from cases TY and AL were subjected to high-resolution
R-banding analysis. In AL, the size of the fusion 21q22.3 band was less than
twice that of the 21 q22.3 band, suggesting a partial deletion of 21q22.3. In
all cases, the karyotype of the parents was apparently normal, as assessed by
standard banding techniques.
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Molecular Analysis
The copy numbers of chromosome 21 single-copy sequences were
evaluated by a slot blot hybridization method described elsewhere (Rahmani et
al. 1989; Blouin et al. 1990). DNA was purified from blood, by standard
techniques. Varying amounts of denaturated DNA from a normal control (C), a
trisomy 21 patient (D), and the subject to be analyzed (X) were loaded onto a
nylon membrane. Successive hybridizations were carried out with both a
reference probe and chromosome 21 probe (32PdCTP-labeled inserts. Intensities
of the signals on autoradiograms were quantified by densitometric scanning
(Shimadzu TLC CS 930 scanner). Linear regressions between reference and
chromosome 21 probe signals for C, D, and X were computed, and the conclusion
that the DNA from the studied subject X has one, two, or three copies for a
given chromosome 21 sequence was assessed by statistical comparison of its
regression slope with those of C and D. Figure 5 summarizes the results of
duplicated estimations of the copy number of eight sequences of the
21q22.1-q22.3 region -namely, SOD1 (superoxide dismutase 1) (Lieman-Hurwitz et
al, 1982), D21S15 (Stewart et al., 1985), D21S42 (Korenberg et al. 1987), CRYA1
(Crystallin, alpha polypeptide 1) (McDevitt et al. 1986), PFKL
(phosphofructokinase, liver typed) (Levanon et al. 1987), CD18 (antigen CD18,
lymphocyte function-associated antigen 1) (Kishimoto et al. 1987), COL6A1
(collagen, type VI, alpha 1) (Weil et a1.1988), and S100B (S100 protein, beta
polypeptide, neural) (Allore et al, 1988). The normal order and localization of
these sequences on chromosome 21, from centromere to telomere, are SOD1 on
21q22.1, D21S15, D21S42, CRYA1, PFKL, CD 18, COL6A1, and S100B on 21q22.3
(Burmeister et al. 1991; Cox and Shimizu 1991; Crété et al. 1991; Petersen et
al. 1991; Delabar et al. 1992; Tanzi et al. 1992; Wang et al. 1992). Table 2
gives typical data obtained for copy-number determinations of three sequences
from each patient.
In patient TY, the copy numbers for SOD1, D21S15, D21S42, CRYA1,
PFKL, CD18, COL6A1, and S100B were 3, 3, 3, 2, 1, 1, 1, and 1, respectively,
thus indicating that the translocation breakpoint lies within the 21q22.3
region, between markers D21S42 and PFKL, but at different loci on each of the
two chromosomes involved in the duplication: between D21S42 and CRYA1 on one
chromosome 21 and between CRYA1 and PFKL on the other. In patient LI, the copy
numbers for the same eight probes were 3, 3, 3, 3, 2, 1, 1, and 1,
respectively, thus indicating that the translocation breakpoint lies within the
21q22.3 region, between markers CRYA1 and CD 18, but again at different loci on
each of the two chromosomes 21 involved in the duplication: between CRYA1 and
PFKL on one chromosome 21 and between PFKL and CD18 on the other. In patient
AL, the copy numbers for the eight probes were 3, 3, 3, 3, 3, 3, 1, and 1,
respectively. The breakpoint of the translocation is thus more distal than it
is in patients TY and LI and is located between markers CD 18 and COL6A1.
