J. med. Genet. (1968). 5, 205.

A Family with D/D TranslocatonE. KRMPOTIC, K. RAMANATHAN, and A. GROSSMAN

With the technical assistance ofK. SZEGO and D. MEEKER

From the Departments of Experimental Pathology and Pediatrics, Mount Sinai Hospital Medical Center; andthe Departments of Pathology and Pediatrics, The Chicago Medical School,

University of Health Sciences, Chicago, Illinois, U.S.A.

Balanced D/D translocation carriers appear to benormal in most instances (Court-Brown et al.,1966; Giannelli and Howlett, 1966). In somecases, however, a variety ofcongenital malformationshas been reported, such as Klinefelter's syndrome(Lejeune, Turpin, and Decourt, 1960), littlesecondary sex development (Walker and Harris,1962), malformation of the spine (de Grouchy et al.,1963), arrested hydrocephalus accompanied bymental retardation and spastic diplegia (Jagiello,1963), and hydrocele and azoospermia (Yunis et al.,1964). Dekaban (1966) described a family withtransmission of a D/D translocation and a highincidence of mental retardation. A D/D translo-cation was found in a patient with Down's syn-drome; in that case, the patient had a modal num-ber of 46 and a trisomy 21 (Zergollern et al., 1964).It has also been suggested as a cause of familialnon-disjunction (Hamerton, Giannelli, and Carter,1963), and was found in association with chronicgranulocytic leukaemia (Engel et al., 1965).When appearance and measurements of the D

group chromosomes were used as criteria for identi-fying the chromosomes involved in reciprocaltranslocation, chromosomes 13 and 15 (Walker andHarris, 1962; Hamerton et al., 1963), and 14 and 15(Lejeune et al., 1960; de Grouchy et al., 1963;Zergollem et al., 1964) were suggested as thechromosomes of origin. Using 3H-thymidinelabelling and autoradiography, Yunis et al. (1964),Giannelli and Howlett (1966), Dekaban (1966), andTiepolo et al. (1967) assumed that the chromosomesinvolved in reciprocal translocation were a late andan intermediate replicator, probably Nos. 13 and 14.' The purpose of this paper is to describe a familyin which a D/D translocation chromosome was

Received February 8, 1968.

transmitted through three generations withoutsigns of mental retardation or of physical abnor-malities in any member of the family; identificationof the D chromosomes involved in the reciprocaltranslocation was attempted with 3H-thymidinelabelling and autoradiography.

Case History of PropositusA 10-month-old Caucasian female infant was ad-

mitted to hospital for failure to thrive. Physicalexamination revealed that she was in the third centile forweight and height. The muscles were flaccid and thejoints were hyperextensible. The laboratory tests,including complete blood count, urine analysis, bloodsugar, urea nitrogen, serum protein electrophoresis,calcium, phosphorus, electrolytes, and pH, were withinnormal limits. Chest and skull x-rays and intravenouspyelogram were normal. While in hospital, the childate well and gained 900 g. At the age of 20 months shewas found to be in the 50th centile for height and overthe 90th centile for weight.

Family StudiesThe patient has an older sister who is apparently

normal. The first pregnancy of the mother resulted inmiscarriage. There was no history ofmental retardationin the family through four generations. The pedigree ofthe family is shown in Fig. 1.

Physical examinations, blood grouping, haptoglobintyping, serum protein electrophoresis, and leucocytealkaline phosphatase determinations were carried out onthe propositus and 6 members of 4 generations of thefamily. No abnormalities were observed.The result of the dermatoglyphic examinations are

shown in Table I. A wide atd angle and t' weie ob-served in several members of the family.

Chromosome StudiesChromosome studies using the method of Moorhead

et al. (1960) were carried out on short-term peripheral

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Krmpotic, Ramanathan, and Grossman

FamilI

o 46 Chromosomesnormal karyotype

2 3 e Not examined_0 45 Chromosomes

D/D translocation* MiscorriaqeQ Dead (not examined)sv Propositus

FIG. 1. Pedigree of Family G.

blood cultures obtained from the propositus and 6 mem-bers of the family. The selected metaphases were ex-amined under oil immersion. 35 mm. photographswere taken with a Zeiss photomicroscope, and the filmswere projected with a 3M Filmac 100 Reader-Printer(3M-Minnesota Mining and Manufacturing Co., St.Paul, Minnesota) to facilitate exact counting of thechromosomes. The chromosomes were then cut outfrom enlarged prints and arranged according to theDenver nomenclature.The propositus, her mother, and grandmother were

found to have a balanced D/D translocation. Results ofthe karyotyping are summarized in Table II.

Autoradiographic StudiesThe pattern of DNA synthesis in the chromosomes

obtained from peripheral blood cultures was studiedby 3H-thymidine labelling and autoradiography; thelabelled metaphases were followed through the W to Zintervals of the synthesis (S) period (German, 1964).

