The existence of chromosome breakage in patients with ataxia
telangiectasia (AT) has been known for a long time [3,5,7]. Chromosomal
rearrangements, of the translocation type, have since been described in
association with chromosome breakage [1,10]. Studies using chromosome banding
have shown the specific involvement of both chromosomes 7 and 14, and
translocation t(14; 14) seems particularly frequent [4,6,9], as also is t(7;
14) [5,8,11]. Other translocations involving chromosome 7 or 14 and another
chromosome have also been reported [8,9].
The study of chromosome banding in 11 AT patients is reported here. The
same types of anomaly were found. However, other rearrangements, especially
pericentric and paracentric inversions, seem almost as frequent, and perhaps
even more specific.
Table 1 : distribution of the 191 chromosome rearrangements
observed in the 11 cases of AT
l, o,o||s, k, i, n||
|complex t(14 ;
|complex t(7 ;
|Other rearrangements of chromosomes 7 or
|Rearrangements of other
|Total of cells
Material and methods
The 11 probands were all unrelated, and no cytogenetic investigations
had previously been performed. The two parents and the three siblings of one
patient, and the father of another were also examined.
Blood cultures, after PHA stimulation, were performed during 72 h and
occasionally 96 h. In patient No. 8, skin fibroblasts were also analysed. The
whole study was carried out by using R-banding. The cells were first examined
under the microscope, and systematically photographed when an anomaly was
suspected. Then the karyotype was established. The number of cells examined for
each patient is indicated in Table 1.
Out of the 927 lymphocytes analysed, a total of 158 chromosomal
rearrangements was detected. Chromatid breaks and gaps, and chromosome gaps
were excluded, since they can only be partially detected on banded chromosomes.
Out of the 187 fibroblasts analysed, 33 were abnormal. The mean fre-quency of
abnormalities was thus 0.17 for lymphocytes, and 0.18 for fibroblasts. This
frequency varied from 0.01 to 0.39 from patient to patient (Table 1). The fact
that the frequencies in fibroblasts and in lymphocytes are the same, in our
sample, is not significant, since a study of fibroblasts was carried out on
only one patient. In our opinion, a far greater significance attaches to the
specificity of the rearrangements and of the breakpoints, which are similar in
fibroblasts and in lymphocytes. This (Table 1) shows that the most frequent was
the pericentric inversion of chromosome 7. Quite frequent also were the t(7;14)
and the paracentric inversion of chromosome 14. Chromosomes 7 and 14 were also
frequently translocated with other elements, but apparently at random.
Curiously, only 5 translocations t(14 ;14) were found. This is a
relatively low frequency (P 0.005) compared with published data.
Specificity of the breakpoints. The 191 rearrangements consisted
mostly of translocations, inversions and deletions. Altogether, they
corresponded to 316 recognized breakpoints. Among them, 112 involved chromosome
7, 47 chromosome 14, 21 chromosome 1,12 chromosome 9,11 chromosome 11, and 10
chromosome 12. The remaining 103 breakpoints seemed to be distributed at random
among the other chromosomes.
The involvement of chromosome 7 was predominant. Furthermore, among
its 112 breakages, 41 seem to affect band p14, and 40 band q35 (Fig. 1). A
study with high-resolution banding will be developed to obtain a more accurate
location of the breaks. Thus, the specific involvement of chromosome 7 could
result from the specific involvement of two sites. The same seems true for
chromosome 14, where two sites were predominantly affected: bands q12 and q
32.3 (Fig. 1).
Specificity of the rearrangements. All the rearrangements involving
chromosome 7 only (pericentric inversions and t(7 ; 7)), chromosome 14 only
(paracentric inversions and t(14;14)), and both chromosomes 7 and 14 (t(7;14)),
resulted from breaks located in 7pl4, 7q35, 14ql2 and 14q ter. The other breaks
involving other breakpoints on these two chromosomes were observed in
deletions, duplications, or translocations with other chromosomes. In these
cases of translocation, we could not find any specificity in the involvement of
any other chromosome.
Fig. 1. Rearrangements of chromosomes 7
and 14. (a) inv(7)(p14 ; q35) (b) t(7 ; 14)(p14 ; q12) (c) t(7 ; 14)(q35 ; q12)
(d) inv(14)(q12 ; q ter) (e) t(7 ; 7)(p14 ; q35) (f) t(14 ;14)(q ter
Distribution of the 14 chromosome rearrangements observed in
the relatives of the AT patients
|Rearrangements||Father of case 8||Mother of
case 9||Father of case 9||Sister of case 9||1st brother of
case 9||2nd brother of case 9
|Rearrangements of other
|Total of examined
Relatives of AT patients
6 individuals fell into this category. 3 were parents of AT
patients, and thus can be considered as highly probable heterozygotes. The
other 3 were siblings of proband No. 9, and were heterozygous with a 2/3
As shown in Table 2, among 2 of the 3 parents, 2 rearrangements of
chromosomes 7 and 14 were observed in a sample of 225 cells. Among 2 of the 3
siblings, 6 rearrangements of chromosomes 7 and 14 were observed in a sample of
205 cells. One parent had no rearrangement of chromosomes 7 and 14 in 102
cells, and one brother no rearrangement in 166 cells.