DNA polymorphism analysis was performed, using blood DNA of the
patients and their parents, by PCR amplification. The PCR polymorphisms were a
(GT)n repeat of locus 21-GT14 (D21S215) close to the centromere on 21q
(Williamson et al. 1991; S. E. Antonarakis and A. C. Warren, personal
communication), a (ATTT)n repeat of the Alu VpA at IVS5 of the IFNAR gene
(McInnis et al. 1991), a (GT)n repeat of locus D21S167 (Guo et al. 1990), and a
(GT)n repeat of locus PFKL (Polymeropoulos et al. 1991). One of the pair of
primers was labeled by adjunction of fluorescein. PAGE was performed using an
ALF DNA sequencer (Pharmacia). The copy number of alleles for the loci studied
was scored by comparing the patterns and intensities of allele peaks in the
patients and their parents (J.-M. Delabar and D. Théophile, unpublished data).
Results in table 3 indicate that parental origin of the duplicated chromosome
21 was paternal in patient TY and maternal in patients LI and AL. In the three
patients the data were consistent with a homozygosity of the duplicated
alleles. Furthermore, in patient TY the deletion of the paternal alleles
confirmed the monosomy for PFKL.
Table 2 - Quantification of Chromosome 21 Sequences in
Patients TY, LI, and AL
Patient and Chromosome 21 Probe(y) / Reference Probe(x) |
Values of Slopes F ± SD of Regression Lines (a) (y =
Fx) |
95 % Confidence Interval of Difference between Slopes
(a,b) |
Conclusion |
TY: |
D21S42/COL1A2 | C1 = .84 ±
.07 | D1-C1 = + .50 to +1.76 | D > C; difference 3:2 |
C2 = .38 ± .03 | D2-C2 = + .09 to +
.34 | |
D1 = 1.96 ± .23 | X1-C1 = + .57 to + 1.26 | X
> C |
D2 = .60 ± .05 | X2-C2 = + .13 to +
.45 | |
X1 = 1.75 ± .11 | D1-X1 = - .52 to + .94 | D =
X; three copies |
X2 = .68 ± .06 | D2-X2 = - .24 to +
.08 | |
CRYA1 /COL1A2 | C1 = 1.75 ±
.21 | D1-C1 = + .67 to + 2.07 | D > C; difference 3:2 |
C2 = 1.70 ± .08 | D2-C2 = + 1.67 to +
2.41 | |
D1 = 3.12 ± .17 | X1-C1 = - .33 to + .79 | X =
C; two copies |
D2 = 3.74 ± .17 | X2-C2 = - .04 to +
.63 | |
X1 = 1.98 ± .17 | D1-X1 = + .46 to + 1.83 | D
> X |
X2 = 2.00 ± .08 | D2-X2 = + 1.37 to +
2.12 | |
PFKL/COL1A2 | C1 = 1.28 ±
.09 | D1-C1 = + .61 to + 1.36 | D > C; difference 3:2 |
C2 = 1.64 ± .09 | D2-C2 = + 1.06 to +
2.21 | |
D1 = 2.23 ± .16 | X1-C1 = - .94 to - .53 | X
< C; one copy |
D2 = 3.28 ± .29 | X2-C2 = - 1.34 to -
.75 | |
X1 = .51 ± .OS | D1-X1 = + 1.42 to + 2.03 | D
> X |
X2 = .60 ± .08 | D2-X2 = + 2.07 to +
3.30 | |
LI: |
CRYA1/COL1A1 | C1 = .86 ±
.11 | D1-C1 = +.51 to + 1.43 | D > C; difference 3:2 |
C2 = .65 ± .09 | D2-C2 = + .38 to +
1.17 | |
D1 = -1.83 ± .20 | X1-C1 = + .29 to + 1.34 | X
> C |
D2 = 1.43 ± .19 | X2-C2 = + .39 to +
1.26 | |
X1 = 1.67 ± .24 | D1-X1 = - .51 to + .82 | D =
X; three copies |
