Systematic Analysis of 95 Reciprocal Translocations of Autosomes

A. Aurias, M. Prieur, B. Dutrillaux *, and J. Lejeune **

Hum. Genet. 45, 259-282 (1978)


Résumé :

Summary. The statistical analysis of 95 cases of reciprocal translocations involving autosomes detected among about 10,000 patients studied with the R-banding technique gives the following information: 1. An excess of break points exists for chromosome arms 4p, 9p, 10q, 21q, and 22q and a deficiency for 1p, 2p, and 6q. Furthermore, there are relatively more break points in the small arms than in the large arms, when the translocation is ascertained through an unbalanced translocation carrier. Except for chromosome 22, an ascertainment bias explain this non random distribution. 2. An excess of telomeric break points exists in all cases of translocations ascertained through unbalanced carriers, aid an excess of centromeric break point exists in the case of 3:1 and 1:3 segregations only. These excesses are also explained by an ascertainment bias. 3. The break points are located usually at the junction of the bands (interfaces). 4. The size of the chromosomal imbalance varies in the ascertainment classes. It is very large in cases ascertained through balanced carriers (at least one break point is far from the telomere), large in cases ascertained through abortion, and relatively moderate in cases ascertained through unbalanced translocation carriers (at least one break point is juxta telomeric). 5. An excess of balanced reciprocal translocations exists in our sample of mentally retarded and malformed children (position effect?). 6. An excess of balanced reciprocal translocations (not involving chromosome 21) exists among the trisomics 21 and their parents (interchromasomal effect?). 7. A large excess of maternal transmission exists in cases of 3:1 segregation of reciprocal translocation.

Sommaire

Deleterious effects of the reciprocal translocations are widely known, but their relation to the topologic changes of the chromatids needs further investigation. Thus, it seemed useful to analyze carefully the 95 reciprocal translocations observed among the 9183 patients studied since banding techniques became available in our laboratory.

Our intention was to seek a correlation among the localization of break points, the chromosomes or segments there of involved in the rearrangements, and the types of segregation observed in the families ascertained.

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Materials and Methods

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1. Samples Studied

All our structural rearrangements were ascertained through pathologic circumstances that provoked a karyotype study. Of 9183 patients examined by chromosome banding, 3211 were children of 15 years or less with malformations and/or mental retardation.

An unbalanced chromosomal anomaly was detected in 870 of these (trisomies 21: 762; trisomies 18: 29; trisomies 13: 23; and 56 other miscellaneous aberrations, including unbalanced translocation carriers).

In the 2341 other children, clinical examination did not suggest any known chromosomal syndrome. The remaining 5972 patients were adults seeking consultation essentially for reproductive difficulties (spontaneous abortion, infertility, malformed children).

It is noteworthy that the proportion of adults referred to us has increased progressively in recent years and now constitutes the majority of our cases.

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2. Cytogenetic Studies

Lymphocyte cultures were carried out according to the usual micromethod. All of our patients were analyzed with the use of R banding (RHG). Among the translocation carriers, 37 were also studied by Q banding (QFQ). Finally, many of the translocations were observed by T banding (THA), C banding (CBG), or after treatment for 7 h with BrdU followed by staining with acridine orange (RBA).

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3. Ascertainment and Classification of the Translocations

Our 95 translocations (see attached list) were separated into two groups and eight classes according to their mode of ascertainment and the type of malsegregation observed:

Group l:

Balanced parental translocations ascertained through children with unbalanced karyotype as follows:

46 chromosomes (2:2 segregation): 30 cases;

47 chromosomes (3:1 segregation): 18 cases;

45 chromosomes (1:3 segregation): 5 cases.

Group ll:

Balanced translocations found:

in couples having had several spontaneous abortions (S.A.): 12 cases;

in children with malformations and/or mental retardation (Bal.): 15 cases;

in children with free trisomy 21 or in one of their parents (possible interchromosomal effect: I.C.E.): 5 cases;

in sterile patients (Ster.): 7 cases;

miscellaneous (Misc.): 3 cases.

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4. Definition of the knits of Chromosome Length Used for our Calculations

Considering that the haploid human karyotype in metaphase consists of approximately 300 bands, we have used 1/300 of the karyotype 24,XY as a basic unit (U) of length in order to quantify the length of the segments involved in the rearrangements. The relative length of the different chromosomal arms was measured on the schema of the Descriptive Plates of Human Chromosomes (Prieur et al., 1973). Thus, for example, the short arm of chromosome 1 measures 12 U and the long arm, 14 U.

