Am J Hum Genet 35:288-300, 1983

Distribution of Break Points in Human Structural Rearrangements

YASUO NAKAGOME,I TAKAKO MATSUBARA, 2 AND HIROKo FUJITA3

SUMMARY

We attempted to resolve the issue on the location of breakages in pa-tients with structural rearrangements, that is, whether they are locatedwithin the light band or are at the interface between a G-dark and aG-light band. Three types of structural rearrangements (inverted dupli-cations, isodicentrics, and rings) were studied as they are capable ofproviding information not obtainable from other rearrangements becauseof reasons given in the RATIONALE.We found that break points are primarily located within the G-light

bands; a small number of breaks are located in G-dark bands. Breakagesat the interface were exceedingly rare. The possibility that they are, infact, located at the interface of subbands within either light or darkbands appears tenuous. Contrary to what is described in the literature,terminal deletions are not useful in the determining of break points.

INTRODUCTION

Nakagome and Chiyo [1], who reviewed 117 reported unrelated cases with two-break rearrangements, found that among 220 breakage points, breakages werepreferentially located within G-light bands. Similar observations have been madeby others [2-4]. On the other hand, Dutrillaux et al. [5], who used Q- andR-band techniques to analyze chromatid breaks in Fanconi anemia, suggested thatthere may be an observation bias in favor of localizing break points at lightlystained bands and concluded that the breakages were, in fact, located at "inter-bands," that is, at a junction (interface) between adjacent Q(R)-positive and Q(R)-

Received January 26, 1982; revised May 25, 1982.This study was supported in part by a grant for Monitoring Handicapped Children from the Ministry

of Health and Welfare, Japan, and a Grant-in-Aid for Scientific Research from the Ministry ofEducation, Japan.

Department of Human Genetics, National Institute of Genetics, Mishima, Shizuoka-ken, 411Japan.

2 Present address: Department of Human Genetics, Tsukuba University, Sakura-mura, Ibaraki-ken,300-31 Japan.3Department of Child Health, Osaka City University, Osaka, 558 Japan.

© 1983 by the American Society ot Human Genetics. All rights reserved. 0002-9297/83/3502-0011$02.00

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BREAK POINTS IN REARRANGEMENTS 289

negative bands. Similar conclusions have been based on studies of reciprocaltranslocations [6] and X-ray or chemically induced aberrations [7]. Buckton [8]examined X-ray-induced aberrations by sequential G- and R-banding on the samecell and found that 30% of the breakages were at the interface.

According to Savage [9], the assignment of break points, particularly in caseswith primary chromosome-type aberrations, is inherently uncertain because of the"three-band uncertainty." Savage et al. [10] used both terminal deletions andX-ray or quinacrine mustard-induced chromatid-type aberrations to identify breakpoints within a specific band. They found that the three-band uncertainty did notapply to terminal deletions and that in chromatid-type aberrations an unchangedchromatid was available for reference in the identification of the break point in theother chromatid. They concluded that in both situations the breakages were lo-cated within G-light bands.We studied patients with a few selected types of congenital structural rearrange-

ments to determine whether the break points were located within light bands orwhether they were at the "interface" between G-positive and G-negative bands.

RATIONALE

In inverted duplications (inv dup) and isochromosomes (i), only one of twobreak points (the only break point in the latter) can unequivocally be identified.When it is within a G-light band, the abnormal chromosome shows symmetry witha light band at the median plane (fig. ID and E). When it is at an interface, themedian light band either disappears or is double in length (fig. 1B and C). Thepresence of a median light band short of double size is evidence for a break withina light band. On the other hand, a break within a dark band should produce adark band at the median plane that is less than twice the length of the broken darkband (fig. IF).

b d

AB

C D E FFIG. 1.-Identification of break points in inverted duplications and isochromosomes. A, Rectangular

blocks represent G-positive bands, and the other parts, G-negative. Open, solid, and hatched blocks aswell as two horizontal lines between theformer two are used to distinguish bands individually. Arrows a,b, c, and d indicate possible sites of breakage at the median plane in the formation of' either anisochromosome (i) or an inverted duplication (inv dup). B and C show consequence of two possibleinterface breakages at different sites (a and c). D, E, and F illustrate outcome of breaks in a light bandclose to "a," the same close to "c," and break in a dark band, respectively (see also RATIONALE).

