Chromosome translocations in man

Raymond TURPIN Jérôme LEJEUNE.

The Lancet p. 617, March 18, 1961.


Sommaire

SIR, -Your editorial (1) on the mongol chromosome and others drew attention to translocations. The practical and theoretical interest of these justifies comment.

The first recorded example was the 22/13 translocation (2), but 6 others are now known. Some involve the mongol chromosome: 21/13 or /14, or /15 (3), 21/22 (4), or 22/22, 21/21 (5), 21/15 (4, 6). You stated (1) that these explain the occurrence of " exceptional 46-chromosome mongols ", and of the rare cases where 2 sibs are affected (4, 6). Other translocations have been reported : 14/15 (7), 22/13 (8), a and a possible 21/Y (9).

Thus translocations appear to play a well-defined role in pathology. It is noteworthy that all the types so far recorded involve acrocentric chromosomes. This kind of rearrangement is, of course, most easily recognised, for reciprocal interchanges between metacentric elements of comparable size would be difficult to assess, and would merely lead to wrong classification when establishing the karyotype. Thus, the observations may be biased. But the presence of satellites in nos. 13, 14, and 21 could play a role in the translocation mechanism, and in determining the probability of its occurrence.

Furthermore, the so-called " centric fusion " implies a deletion of the chromosomal segments attached to the eliminated centromere. Hence the more acrocentric the elements, the smaller will be the chromosomal loss. In view of the possible lethal effect of big autosomal deletions (none has been observed as yet) this prevalence of translocations between acrocentric chromosomes could well result from natural selection.

The practical interest of translocations is not restricted to genetic counselling in familial mongolism. The 14/15 type was found in an individual also exhibiting the XXY Klinefelter syndrome (7). A mother carrying a balanced 22/13 translocation gave birth to a classical mongol with 47 normal chromosomes and 3 no. 21 chromosomes, and without the maternal translocation (8). The fact that translocations seem to increase the probability of non-disjunction in other chromosomes invests the discovery of a translocation in an apparently healthy individual with eugenic significance. The diagnostic interest of translocations is mainly dependent on their phenotypic consequences. For example, all the healthy carriers of the different 21/13 varieties with a balanced 45-chromosome genotype have been reported to be normal. The " exceptional 46-chromosome mongols " are phenotypically indistinguishable from classical trisomics.

A possible conclusion would be that the loss of satellites does not have harmful effects, because of the low genic content of these segments.

By contrast the two varieties of the 22/13 type seem harmful. In the first case (multiple vertebral dysgenesis) (7) vertébral deformities and mental and physical retardation were observed. The second exemple (8), observed in a mother and in 4 of her children, determined various degrees of speech defect and mental retardation, ranging from very severe in the children to normality in the mother.

These intrafamilial variations between carriers of the same variety demonstrate the influence of the rest of the genotype. But the interfamilial variation between different. varieties of the same type could be attributed to the extent of change in each variety-i.e., the eliminated fragments could differ.

If the effect of position is ignored, at any rate in a preliminary survey, a sample of, say, 20 varieties of the 22/13 type could yield much information about the genic content of the eliminated fragment. For example, if it was observed that 2 characters, which are sometimes independent, are always accompanied by a 3rd, when both are present together, a threepoint linkage map would be obtained; and its spatial relationship to the centromeres could be established. To determine whether the eliminated fragment belonged to no. 22 or to no. 13 would depend upon comparisons between types 22/13 and 22/15.

The method is limited by the shortness of the analysable fragment. This is due to the harmful effect of autosomal deletions.

Some types in which the deleted fragments are genetically quite inactive could very well be transmitted unknowingly in our species. Thus, a possible polymorphism of the karyotype among apparently normal people, even though very rare (7), cannot be ruled out.

This discussion of cytogenetic mapping of chromosome segments would probably have been considered unrealistic a year ago. But with the worldwide expansion of research in cytogenetics, the requisite sample of many varieties of the same type is likely to be obtainable fairly soon.

It would be beneficial if authors working in this field gave as much attention to precise phenotypic description as to accurate chromosome analysis.


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Bibliographie

1. Lancet, 1960, ii, 1068.

2. Turpin, R., Lejeune, J., Lafourcade, J., Gautier, M. C.R. Acad. Sci., Paris, 1959, 248., 3636.

3. Polani, P. E., Briggs, J. H., Ford, C. E., Clarke, C. M., Berg, J. M. Lancet, 1960, i, 721.

4. Penrose, L. S., Ellis, ]. R., Delhanty, J. D. A. ibid. 1960, ii, 409.

5. Fraccaro, M., Kaijser, K., Lindsten, J. ibid. 1960, i, 724.

6. Carter, C. O., Harnerton, J. L., Polani, P. E., Gunalp, A., Weller, S. D. V. ibid. 1960, ii, 678.

7. Lejeune, J., Turpin, R., Decourt, J. C.R. Acad. Sci., Paris, 1960, 250, 2468.

8. Moorhead, P. S., Mellman, W. J., Wenar, C. Amer. J. Genet. (in the press).

9. Turpin, R., Lejeune, J., Gautier, M. Conference on Congenital Malformations. London. July 18-22. 1960.