Having voluntarily excluded translocations involving sex chromosomes (whose combined length represents 20 U), we base our calculations on the 280 U of length of the autosomes.

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Results

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1. Localization of Break Points

The break points of each translocation were determined by two independent groups of observers and the results compared. The localizations retained for our 190 points are represented in Figure 1.


Fig. 1. Localization of break points

a) Localization of Break Paints in Relation to Bands and Interfaces.

We have retained, for this part of the analysis, only the 37 translocations that were studied both by R bands and Q bands. The distribution of the 74 break points at the level of R bands, Q bands and their interfaces, and tips of the chromosomes is indicated in Table I. It is clear from this table that there is an obvious excess at the level of the interfaces.

b) Distribution of Breakpoints According to the Chromosome Arms.

In Figure 1, we have noted, next to each chromosome arm, the number of break points expected in function of its length. Certain chromosome arms present an obvious deficiency or excess of break points. In order to consider only those translocations whose malsegregation leads to an unbalanced state known a priori to be compatible with life, and in order to normalize the length of the segments involved, we have taken into account only those break points situated on terminal segments 3.5-U-long carried on chromosome arms of at least that length (a length of 3.5 U corresponds to the long arm of chromosome 21 and represents 1/80 of the haploid karyotype); 71 break points situated on non terminal segments are thus excluded. In addition, this method of weighting has obliged us to exclude a certain number of chromosome arms whose length is clearly less than 3.5 U (smallest arms: Sm.a.). Thus, we have not considered the 15 break points situated on the short arms of the acrocentrics, and on the 17p, 18p, 19p, and 20p (total length of these arms is 18.5 U). There remain 104 break points situated on the 122.5 U of the 35 terminal segments (each of which is 3.5 U long). The distribution of these 104 terminal break points is given in Table 2. Here again, we have subdivided the sampling into two classes according to whether the break points sit on large arms L (greater than 6 U) or on small arms S (less than, or equal to, 6 U).

A total of 175 break points was observed on chromosome arms longer than 3.5 U (104 on terminal segments plus 71 on non terminal segments, as noted above). If these had been evenly distributed throughout the length of the chromatids, we would have expected 81.6 terminal break points instead of the 104 observed (?2 = 11.52 for v = 1).

There is, therefore, a significant excess of terminal break points, the mean observed being 2.97 break points per terminal segment. In order to determine if certain of these segments present an excess of break points, the probability of finding k break points on a given terminal segment can be calculated by applying Poisson's law: P(k) = e-2.97x(2.97k)/(k!).

This law shows that the excess becomes significant in the case of seven o more break points (probability of observing at least seven points: P= 0.032). In our sampling, this excess exists for the 4p, 9p, 10q, 21q, and 22q. The mode of ascertainment of the translocations involving these chromosome arms is indicated in Table 3.

We could not detect a possible deficiency of break points on certain arms because the absence of break points on a terminal segment is at the limit of statistical significance (P = 0.051). For this reason, we have grouped our data with that obtained by two other authors (Jacobs et al., 1974b; Turleau et al., 1975) which permits us to add 57 terminal break points to our sampling (Table 2). The average expected number of break points per terminal segment is thus 4.6. The absence of break points on a terminal segment has a probability of only 0.01 and becomes significant for the 1p, 2p and 6q. The excess of break points becomes significant with nine or more (probability of observing at least nine points: P=0.045) and still exists for the 4p, 9p, 10q, 21q, and 22q, and only for these.