This study of 1114 AT cells, in which chromosome banding was used,
shows that several structural rearrangements are common to many patients. Two
of these rearrangements, i.e. the t(14 ; 14) and the t(7 ; 14), have previously
been reported to be fairly frequent in AT cells. On the contrary, there are no
reports on the other rearrangements we observed in AT cells, i.e. inv(7),
inv(14), and t(7 ; 7), although inv(7) was a most common rearrangement in our
sample. In previous reports, t(14 ; 14) was the most frequent anomaly, but we
found it relatively rarely.
This discrepancy between the reported cases and our own study has not
yet received a clear explanation. One possibility is that various
rearrangements may correspond to various forms of ataxia telangiectasia: all
our cases were of French or North-African origin, and there are no available
data concerning the cytogenetics of AT in these countries.
Another possibility is that of a methodological bias. The first cases
of structural rearrangements were described without use of the banding
techniques, and led to the discovery of Dq+ chromosomes. Later, this type of
anomaly was particularly screened by investigators, and it is not clear from
the reports whether banding techniques were used as a matter of routine.
At least it is certain that our study is the first to use R-banding
systematically for all cells examined. In our experience, the most frequent
rearrangements (pericentric inversions) were totally ignored when the slides
were first examined without chromosome banding.
The frequency of the 14q + chromosomes, observed in two patients only,
was relatively low in our sample. These two patients (cases 8 and 11) are those
with the highest rate of chromosomal rearrangements and possibly those with the
most severe syndrome. Thus, a question of age, of severity of the disease, and
a possible development of cancer, may also influence the results.
Several authors have previously suggested a correlation between the
structural rearrangements observed in the lymphocytes of presumed normal
patients and those of AT patients [12,13]. They observed the same
translocations t(7 ; 14) in both circumstances.
Among the last 12 500 patients examined for various reasons other than
AT, in the Institut de Progénèse (Prof. J. Lejeune), about 50 000 karyotypes
were established with the routine use of R-banding. Among them, 29 inv(14)(q12
; q ter), 28 t(7 ; 14)(p14 ; q12), 16 t(7 ; 14)(q35 ; q12), 9 inv(7)(p14 ;
q35), 3 t(14 ; 14)(q ter ; q12), and 1 t(7 ; 7)(p14 ; q35) were detected in a
total of 188 rearrangements.
It must be stressed that, here again, the inversions had not been
noticed in most of the other studies of non-AT patients, and in our opinion, a
biased analysis is the most probable explanation. It must be concluded that the
inversions of chromosomes 7 and 14 are among the most common, if not the most
common chromosomal change, both in cells from AT patients and in cells from
presumed normal individuals. In both categories, the frequency of inversions is
probably underestimated, because of the difficulty in detecting them.
In AT cells, the frequency of rearrangements in both chromosomes 7 and
14 may be 40 times higher than in presumed normal cells (0.065 vs. 0.0017).
A rearrangement of a D-group chromosome has been reported in a total
of 6 cells from 5 relatives of AT patients .
In the 6 individuals, possibly heterozygous for the AT gene, we found
(Table 2) 8 rearrangements involving chromosome 7 and/or 14. After correction,
because the sibling of the propositus had a 2/3 probability of being
heterozygous, it can be concluded that the frequency of these rearrangements is
about 0.014. This frequency is thus about 9 times higher than in the presumed
normal cells and about 4 times lower than in AT patients.
If we consider the 12 500 non-AT patients studied in the Institut de
Progénèse, and knowing that the frequency of the AT gene is about 1/200, we
may conclude that about 125 heterozygotes are included in this sample. Thus,
the study of 4 karyotypes of each should have led to the detection of 500 X
0.014 = 7 rearrangements of chromosomes 7 and/or 14, and the remaining 79
rearrangements observed in this sample cannot be related to the status of
heterozygote for the AT gene only.
Because the AT heterozygotes may be more sensitive to radiation than
the normal population, it seems of interest to improve the possibility of
detecting them by cytogenetical methods.
From our data, it can be concluded that among the presumed normal
subjects, where a rearrangement of chromosomes 7 and/or 14 has been detected by
chance, about one-tenth should be heterozygote carriers of the AT gene.
Note added in proof
Since the paper was submitted, the study of several new cases of
heterozygotes showed the specific anomalies of chromosomes 7 and 14, in a small
percentage of their lymphocytes.
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