NAKAGOME ET AL.

All chromosome arms, save the short arms of acrocentrics and a few otherexceptions, have a light band at their distal ends. Upon chromosomal ring forma-tion, the most distal dark band of each arm is usually included in the ring. A lightband, consisting of a part of one or both of the most distal bands of each arm,separates the two dark bands (fig. 2B). If all breakages are located at the interfacebetween the most distal light band and the adjacent dark band, no light band isexpected to exist between these two dark bands in any of the rings (fig. 2C). Theonly explanation compatible with both the presence of a light band at the fusionsite of a ring and breakage at the interface would be fusion of a broken end of onearm with the intact telomere of another, although we do not have evidence that thiscan indeed happen (fig. 2D). Rings with larger deletion (i.e., those lacking multiplebands from each arm) were excluded from this study to simplify the identificationof break points. The simplest condition is presented by ring formation of anacrocentric chromosome: As the short arm consists of only variable bands, thebreak point in the long arm can be identified unequivocally regardless of thenumber of missing bands.As to terminal deletions, it is controversial whether a broken end can remain

unhealed [11]. As far as we are aware, no definitive evidence has been provided forthe terminal, rather than interstitial, nature of the breakage; the former type ofbreakage is not included in our study.

In other types of structural rearrangements (e.g., reciprocal translocations, in-versions, direct duplications, and second breakage of an inv dup), determinationof the break point involves a much smaller change in the length of the band thanwe dealt with in our study.

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t a"\2

A D

FIG. 2.-Identification of break points in rings. A, Rectangular blocks represent the most distal G-positive band in each arm, open blocks being in the short arm and solid ones in the long arm. G-negativesegment is shown by either a thick (short-arm) or a thin (long-arm) line. cen denotes centromere; t or t',distal end of each arm. a(a') and b(b') are breakages in a light band and at an interface, respectively. B,C, and D illustrate rings formed by two breakages in light bands (break points a and a'), the same atinterfaces (break point b and b'), and an interface breakage (b') combined with the fusion of an intactend (telomere) of the short arm (t). We are skeptical, however, of the presence of the last mechanism.

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BREAK POINTS IN REARRANGEMENTS

MATERIALS AND METHODS

From 1972 to early 1981, six cases with inverted duplications (inv dup), seven isodi-centrics (idic), and 12 rings (r) were studied in the senior author's laboratory. For compara-tive purposes, a case with direct duplication (dir dup), two cases with unidentified duplica-tions (dir or inv), and a translocation dicentric (tdic) are included here. None of these caseswere related to each other. Most cases were studied by GTG, QFQ, and CBG techniques [12].Other techniques including DAPI, distamycin-DAPI [13], RBA [12], and/or Ag-I [14],were applied in cases 2106, 2205, 2383, 2403, 2420, 2421, 2422, 2430, and 2444 to obtainadditional information. However, the trypsin-G (GTG) technique sufficed in all but threecases for the detection of a G-light band at either the median plane (inv dup and idic) or thefused site (r) for reasons given in the RATIONALE. In three cases (2383, 2420, and 2421), othertechniques were needed because of the lack of either quality or quantity of G-bandedmetaphases.

RESULTS

The results on nine cases with duplications are summarized in table 1, andpartial karyotypes are shown in figure 3. In both cases 2436 and 2419, one of thetwo no. 1 chromosomes had extra bands in the distal part of the long arm (lq+).They included a segment from a part of q32 through a part of q44. They werearranged in a mirror-image position with the corresponding original segment. Atthe median plane, a light band was detected. Although it was narrow, it was therebeyond doubt (solid squares). The lq+ chromosomes had a structure invdup(l)(q44-q32) in both cases (unrelated). Case 2205 also had a mirror-imagestructure that included two dark bands within the 2ql region. At the medianplane, a light band was detected. It was sandwiched between two segments, each ofwhich included bands q21-q1 1.2. The median light band consisted of a part ofq21. The short arm and the long arm distal to q21 showed a normal band pattern.Case 2450 represented a duplication of a major part of 7q. Both the symmetricnature of the duplicated segment and the small size of the segment distal to themost distal and conspicuous G-dark band (q21 or q31) in the dup chromosomemade the presence of dir dup unlikely. In dir dup, the segment is expected toinclude five bands (q3200 to qter) as does a normal no. 7. In the dup 7, the size of