Table I. - Localization of 74 break points in the 37 translocations studied both in R and Q banding
Group 1S.A.Bal.I.C.E.Ster.Mise.Total
R3216
Q415
13081113255
Tips718
Total44101224274
R: R bands; Q: Q bands; I: interfaces; Tips: tips of the chromatids; Group I: unbalanced translocation carriers; S.A.: spontaneous abortion; Bal.: malformed children carriers of a balanced translocation; I.C.E.: possible interchromosomal effect; Ster.: sterility; Misc.: miscellaneous
Table 2. - Distribution of break points on terminal segments 3.5 U long
Large Arms, L (> 6 U)
I.P.J.T.TotalI.P.J.T.Total
1p0000*7q2158
1q13158q5005
2p0000*9q1001
2q400410q8**1211**
3p4116 .11q4105
3q111312q4127
4q411613q2215
5q202414q2204
6q0000*15q3115
Table 3. - Ascertainment of translocations involving arms with an excess of break points
Group IS.A.Bal.Ster.Misc.
4p 43
9p61
10q5111
21q9
22q72
Group I: unbalanced-translocation carriers; S.A.: spontaneous abortion; Bal.: malformed children carriers of a balanced translocation; Ster.: sterility; Misc.: miscellaneous
Small Arms, S (= 6 U)
I.P.J.T.TotalI.P.J.T.Total
4p7**119**16p0101
5p601716q2204
6p300317q1203
7p300318q4217
8p111319q0213
9p7**2211**20q1012
10p200221q9**009**
11p110222q9**2011**
12p0011
I.P.: present study of lnstitut de Progenese; J.: study of Jacobs et al., 1974 b; T.: study of Turleau et aL, 1975). * Significant deficiency ** Significant excess
c) Distribution of Break Points Along the Chromatids.

We looked for a possible accumulation of break points in the centromeric or telomeric regions of the chromosome arms. In view of this, we have arbitrarily decided that a break point is telomeric or centromeric when it is situated at a distance less than, or equal to, one length unit from the telomere or the centromere. The arms previously excluded (short arms of the acrocentrics, and 17p, 18p, 19p, and 20p) form a separate category (smallest arms: Sm.a.) for which it is impossible to define the centromeric (C), median (M), and telomeric (T) regions.

Table 4 represents the observed distribution (o) of break points according to this classification (T, C, M, and Sm.a.) and takes into account the mode of ascertainment of the translocation. It also indicates the theoretical distribution (t) in function of length for each of the categories.

Among the translocations taken as a whole, we do indeed find the excess of telomeric and centromeric break points previously noted (Lejeune et al., 1972; Jacobs et al., 1974b). Furthermore, close analysis of our data shows that most of this excess falls into group I.

Let us recall that:

Group I is composed of translocations ascertained though live-born 'unbalanced' children (segregation 2:2, 3:1, and 1:3). This group farms a statistically homogeneous ensemble; after having grouped together the 3:1 and 1:3 segregation classes of translocations (for reasons of insufficient individual samples), the test for homogeneity gives:

?2 (2:2)/(3:1 + 1:3) = 4,98, for v = 3.

Group II is composed of translocations ascertained through a balanced carrier (S.A., Bal., Ster., I.C.E., Misc.) and also forms a statistically homogeneous ensemble. Grouping together translocations Ster., I.C.E., and Mist. and classes M and Sm.a., the test for homogeneity gives:

?2 (S.A.)/(Bal.)/(Ster. + I.C.E. + Misc.) = 3.32, for v=4.

The distributions observed in these two groups are significantly different (test for homogeneity: ?2 = 8.06 for v = 3).

The first group of translocations differs from the theoretical distribution (?2 = 42.5 for v = 3) as a consequence of:

- an excess of telomeric break points in the 3:1 and 1:3 classes (?2 = 7.74 for V =1);

- an excess of centromeric break points in the 3:1 and 1:3 classes (?2 = 5.48 for v = 1);

- a large excess of telomeric break points in the 2:2 class (?2 = 23.8 for v = 1).

The second group of translocations does not differ from the theoretical distribution (?2 = 5.45 for v = 3).

The slight excess of telomeric break points is not significant (?2 = 3.29 for v = 1).

Table 4. - Distribution of break points along the chromatids
NTelomeric regionCentromeric regionMedian regionSmallest arms?2 v = 3
otototot
Group I2/260207.5057.502741.0084.00 ?2 homogeneity: 4.98 v=3
3/13684.5094.501524.6042.40
1/31041.2521.2536.8410.66
Total group I1063213.2516J3.254572.44137.0642.5
Group IIS.A.2453.0033.001516.4011.60 ?2 homogeneity: 3.318 v=4 (a)
Bal.3083.7553.751620.5012.00
I.C.E.1001.2521.2576.8410.66
Ster.1421.7541.7589.5700.93
Misc.610.7500.7544.1010.40
Total group II841610.501410.505057.4145.595.45
Total group I + II1904823.753023.7595129.851712.65
(a) see text. o: observed; t: theoritical

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2. Analysis of the Types of Translocations

a) Distribution of the Classes of Translocations Described Above in Function of Break Points.