X2 = 1.48 ± .21 | D2-X2 = - .64 to +
.54 | |
PFKL/COL1A1 | C1 = 3.91 ±
.36 | D1-C1 = + 1.11 to + 3.60 | D > C; difference 3:2 |
C2 = 1.01 ± .12 | D2-C2 = + 0.20 to +
1.00 | |
D1 = 6.27 ± .46 | X1-C1 = - 1.93 to + .19 | X
= C; two copies |
D2 = 1.62 ± .14 | X2-C2 = - .57 to
+.10 | |
X1 = 3.05 ± .33 | D1-X1 = + 2.06 to + 4.38 | D
> X |
X2 = .77 ± .08 | D2-X2 = + .52 to +
1.16 | |
CD18/COL1A1 | C1 = 3.56 ±
.10 | D1-C1 = + 2.53 to + 3.61 | D > C; difference 3:2 |
C2 = 3.16 ± .30 | D2-C2 = + 3.06 to +
4.69 | |
D1 = 6.63 ± .26 | X1-C1 = - 2.55 to - 1.99 | X
< C; one copy |
D2 = 7.04 ± .23 | X2-C2 = - 2.84 to -
1.28 | |
X1 = 1.28 ± .06 | D1-X1 = + 4.81 to + 5.87 | D
> X |
X2 = 1.10 ± .07 | D2-X2 = + 5.40 to +
6.47 | |
AL: |
PFKL/C0L1A1 | C1 = .70 ±
.03 | D1-C1 = + .22 to + .59 | D > C; difference 3:2 |
C2 = 1.53 ± .12 | D2-C2 = + .40 to +
.79 | |
DI = 1.11 ± .08 | X1-C1 = + .12 to + .40 | X
> C |
D2 = 3.58 ± .28 | X2-C2 = + .19 to +
.56 | |
X1 = .96 ± .O5 | D1-X1 = - .O5 to + .35 | D =
X; three copies |
X2 = 4.45 ± .06 | D2-X2 = - .07 to +
.48 | |
CD18/C0L1A1 | C1 = .59 ±
.O5 | D1-C1 = + .54 to + .85 | D > C; difference 3:2 |
C2 = .52 ± .03 | D2-C2 = + .32 to +
.83 | |
D1 = 1.28 ± .O5 | X1-C1 = + .32 to + .70 | X
> C |
D2 = 1.10 ± .12 | X2-C2 = + .26 to +
.57 | |
X1 = 1.10 ± .07 | D1-X1 = - .02 to + .39 | D =
X; three copies |
X2 = .93 ± .O5 | D2-X2 = - .08 to +
.42 | |
C0L6A/C0L1A2 | C1 = .53 ±
.06 | D1-C1 = + .26 to + .59 | D > C; difference 3:2 |
C2 = .36 ± .02 | D2-C2 = + .54 to +
1.16 | |
D1 = .96 ± .04 | D1-C1 = - .53 to - .31 | X
< C; one copy |
D2 = 1.21 ± .16 | D2-C2 = - .28 to
-.20 | |
X1 = .11 ± .O1 | D1-X1 = + .76 to + .92 | D
> X |
X2 = .12 ± .01 | D2-X2 = + .79 to +
1.39 | |
(a) Numbers after C, D, and X refer to
independent experiments different membranes). (b) For two compared slopes, when
the 95 % confidence interval of their difference contains the zero value the
slopes are not statistically different, whereas when the confidence interval
does not contain the zero value the slopes are different (for more details on
the method, see Blouin et al. 1990). |
Table 3 - DNA Polymorphism Analysis in Families of Patients
TY, Ll, and AL
|
Genotype (b) of |
Family of TY |
Family of LI |
Family of AL |
Locus, LOCALIZATION (a) |
Father |
Mother |
Child |
Father |
Mother |
Child |
Father |
Mother |
Child |
D21S215(GT14),
21q11 | 13 | 12 | 133 | 12 | 23 | 133 | 12 | 12 | 112 |
IFNAR,
21q22.2 | 12 | 13 | 122 | 12 | 13 | 112 | 12 | 33 | 233 |
D21S167,
21q22.2 | 23 | 12 | 122 | 34 | 12 | 224 | 23 | 12 | 112 |
PFKL,
21q22.3 | 23 | 14 | 1 | ND | ND | ND | 23 | 12 | 223 |
(a) The regional localization of the loci is
according to the consensus maps of Cox and Shimizu (1991) and Williamson et al.
