High frequencies of inversions and translocations of chromosomes 7 and 14 in ataxia telangiectasia

Alain AURIAS (a), Bernard DUTRILLAUX (b), Diego BURIOT (c) and Jérôme LEJEUNE (a).

Mutation Research, 69 (1980) 369-374. (Received 17 September 1979) (Accepted 3 October 1979)


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
b, l, o,os, k, i, n
t(7q ; 14q)21238
t(7p ; 14q)11113119
t(7p ; 7q)123
ttan(14 ; 14)112
complex t(14 ; 14)33
complex t(7 ; 7)33
Other rearrangements of chromosomes 7 or 1411132101524
Rearrangements of other chromosomes21110372214116104
Total of cells examined5843141001054812314918794701231114


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.




AT patients

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 ;q12).

Distribution of the 14 chromosome rearrangements observed in the relatives of the AT patients
RearrangementsFather of case 8Mother of case 9Father of case 9Sister of case 91st brother of case 92nd brother of case 9
t(7q ; 14q)1
t(7p ; 14q)14
ttan(14 ; 14)1
Rearrangements of other chromosomes141
Total of examined cells12010210512580166


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 probability.

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 [2].

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.



1 Bochkov, N.P., Y.M. Lopukhin, N.P. Kuleshov and L.V. Kovalchuk, Cytogenetic study of patients with ataxia-telangiectasia, Humangenetik, 24 (1974) 115-128.

2 Cohen, M.M., M. Shaham, J. Dagan, E. Shmueli and G. Kohn, Cytogenetic investigations in families with ataxia-telangiectasia, Cytogenet. Cell Genet., 15 (1975) 338-356.

3 Gropp, A., and G. Flatz, Chromosome breakage and blastic transformation of lymphocytes in ataxia-telangiectasia, Humangenetik, 5 (1967) 77-79.

4 Hayashi, K., and W. Schmid, Tandem duplication q14 and dicentric formation by end-to-end chromosome fusions in ataxia-telangiectasia (AT), Humangenetik, 30 (1975) 135-141.

5 Hecht, F., R.D. Koler, D.A. Rigas, G.S. Dahnke, M.P. Case, V. Tisdale and R.W. Miller, Leukemia and lymphocytes in ataxia-telangiectasia. Lancet, 2 (1966) 1193.

6 Hecht, F., and B.K. McKaw, Evidence for a consistent chromosomal abnormality in ataxia-telangiectasia (A-T) lymphocytes. Am. J. Hum. Genet., 25 (1973) 32A.

7 Lisker, R., and B. Cobo, Chromosome breakage in ataxia-telangiectasia. Lancet, 1 (1970) 618.

8 McKaw, B.K., F. Hecht, D.G. Hamden and R.L. Teplitz, Somatic rearrangement ox chromosome 14 in human lymphocytes, Proc. Natl. Acad. Sci. (U.S.A.), 72 (1975) 2071-2075.

9 Oxford, J.M., D.G. Hamden, J.M. Parrington and J.D.A. Delhanty, Specific chromosome aberrations in ataxia-telangiectasia, J. Med. Genet., 12 (1975) 251-262.

10 Pfeiffer, R.A., Chromosomal abnormalities in ataxia-telangieclasia (Louis Bar's syndrome)., Human-genetik, 8 (1970) 302-306.

11 Rary, J.M., M.A. Bender and T.E. Kelly, Cytogenetic studies of ataxia-telangiectasia. Am. J. Hum. Genet., 26 (1974) 70A.

12 Welch, J.P., C.L.Y. Lee, J.W. Beatty DeSana, M.J. Hoggard, J.W. Cooledge, F. Hecht, B.K. McKaw, D. Peakman and A. Robinson, Non-random occurrence of 7-14 translocations in human lymphocyte cultures. Nature (London), 255 (1975) 241-244.

13 Zech, L., and V. Haglund, A. recurrent structural aberration, t(7 ; 14), in phytohemagglutimin-stimulated lymphocytes, Hereditas, 89 (1978) 69-73.