We have just localized the break points in telomeric (T), median (M), and centromeric (C) regions, or on the smallest chromosome arms (Sm.a.). This permits us to define a translocation by localization of its two break points. Thus, one may observe TT, TM, or TC translocations, etc. The distribution of our translocations according to this classification is indicated in Table 5. Several casses of translocations contain a sampling sufficiently large to permit statistical analysis. Thus we observe:

2:2 class: clear-cut excess of forms TM in relation to the other classes of transiocation (?2 = 10.36 for v = 1, P < 0.001);

3:1 class: excess of forms CM (?2 = 5.69 for v = 1, P < 0.0125) and no excess of forms TM;

S.A. class: excess of MM (?2 = 4.45 for v = 1, P < 0.05);

Bal. class: no significant excess of any of the forms.

The other classes of translocations contain a sampling too small to justify statistically study.


Table 5

b) Distribution of the Classes of Translocation in Function of the Length of the Arms evolved.

Let us recall that the definition of large arm (L) is any arm measuring more than 6 U, and that an arm is considered small (S) when it measures 6 U at the most. (6 U corresponds to the short arm of chromosome 6.) For purposes of this analysis, the short arms of the acrocentrics, and 17p, 18p, 19p, and 20p, have yen included in the category of small arms (S).

The total length of the small arms of the autosomes is 93 U; that of the large arms is 187 U (i.e., a ratio of 1/3 S to 2/3 L). Our translocations may thus be classified as SS, LS, SL, and LL where the theoretical distribution is 1/9, 2/9, 2/9, and 4/9, respectively. Table 6 gives the distribution of our 95 translocations according to this classification. The two categories SL and LS are distinguished by placing first the chromosome arm (L or S) that is lengthened by the rearrangement.

The distribution observed in the total sampling differs significantly from the theoretical distribution (?2 = 14.05 for v=3). This discrepancy is the consequence of an excess of forms SS and SL and a deficiency of forms LL and LS. However, the abnormal distribution is not found uniformly among the classes of translocations denoted, not being observed in the group of translocations ascertained in a balanced carrier (group II), but observed in the group of translocations ascertained through an unbalanced carrier (group I) (?2 = 27 for v = 3, P < 0.0005). In this group I, the excess of small arms involved (2 SS + SL + LS) is marked (?2 = 21.8 for v = 1).

We wanted to know if this excess of small arms (S) would persist if we were to exclude translocations involving any of the smallest arms (Sm.a.: short arms of the acrocentrics, and 17p, 18p, 19p, and 20p). In fact, even after this correction, the excess of small arms (S) in translocation group I is still very significant (?2 = 11.12 for v = 1, P < 0.005).

c) Analysis in Function of the Possible Induced Imbalances.

For each class of translocation, we can calculate in length units the possible unbalanced states induced at the time of malsegregation. The results of this analysis are indicated in Table 7 and 8.

Translocations of the 2:2 segregation class and of the telomeric-median category (TM) generally lead to an unbalanced karyotype, consisting of trisomy of a medium-sized segment, with a small terminal monosomy. However, several translocations in the same category have led, on the contrary, to a small terminal trisomy and a monosomy for a medium-sized segment. In these three particular cases, the monosomic segments are: the 4p (two instances, IP No. 12563 and If` No.14619) and the 5p (one instance, Laurent et al., 1974).

In the class of the 3:1 segregation translocations, four have produced an imbalance longer than 6 U. These four observations were ascertained through a child carrying a trisomy of the short arm of chromosome 9.