TABLE I

BREAK-POINT DISTRIBUTION IN DUPLICATIONS

LOCATION OF BREAKAGES

CASE KARYOTYPES Breakages at median plane Other breakages

2205 ...... 46,XX,inv dup(2)(q21-qll.2) L L or I2419 ...... 46,XX,inv dup(I)(q44-q32) L L or I2420 ...... 46,XX,inv dup(4)(p16-pl5) L L or I2429 ...... 46,XX,inv dup(11)p 15.5-p 13) L L or I2436 ...... 46,XX,inv dup(l)(q44-q32) L L or I2450 ...... 46,XX,inv dup(7)(q33-ql 1) D L or I2387 ...... 46,XY,dir dup(I4)(q24.3-q32.3) L or I / L or I2388 ...... 46,XX,dup(5)(p5-p?l1) L or I / L or I2067 ...... 46,XX,dup(21)(qII-q22) L or I / L or I

NOTE: In inv dup cases, breakages at the median plane and other breakages are scored separately for the reasonsgiven in the RATIONALE. L = light band; D = dark band; I = interface.

291

NAKAGOME ET AL.

FIG. 3.-Partial karyotype of patients with duplications. The G-band pattern of duplicated chromo-somes and their homologs are shown. From left to right, top row: two no. 1 pairs from case 2436(left-hand side of each pair being abnormal throughout this figure), two no. I pairs from case 2419 (notrelated to 2436), and three no. 2 chromosomes from case 2205. In both cases 2205 and 2450, anabnormal chromosome from a cell and a pair from another cell are shown. Bottom row: three no. 7sfrom case 2450, a no. II pair from case 2429, two no. 4 pairs from case 2420 (DAPI and G staining),and a no. 14 pair from case 2387. Solid squares indicate point of breakage at each median plane (seeRESULTS and table 1).

this segment was only about 1/3 of the normal one. At the median plane, a smalldark band was recognized that consisted of a part of q33 bands (square). In case2429, a small light subband was detected at the median plane. On both sides of it,two slightly dark subbands (p15.4 and 15.2) and a dark p14 band were arrangedsymmetrically. Case 2420 represented a very small duplication of 4p. There was asmall but distinctly light (faint in a DAPI-stained chromosome) band near thedistal end of dup 4p. It was identified as a part of p16 as there was no abnormalityin the banding pattern from qter through this band. Two dark (DAPI-bright)bands were detected on both sides of it. The distal of them was much smaller thanthe proximal one, although the intensity of them roughly corresponded. At thedistal end of the short arm, no (or very narrow, if any) G-light band was recog-nized not in agreement with the dir dup or ins. The structure was identified to beinv dup with breakages in the distal p16 and around the middle of p15 (i.e., themedian plane consisted of a part of p16 and the small dark band distal to itrepresented a part of p15). In case 2387, two 14q31 bands were recognized. It wasidentified to be dir dup and not inv dup as each of the q31 bands was followed bysubbands q32.1 and q32.2 in its distal side and no mirror-image structure wasdetected. In both cases 2388 and 2067, it was not possible to determine the orienta-tion of duplicated segment, and it was not included in figure 3. In five of thesecases, both parents had a normal karyotype (2205, 2388, 2420, 2429, and 2436). Inthe remaining cases, parents were not examined.

In summary, all cases with inv dup, excepting case 2450, had a light band at themedian plane; none of these bands was twice the length of the original light band.To the contrary, they were much shorter than the original size, indicating that all

292

BREAK POINTS IN REARRANGEMENTS

points of breakage were within a light band and not at an interface. In case 2450,the breakage was within a dark band.