(1991). (b) The numbers represent the different alleles at a specific
locus. |
 Figure 4. - Top, Karyotypes showing the banding
patterns of patients AL, TY, and LI, by using the standard techniques RHG, GTG,
CGB, and NOR. Left, High-resolution R-banding (RTBG) analysis of patients AL
and TY.
 Figure 5. - Results of the dosage analysis of tested sequences
(no. of copies) in patients TY, LI, and AL.
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DiscussionHaut
Chromosome Rearrangement
Cytogenetic and molecular analyses of partial duplications or
deletions of chromosome 21 are useful for studies on phenotype-genotype
correlations in Down syndrome (Epstein 1990. Such cases may include patients
with tandem or reverse tandem translocations of the long arm of chromosome 21.
Most cases described in the literature (Niebuhr 1974; Cantu et al. 1980;
Turleau et al. 1980) are reverse tandem (i.e., mirror) translocations of all or
part of the long arm of the chromosome. We performed combined clinical,
cytogenetic, and molecular analysis of three patients with Down syndrome
resulting from such a mirror duplication of chromosome 21. There are two
theoretical mechanisms for such chromosomal rearrangements: first, a telomeric
fusion of two chromosomes 21 after opening of telomeric palindromes, without
loss of chromosomal material, and, second, a translocation between the long
arms of two homologous chromosomes 21 or between the two chromatids of the same
chromosome 21. If the translocation breakpoints are at the same sites in each
chromosome or chromatid - i.e., are "homotopic" breaks - the resulting
chromosome would be symmetrical. If the translocation breakpoints are at
different sites - i.e., are "heterotopic" breaks - the derived chromosome would
be asymmetrical. The derived chromosome is stable only if one of the two
centromeres is deleted or inactivated. In two of the cases, TY and AL,
high-resolution banding was performed. The fused 21q22.3 band was less than
twice the size of the 21q22.3 band, suggesting a partial deletion. In all
cases, one of the two centromeres was inactivated.
The copy numbers of eight chromosome 21-specific sequences indicate
partial deletion of the region 21q22.3, in all cases. The extent of the
deletion is different in each case: the deletion in TY is largest, that in LI
is intermediate, and that in AL is smallest. Moreover, the translocation
breakpoints on the two chromosomes 21 involved in the minor duplication are
located in homologous regions in case AL and in different regions in cases TY
and LI. Thus, AL has undergone a homotopic translocation giving a symmetrical
derived chromosome leading to partial trisomy 21 and partial monosomy of
21q22.3 without disomy. Conversely, in cases TY and LI, the translocation is
heterotopic, and the derived chromosomes are asymmetrical, leading to partial
trisomy 21, partial monosomy of 21q22.3, and disomy for the CRYA1 and PFKL
regions, respectively.
DNA polymorphism analysis shows that the parental origin of the
duplicated chromosome material is paternal in patient TY and maternal in
patients LI and AL. The loss of the two paternal PFKL alleles in patient TY
strongly suggests that the mirror chromosome is formed by two elements of
paternal origin. In all cases, data were consistent with the duplicated alleles
being homozygous. Therefore, the simplest mechanism leading to the mirror
chromosome would be a translocation for fusion) between sister chromatids,
occurring at a prezygotic stage. This type of rearrangement at a postzygotic
stage is less likely, since no normal and/or ( - 21 ) cells were observed in
the karyotype of the patients. There is a possible alternative mechanism:
translocation between two chromosomes 21 in a trisomy 21 zygote at a very early
stage of the postzygotic development.
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Phenotype-Genotype Correlations with Regard to Partial
Trisomy 21
The phenotype of all three patients was not significantly different
from that of patients with trisomy for the whole chromosome 21. Table 1 gives,
for each patient, the total number of signs on Jackson's checklist that were
observed. At an early age, TY, LI, and AL had 12, 12, and 15 signs,
respectively, which correspond to 84 %, 84 %, and 100 % probability of trisomy
21. When examined later, TY and AL had 12 and 14 signs, respectively, which
correspond to 84 % and 100 % probability of trisomy 21. The 10 most
discriminating signs of Down syndrome for trisomy 21 patients younger than age
2 years (table 1) were scored for each patient, and their respective
discrimination coefficients were summed; the results were .1137 for TY, .0956
for LI, and .1119 for AL. These values are typical scores for trisomy 21 and do
not fall within the overlap area between normal and Down syndrome subjects
(Jackson et al. 1976). Transverse palmar creases were not present in TY and LI.