Table 6. - Distribution of the classes of translocation in function of the length of the arms involved
SSLSSLLLTotal ?2 v = 3
otototot
Group I2:2103.3336.6796.67813.3330
3:142.0054.0074.0028.0018
1:330.5611.1101.1112.225
Total I17'5.89911.781^11.781123.555327.00
Group IIS.A.11.3322.6722.6775.3312
Bal.11.6713.3363.3376.6715
Ster.00.7821.5631.5623.107
LC.E.+Misc.10.8931.7811.7833.558
Total II34.6789.34129.341918.65421.56
Total2010.561721.122821.123042.2095 14.0514.05
a 10 translocations involving smallest arms; b 2 translocations involving smallest arms. (S: small arms < 7 U; L: large arms > 6 U; o: observed; t: theoretical)
Table 7. - Observed mean imbalance. Group I (unbalanced-translocation carriers)
Classes of segregationMean trisomyMean monosomyTotal mean imbalance
2:2TM : 3.85 ± 1.83 n = 17TM : 0.47 n = 174.03 ± 1.63 n = 30
non-TM: 2.63 ± 1.42 n = 13non-TM: 1.01 n = 13
3:14.22 ± 2.43 n = 1804.22 ± 2.43 n = 18
1:301.68 ± 0.90 n = 51.68 ± 0.90 n = 5
Table 8. Possible mean imbalance. Group II (balanced-translocation carriers) in case of 2:2 segregation
Classes of segregationPossible mean imbalance
S.A.7.47 ± 3.39
Bal.8.14 ± 3.60
Ster.8.46 ± 4.60

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Discussion

In this section we intend to discuss the different steps in our analysis, but will begin with a discussion of the frequency of balanced translocations observed in malformed children, and in trisomics 21 and their parents.

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Balanced Translocations Found in Children Kith Malformations and/or Mental Retardation

In the 2341 children not suspected of having chromosomal abnormalities whose karyotypes we recently studied, we end 13 reciprocal balanced translocations (see attached list, numbers greater than 10,000). Four translocations figuring in this list represent reexaminations and are not taken into consideration.

Routine study of the karyotypes of newborn children carried out in various laboratories (Lubs and Ruddle, 1970; Walzer and Gerald, 1972; Jacobs et al., 1974a; Nielsen and Sillesen, 1975; Hamerton et al., 1975) shows that the frequency of this type of rearrangement in the general population is approximately 1 in 1200 births.

The probability of observing, as in our sampling, 13 balanced translocations among 2341 children is furnished by the binomial distribution:

P = 1.5 x 10-7.

Our sampling thus differs significantly from the general population.

To explain this difference, we might suppose that the translocations observed de novo in a proband are slightly unbalanced, the loss or alteration of genetic material remaining undetectable by current banding techniques. There remain seven familial translocations for which no cytologic technique has permitted us to demonstrate a difference between the translocation carried by the relatives with normal phenotype and that observed in the proband. We might therefore suppose that these seven translocations are not unbalanced. The binomial law, applied only to these seven translocations, furnished a probability of:

P = 4 x 10-3.

In function of these results, it seems reasonable to consider the possibility in these cases of a relationship of causality between the translocation and the observed syndrome, as several authors have proposed (Jacobs, 1974; Tharapel et al., 1977; Viguié, 1977; Funderburk et al., 1977).

It should be noted that the great majority of these balanced translocations are accompanied by a marked modification of the centromere index of the involved chromosomes. These topologic changes, while modifying the respective positions of different segments of the genome, might also disturb its replication or regulation (position effect).

This explanation seems to have received cytologic confirmation for X chromosome translocations which we have voluntarily eliminated from our study (Dutrillaux, 1974; Dutrillaux et al., 1974a).

The phenotypic discordance observed between a parent carrying the translocation and the malformed child is not easily understood. One hypothesis could be that the phenotype depends upon the alleles carried by the translocated chromosomes and by their normal counterparts. Allelic differences between parent and child are expected both by cross-over and normal segregation.

It is interesting to note that the diseases observed in these children are often genie disorders considered dominant with variable expression. One of the translocations involving chromosome 2 was ascertained through two children affected by Crouton's syndrome (craniofacial dysostosis). We have observed the same syndrome in a child with a pericentric inversion of chromosome 2. In addition, a translocation involving chromosome 15 was found in a child who had Prader-Willi's syndrome. Besides this, two observations of translocations involving chromosome 15 and associated with the same disorder have already been published (Hawkey and Smithies, 1976; Emberger et al., 1977).

Although outside the framework of this study, let us note that reciprocal translocations do not seem to be the only rearrangements capable of modifying the phenotype. In the same sampling of 2341 phenotypically abnormal children, we observed five translocations t(13q14q) and two pericentric inversions. In the general population, the estimated incidence of these rearrangements is, respectively, 1 in 1200 and 1 in 10,000. The probability of observing in our sampling five translocations t(13q14q) is thus 4.8 x 10-2 and that of observing two pericentric inversions is 2.3 x 10-2.