Methods. Seven hours before termination of theshort-term peripheral blood cultures, 3H-thymidine

TABLE IDERMATOGLYPHS OF FAMILY G

InterdigitalPatient and Left and atd Patterns Finger Patterns Thenar Hypo-Family Right Hand Angle Pattern thenar

3 IS 4 IS 1 2 3 4 5 Pattern

Mother L 7°'(t) VL VL W W UL UL ULR 47'(t') VL 0 W RL UL UL UL 0 0

Propositus L 47' (t') DL DL W UL UL UL W 0 0R 47' (t') DL 0 W UL RL W UL 0 0

Sister L 46 (t') 0 DL W W W W W 0 0R 50° (t') DL 0 W W UL W W 0 0

Maternal aunt L 380 (t) DL VL UL A UL UL UL 0 0R 340 (t) DL 0 W RL UL UL UL 0 0

Grandmother L 530 (t') DL 0 UL UL UL VL 0 0R 560(t') DL 0 W RL A UL UL 0 0

atd, angle formed by line drawn from the most lateral tiradius (a) to the most distal palmar triradius(t, t', or t') to the most medial triradius (d); IS, interdigital space; DL, distal loop; VL, vestigial loop;0, open field; W, whorl; UL, ulnar loop; RL, radial loop; A, arch.

TABLE IISUMMARY OF CHROMOSOME ANALYSIS OF THE PROPOSITUS AND HER FAMILY

Chromosome CountsPedigree No. Members of Family Karyotype Interpretation

<45* 45 46

IV.1 Father 2 10 NormalIV.2 Mother 2 11 Balanced translocation, D/DV.3 Propositus 4 86 Balanced translocation, D/DV.2 Sister 3 11 NormalIV.3 Maternal aunt 1 10 NormalIII.2 Grandmother 5 24 Balanced translocation, D/D11.2 Great-grandfather 4 21 Normal

* Random loss.

206

I

II

III

IV

V

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A Family with DID Translocation

(obtained from Schwartz Bioresearch, Inc.,* as a sterileaqueous solution, specific activity 6-0 Ci/mmole, conc.1 Ci/ml.) was added to the medium for a final concen-tration of 1 jCi/ml. After 3 hours, the cultures weretreated with colchicine.The chromosomes were prepared by the technique

described by Moorhead et al. (1960). The slides werecoated with Kodak Nuclear Track Emulsion TypeNTB-3, and after 9 days of incubation at 40 C. theywere developed with Kodak D-19 developer. Theywere then stained with Giemsa's stain, and scored formetaphases containing readily distinguishable late-labelling X chromosomes. The location of each meta-phase on the slide was recorded and photographed, andphotographic prints were prepared. After removingthe grains with Kodak Farmer's Reducer, the slideswere restained, the metaphases relocated and rephoto-graphed, and prints made with a 3M Filmac 100 Reader-Printer. The matching prints were then paired andexamined.

Results. Of 103 labelled and photographedmetaphases scored, 55 were selected for examinationusing the following criteria: (1) presence of a late-labelling X chromosome, indicating that this metaphasehad been exposed to 3H-thymidine during the W to Zinterval of the S period; (2) a chromosome complementof 45; (3) absence of overlap between the chromosomesof groups A and D. The results are summarized inTables III and IV.

DiscussionThough the combination of labelling pattems

of the D chromosomes not involved in the transloca-tion varies (Table IV), a classification of the 13-15group chromosomes is possible, since the majorityof metaphases out of a large number examined willfollow a distinct DNA replication pattern (German,1964; Giannelli, 1965; Giannelli and Howlett,1966). The end of the DNA synthesis (S) periodin which the chromosomes complete their replica-tion was divided by German (1964) into six intervals:U, V, W, X, Y, and Z. In most instances, the No.13 pair replicates the middle and distal portions ofthe long arms during the X interval and was re-ferred to by German (1964) as late replicator; byGiannelli (1965) as chromosomes with labellingpattern A. The No. 14 pair replicates portions ofits DNA (short arms and centromeric regions) alsoduring the X interval (German: intermediate repli-cator; Giannelli: labelling pattern B). The No. 15pair completes its synthesis during the U interval"(German: early replicator; Giannelli: labellingpattern C).

In our study, most of the metaphases showing thetranslocation chromosome contained one No. 13,* Orangeburg, New York.

one No. 14, and two No. 15 chromosomes (TablesIII and IV; Fig. 2 and 3). The translocationchromosome resembled morphologically a No. 3chromosome, but the labelling differed from that ofthe two chromosomes of pair No. 3, and resembledthat of the No. 13 and 14 chromosomes. It wasa large metacentric chromosome, in most meta-phases heavily labelled over the distal and middleportion of one arm, which is consistent with thelabelling pattern of the No. 13 chromosomes. Theother arm was labeled in most metaphases aroundthe centromeric region, suggesting a No. 14 chro-mosome. These observations indicate that thetranslocation chromosome was a t(13ql4q) chro-mosome (Chicago Conference, 1966), i.e. the resultof a translocation of the long arms of a No. 13 andNo. 14 chromosome.