In the dir dup case (2387), the breakages appeared to be at 14q24.3 and 14q32.3;however, it was difficult to determine whether the breakages were within thesebands or at their border (interface). In cases 2388 and 2067, it was not possible todetermine dir or inv nature of duplications.The second group consisted of seven patients with an isochromosome (i). Cases

with i(Xq) were excluded unless they were distinctly dicentric. A case of transloca-tion dicentric (tdic) is also included (table 2). All of these cases manifested amonocentric appearance (psu dic) due to inactivation of one of the centromeres[18]. None of the break points was at any of the interfaces. In five of sevenisodicentrics (idic), the breakages were within a light band; in the remaining two,they were within a dark band (fig. 4). In case 2383, a small but distinct RBA-brightband was detected at the median plane (square) of the psu dic X that correspondedto a part of G-negative Xq22 band. In case 2421, the psu dic X had two C-positivespots (left, CBG staining). RBG staining revealed a short bright band at themedian plane that corresponded to the segment between the two C-positive spotsin the CBG preparation (triangle). It corresponded to a part of a G-negative Xpl 1band. In case 2422, subbands were identified between two conspicuous Xp2lbands on a psu dic (X). At the median plane, a very short faint segment was barelyrecognizable. On each side of it, a short, moderately dark segment was present.The latter was identified to be subband p22.2 based on its position to the p21band. The faint segment, therefore, consisted of a part of the subband p22.3. Incase 2444, the psu dic X was formed through breakage near the distal end of Xq.At the median plane, there was a dark band that was barely detectable andconstituted a third dark band from either of distinct q21 bands. In a case oftranslocation dicentric (tdic) (1925), one break was located in each a dark and avariable band.

Table 3 shows the break-point distribution in seven cases with a ring chromo-some. Two of these cases (2066 and 2076) involved acrocentrics; therefore, one oftwo break points was within variable bands. Eleven break points were located

TABLE 2

BREAK-POINT DISTRIBUTION IN ISODICENTRICS

Cases Karyotypes Location of breakages

2106*. 47,XY,+psu dic(9)(q2101) D2383. 46,X,psu dic(X)(q22) L2403*. 46,XX,-21,+psu dic(21)(q22) L2421. 46,Xpsu dic(X)(pll) L2422. 46,X,psu dic(X)(p22.3) L2430. 46,X,psu dic(X)(q22) L2444. 46,X,psu dic(X)(q27) D1925*. 45,XX,tdic(7; 15)(p21;pl 1) D Vt

* For further details, see Abe et al. [15], Matsubara et al. [16], and Nakagomeet al. [17].

t One breakage in each a dark and a variable band.

293

NAKAGOME ET AL.

ji f~~~~~~~~~~~~~~~'FIG. 4.-Partial karyotype of patients with isodicentrics and rings. From left to right, top row: an

X-chromosome pair of case 2383 (RBA staining), a CBG-stained psu dic X, RBA-stained X pairs fromcase 2421, and an X pair of case 2422 (GTG). Bottom row: two X pairs from case 2444, a normal no. 6,and an r(6) from two cells of case 2410, and an X pair from case 2131 (see RESULTS and tables 2 and 3).Squares indicate a dark (cases 2444 and 2131) or a light band (all other cases) at either the median plane(i) or the site of break and reunion (r).

-within the most distal light band of each arm. A breakage (case 2131) was locatedwithin a dark subband (Xp22.2); however, the possibility that it was at the inter-face between subbands p22.2 and 22.3 was not excluded. In none of these caseswas the second distal band (dark) of each arm fused with each other or with avariable band. These results are not compatible with the suggestion that breaks arealways located at the interface. Further, in none of our cases did the length of thelight band between the most distal dark bands coincide with the additive length ofthe most distal light bands. Thus, the fusion of telomeres does not appear to occurfrequently, if it does at all.A review of the literature and Borgaonkar's catalog [23] disclosed seven cases of

inv dup in which each break point was identified within a single band [24-28]. Anadditional two cases were retrieved from the Repository [29]. In five of these[25-27], we were able to confirm the location of the break points in the publishedphotographs (table 4). For case 1 of Taylor et al. [26], we used the photographpublished by George and Francke [30] on the same case (fig. 1 C) because it showedmany more details. In all of them, a light band was detected at the median plane;its length was much less than twice the length of the original light band. In onecase, the breakage was probably in a dark band [24]. In an additional three cases[28, 29], breakages were probably in a light band. While there are other reports ofcases with inv dup, in many instances an idic (or psu dic) chromosome may havebeen erroneously labeled as an inv dup.