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Balanced Translocations Found in Children With Trisomy 21 and Their Parents

In the 762 children with trisomy 21, we observe three inherited balanced reciprocal translocations affecting other chromosomes than No. 21. The two other translocations observed in our general sample represent reexamination and are therefore eliminated from this analysis. The probability of observing these three translocations in a population of 762 children is:

P = 2.6 x 10-2 (binomial distribution).

This excess of reciprocal translocations is in harmony with the hypothesis of the interchromosomal effect (I.C.E.) postulated by Lejeune (1963). These observations would lead one to think that balanced structural rearrangements may influence the segregation of other elements, and the chromosome 21 in particular.

This interchromosomal effect does not seem to be limited to reciprocal translocations since, in the parents of these 792 children with trisomy 21, we observed also two pericentric inversions (excluding those affecting chromosome 9). Among the chromosomes involved in the five translocations and the two pericentric inversions we observed, it is noteworthy that the majority are carriers of DNA coding for ribosomal RNA (Henderson et al., 1972; Johnson et al., 1974; Pardo et al., 1975) or of segments with very late replication, seemingly corresponding to heterochromatin (Dutrillaux,1975).

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Localization of Break Points in Relation to Bands and Interfaces

We observed an excess of break points at the level of the interfaces between chromosome bands. This observation may be compared with the results obtained by analysis of the exchange of chromatids (Dutrillaux et al., 1974b), of break points in Fanconi's anemia (Dutrillaux et al., 1977), and of radiation-induced chromosomal rearrangements (Buckton, 1976; Dubos et al., 1978) where the same excess has been noted.

This reinforces the idea that there may be 'fragile' sites at the level of the interfaces whose particular structure favors the occurrence of chromosomal rearrangements (Dutrillaux,1977).

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Chromosome Arms Showing an Excess of Break Points

With the notable exception of chromosome 22, all of the chromosomes tending to show an excess of break points are implicated in the etiologies of well known and relatively frequent chromosomal disorders (4p-, tri4p, 9p-, tri9p, tri 10q, tri21).

Two hypotheses may account for this observation:

These chromosome arms manifest a particular fragility and the excess of break points observed in our translocations and in the 'classical' syndromes is merely a reflection of this fragility.

These chromosome arms have no particular fragility, but monosomies and trisomies of these segments are relatively well tolerated. The translocations involving these chromosome arms are thus more readily ascertained, especially in children carrying unbalanced karyotypes.

This second hypothesis seems the more probable. However, it does not permit us to explain the excess of break points observed an chromosome 22, an excess all the more surprising because pathology of this chromosome is exceptionally rare and limited to small segments. In the translocations of chromosome 22 that we present, when an imbalance was observed in a child, the contribution of chromosome 22 was always very slight, mostly limited to the juxtacentromeric or the telomeric regions of the long arm.

It is interesting to note that we have three identical translocations t(8;22) and two identical translocations t(11;22). In addition, this last translocation is found very frequently at the time of ascertainment through a child with trisomy 11q.

These remarks lead us to believe that chromosome 22 possesses a preferential subcentromeric break point (which is also found in the formation of the Philadelphia chromosome) and that it manifests, in addition, a certain 'affinity for translocation' with specific chromosomes such as 8, 9, and 11.

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Chromosome Arms Manifesting a Deficiency of Break Points

In our sampling, three chromosome arms, the 1p, 2p, and 6q, manifest very few break points. Trisomies and monosomies involving these segments are extremely rare in human pathology but have already been observed in the products of early spontaneous abortions.

One might think that an aneusomy involving these chromosome segments permits only brief intrauterine survival. The absence of break points observed in these segments would therefore be the consequence of a bias of ascertainment.

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Localization of Break Points on the Chromatids

When translocations are ascertained through a balanced carrier (group II), the break points distribute themselves regularly along the different chromosome segments. There is, nevertheless, a slight excess of telomeric break points that is not felt to be significant.

On the other hand, the excess of telomeric break points among the translocations ascertained through a child with an unbalanced karyotype (group I) is significant. This is particularly clear for the class of 2:2 translocations and corresponds, in unbalanced probands, to monosomy (and far more rarely to trisomy) for very small segments.

This situation is probably directly related to the eventual survival of subjects with unbalanced karyotypes. The excess of telomeric break points observed here may also be explained by a bias of ascertainment.