Muscular hypotonia was moderate in TY and AL. These characteristics are within
the limits of the variability of the phenotypic expression of Down syndrome,
and in no case could the absence of a Down syndrome feature in a patient with
partial trisomy 21 be interpreted as resulting from nonduplication of a
particular region, since none of these features except mental retardation is
expressed in 100 % of patients with full trisomy 21. The presence of Down
syndrome features in these patients strongly suggests that the genes involved
in their pathogenesis are localized proximally to the translocation breakpoints
in 21q22.3. Thus, the trisomy 21 signs present in TY and/or LI (table 1)
presumably result from the duplication of genes proximal to CRYA1 and/or PFKL.
These signs include many of the facial and hand features, the gap between the
first and second toes, the congenital hear disease with tetralogy of the Fallot
type, muscular hypotonia, mental retardation, and short stature. Similarly,
other signs not present in TY and LI but present in AL, such as Brushfield
spots, abnormal teeth, joint hyperlaxity, and ventricular septal defect (table
17, are probably linked to the duplication of genes proximal to COL6A1. Some of
the Down syndrome features observed in these three patients, including flat
nasal bridge, macroglossia, incurved fifth finger, hypotonia, short stature,
and mental retardation, have been associated with the duplication of the region
around D21S55 ("Down syndrome chromosome region") (Rahmani et al. 1989,1990;
Sinet et al. 1991), located between D21S17 and ETS2, on 21q22.2-q22.3 proximal.
The central role of the duplication of this region in the pathogenesis of Down
syndrome has also been reported by others (Korenberg et al. 1989, 1992). This
region, proximal to D21S15, does not overlap the PFKL-telomere region. Other
facial and hand features, as well as mental retardation, have been observed in
Down syndrome patients with molecularly defined duplications of 21q22.3
(McCormick et al. 1989; Korenberg et al. 1990b, 1992; Petersen et al. 1990).
Our results strongly suggest that duplication of the genes of the PFKL-21qter
region is not necessary for the generation of these features.
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Phenotype-Genotype Correlations with Regard to Partial
Monosomy 21
Finally, these patients did not have the following phenotypic
features typical of monosomy 21: hypertonia, high nasal bridge, down-slanted
palpebral fissure, and prominent occiput. Such features have been described in
karyotypically full or partial monosomies 21, including ring chromosome 21 and,
in some cases, have been defined at the molecular level (Pellissier et al.
1987; Phelan et al. 1988; Chettouh et al. 1991; Korenberg et al. 1991). It is
interesting that individuals with ring chromosome 21 have been reported without
phenotypic anomaly (reviewed in Dallapiccola et al. 1986). These cases have a
monosomy for the distal part of 21q22.3 (Korenberg et al. 1990a, McGinniss et
al. 1992). Further molecular characterization of normal individuals with ring
chromosome 21 should define the maximum monosomy which does not result in
phenotypic modifications. Of the three patients described above, only TY had
one sign which could be interpreted as a phenotypic expression of monosomy 21 -
i.e., large ears with unfolded helices. Except for this specific feature,
monosomy of distal 21q22.3, from the telomere to PFKL, had no significant
effect on the expression of Down syndrome phenotype. This adds further weight
to the suggestion that the genes contained in this region - approximately the
distal third of 21q22.3, i.e., 1.5-3 Mb (Burmeister et al. 1991; Wang et al.
1992) - are not necessary for the expression of the Down syndrome features,
including most of the facial and hand features, short stature, muscular
hypotonia, cardiopathy of the Fallot-type tetralogy, and part of the mental
retardation, which are found in our patients.
Haut
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