In cases with idic or psu dic chromosomes (table 4), most (22/29) of the breakpoints were within light bands ([31, 32, 34, 36, cases 5-7], [38-40, cases 02 and 08],[41, case 2], and [42, case 3]). In five cases, breakages were identified within a darkband ([33, 35, 36, case 1] and [41, cases 3 and 4]). No breakage was locatedat any of the interfaces. An additional 27 breakages were retrieved from the

294

BREAK POINTS IN REARRANGEMENTS

TABLE 3

BREAK-POINT DISTRIBUTION IN RINGS

LOCATIONS OF BREAKAGES

CASES KARYOTYPES Short arm Long arm

1578* ....... 46,XYq+,r(5)(p15q35) L L1849* ....... 46,XX,r(17)(p13q25) L L1985* ....... 46,XY,r(9)(p24q34) L L2066* ....... 46,XX,r(13)(pl 1q34)/46,XX,-13,+t(13q13q) V L2076t ........ 46,XX,r(13)(p1q34) V L2131 ....... 46,X,r(X)(p22.2 or 22.3q28)/45,X D or I L2410 ....... 46,XY,r(6)(p25q27) L L

* For further details, see Nakagome et al. [19], Ono et al. [20], Nakajima et al. [21], and Oka et al. [22].t Only photographic prints were available for analysis.

literature; however, it was not possible to confirm the results based on publishedphotographs.

Thirty acrocentric rings and 18 nonacrocentric rings were collected from theliterature. In 10 of each group, breakages were identifiable based on publishedphotographs [43-61]. Out of 10 breakages in the long arm of acrocentric rings,eight were in the light bands, one in a dark subband in a terminal light band [59],and one at the interface [45]. All 20 breakages of nonacrocentric rings werelocated in a light band, two of them being in a light subband in the most distallight band [58].Out of 148 breakages, including 25 of our own and 123 from the literature, only

one was positively located at the interface. An additional breakage was possibly atthe interface.

DISCUSSION

As pointed out in the RATIONALE, inverted duplications, isochromosomes, andrings are three optimal materials to determine whether a breakage is locatedwithin a band or at the junction of two bands (an interface). In our study, nobreakage was positively located at any of the interfaces out of a total of 25. In onlyone breakage, we were not able to exclude an interface from its possible sites. Anadditional 123 breakages were retrieved from the literature, making the totalnumber 148. Only two of them were located at the interface including a probableone.

It might be argued that all breakages are, in fact, at the interface of subbandsand that they are assigned within a band primarily because of the inadequateresolving power of the present banding techniques. This does not appear to be thecase. Upon application of the standard technique, a mitotic cell is seen to containabout 300-350 bands per haploid set [12]. Upon examination of data presented byYunis et al. [62], a high-resolution banded preparation appears to yield an averageof 600-700 bands (i.e., it contains twice as many interfaces as does a cell preparedby the standard technique). We find it difficult to believe that all of the breakagesobserved within light (dark) bands are in fact located at the interface of subbands

295

NAKAGOME ET AL.

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BREAK POINTS IN REARRANGEMENTS

within them. If this was the case, then, more than half of the observed breakagescould be expected to locate at the 300-500 interfaces detected by the presenttechnique.

ACKNOWLEDGMENTS

We are grateful to Dr. Ei Matsunaga for his encouragement throughout this study. Cases2067, 2131, 2387, 2388, 2419, 2420, 2421, 2429, 2430, and 2450 were from St. Mary'sHospital, Kurume. The blood samples were kindly made available as follows: case 2106,Dr. T. Abe, Kyoto Prefectural University; case 2205, Dr. T. Naito, National Children'sHospital; case 2383, Dr. Y. Yukimura, Institute of Adaptation Medicine, Shinshu Universi-ty; case 2410, Dr. K. Konno, Fukushima Medical College; and case 2436, Mr. T. Yokochi,Department of Clinical Pathology, Shizuoka Children's Hospital. The kind cooperation ofDr. M. Matsumoto, Osaka Boshi Center, in the analysis of case 2444 is appreciated. Wealso thank Mrs. M. Sakai for technical assistance and Ms. U. Petralia for reading themanuscript.

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