In the 3: and 1:3 segregation classes of translocations, we note in addition an excess of centromeric break points. This type of translocation always corresponds to the formation of a small element that malsegregates at the time of parental meiosis. The majority of these translocations involves an acrocentric chromosome that furnishes the short arm and the centromeric region of the small element.

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Analysis of the Malsegregations Observed in Group I (translocations ascertained through a proband with unbalanced karyotype)

The translocations with 2:2 segregation of this group are ascertained through unbalanced carriers. This presupposes that a segregation of the adjacent type occurs at the time of parental meiosis.

The type of meiotic segregation of translocation probably depends on the number of crossing-over that can occur between the centromere and the point of exchange of the translocation (McClintock, 194; Burnham, 1956; Hamerton, 1971):

If there is no crossing-over on the segment, an adjacent segregation is to be expected and the gametes will be unbalanced.

If there is a single crossing-over, half of the gametes could be unbalanced.

If there is a crossing-over on each of the chromatids, the segregation will generally be of the alternate type and the gametes will be normal.

If the segment situated between the centromere and the point of exchange of the translocation is small, one can expect an excess of unbalanced gametes. For large segments, the number of crossing-over becomes random and this excess of unbalanced gametes should not, theoretically, be noted.

Perhaps these theoretical remarks furnish an explanation for the clear excess of chromosomal small arms involved in this class of 2:2 segregation translocations.

We have seen that the 3:1 segregation translocations correspond to the malsegregation of a small structurally rearranged element at the time of parental meiosis.

In the 18 cases that we present, this malsegregation always occurred during the first meiotic division so that the proband received, along with the small supernumerary element, 46 other normal chromosomes. It is therefore indispensable to study the parent's karyotypes to determine the precise nature of this small element.

One might conclude that the malsegregation of the small element is the consequence of a particular topological configuration imposed by the size of this element at the time of the pairing of the chromosomes in the first meiotic division.

It is interesting to note that, of our 18 cases, 17 are the consequence of maternal translocation. This preponderance of maternal origin has already been noted for trisomy 9p, where the 16 cases collected by Lurie et al. (1976) corresponding to a malsegregation of the 3:1 type, all result from maternal translocation. The same is true for the seven published cases of trisomy 11q by translocation t(11;22) (Aurias et al., 1975; Laurent et al., 1975; Giraud et al., 1975; Ayraud et al., 1976; Noel et al., 1976; Kessel and Pfeiffer, 1977).

This maternal preponderance is not found among translocations having undergone a segregation of the 2:2 type. 0f the 28 cases that we report, 12 are of paternal origin and 16 of maternal origin.

We have not found any obvious bias of ascertainment that would allow us to explain the excess of maternal translocations in the 3:1 segregations. There is no increase in the mean maternal age.

Perhaps explicable in terms of diminished fertility or even sterility among men carrying such translocations (Dutrillaux,1973a; Laurent et al., 1977), this excess probably reflects a fundamental difference between the male and female meiosis, a difference whose precise nature remains unknown.

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Average :Length of Possible Induced Imbalance in Cases of Malsegregation

Our results permit us to quantify to a certain degree the importance of the observed chromosomal imbalances.

Thus, 1:3 segregation (leading to monosomies) manifest an average imbalance of 1.68 U, while 3:1 segregations (leading to trisomies) yield an average imbalance of 4.22 U. This could indicate that the trisomies are relatively better tolerated than the monosomies. This feeling is strengthened by the analysis of 2:2 segregations, where the segment in triplicate is generally longer than the monosomic segment, and where the length of the trisomic segment is reciprocally proportional to that of the monosomic one (TM translocations: 3.85 U long trisomy for a 0.47 U long monosomy; non TM translocations: 2.63 U trisomy for 1 U Long monosomy).

The translocations ascertained through spontaneous abortions (S.A.) present a total imbalance of 7.5 U, which is less marked than that observed in cases of sterility (8.46 U) or balanced translocations (8.14 U).

These results are on the whole satisfying and permit us to relate the severity of the resulting disorders to the length of the involved chromosome segments.

However, a certain number of translocations disobey this rule appreciably. Other parameters beside length must therefore influence the severity of chromosome disorders. Among these, two seem to play an important role:

the genic content of the involved segments;

the replication time of these segments.

It seems quite possible to us that trisomy or monosomy of early replicating R bands are less well tolerated than imbalances of late replicating R bands or Q bands (whose replication is always late) (Dutrillaux et al., 1976).


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