Concurrent translocation and non-disjunctionwere observed in some families, and a causal re-lation between them was suggested (Hamerton et al.,1963; Yunis et al., 1964). Richards and Stewart(1965), however, found only one balanced D/Dtranslocation carrier in about 900 mongols, andsuggested that the occurrence was fortuitous. Inour family, studied through 4 generations, non-disjunction was not observed.

In cases in which the D/D translocation isaccompanied by clinical manifestations, theirvariety may be explained by the fact that eitherdifferent chromosomes are involved in the transloca-tion or that the deleted portions of the short armsvary in size; or the D/D translocation may haveno aetiological connexion with the clinical signs,since the minute deletions ofthe short arm may havebeen buffered by the individual genetic constitution.

In most reports, it was not established whichchromosomes of the 13-15 group were involved inthe D/D translocation or whether these chromo-somes were identical in aU cases. Identificationhas been attempted by chromosome measurementsand by autoradiographic studies. The five casesexamined so far by autoradiography (Yunis et al.,1964; Giannelli and Howlett, 1966; Dekaban,1966; Tiepolo et al., 1967) and our case, suggestthat the No. 13 and No. 14 chromosomes were in-volved in the translocation, though there mighthave been differences in the size of the deletions.

In the family described by Yunis et al. (1964),neither phenotypic abnormalities nor mental re-tardation were present, but diminished fertilityand repeated miscarriages were reported. Giannelliand Howlett (1966) analysed the D group chromo-somes in a phenotypically normal woman by auto-radiography as well as chromosome measurements.In the family reported by Dekaban (1966), a high

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Krmpotic, Rama a, nd Grossman

TABLE IIIDISTRIBUTION OF COUNTED GRAINS IN 55 METAPHASES

Number of GrainsMetaphase Number of D ChromosomestNo. Chromosomes X Chromosomes Arms of D/D No. 3 D Chromosomest

Chromosome Chromosome* No. 13 1No. 141 No. 15

12345678910111213141516171819202122232425262728293031323334353637383940414243444546474849505152535455

45454545454545454545454545454545454545454545454545454545454545454545454545454545454545454545454545454545454545

1065*373739t31*1647*45*1128*31t16t27t28*24*5

32*1428t20*43*37*8t

35t24t30*34*28*34t25*28*22*28*3127t35*40*34*4090*48*301748t1060*131232t713151441*

1013151216101317125915913111228471410177*

13101283710117128

1114136

1520*2314

24

1

55359523433321213526315033034441458452

2

130132221042

72214181361228*24*59

111252461217

11267*78*18*2714*58651675

11

820t12131282496

152715281668

26*32*6

1114

135813586*88t

22*33985

733897121229t154513336171341684

530*121118101520*19*512148 7

91017125 7

111313121299*

314t91261211

887 6815t179

77

5

87

77

210

7 6137*5

11125776 33 763

6

21726

3

8255

55

3632 8

5

716t5

4 65213

522 326 62

203112 20

430143030200

1500

101010000

10210

0

2

2

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

10

0

0

0

0

0

0

0

0

1

0

* Grain count was not divided between the two arms because labelling occurred mostly in the centromericregion.t Classified according to their labelling patterns (see text).Approximate number; exact count not possible because of overlap of grains.

TABLE IVLABELLING PATTERNS OF FOUR D GROUP

CHROMOSOMES NOT INVOLVED INTRANSLOCATION

Combination of Labelling Patterns MNtapros

1 No. 13 + 1 No. 14 + 2 No. 15 341 No. 13 + 3 No. 15 8

1 No. 14 + 3 No. 15 42No. 14 + 2No. 15 4

1 No. 13 + 2 No. 14 + 1 No. 15 22 No. 13 + 2 No. 14 22 No. 13 + 1 No. 14 + 1 No. 15 1

Total 55

incidence of mental retardation was observed andfamily studies revealed repeated miscarriages. Inthe case studied by Tiepolo et al. (1967), the D/Dtranslocation carrier had Klinefelter's syndrome.In our family, there were neither phenotypic ab-normalities nor mental retardation; there was one.miscarriage.

We believe that there are no characteristic clinicalsigns for the t(13ql4q) translocation, but additionalautoradiographic studies of D/D translocationcarriers will be necessary to come to a conclusion.

208

i

t

t

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A Family with DID Translocation 209

:: @ ..~~~~~~~~~~~~~~~~~~~~~~~~..:.-...... .. ..'1tIii"'.;t i*...,F:.=E.E_W...v̂..........~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~......

t;g. .;

.^ R'4'd

.g.W .4*, Ii.., X ..

~~AA A ..iii

: S ww..:.....-..B.:.

FIG. 2. Autoradiographic labelling of chromosomes from a karyotype of the propositus (No. 10 in Table III). Upper row: labelledchromosomes. Lower row: the same chromosomes after grain reduction.

SummaryA D/D translocation chromosome transmitted

through 3 generations was studied by 3H-thymidinelabelling and autoradiography. The results sug-gested that it was a t(l3ql4q) chromosome.

Clinical, laboratory, cytogenetic, and dermato-glyphic data of the family were presented. Neithercongenital abnormalities nor mental retardationwere observed. Non-disjunction did not occur inany member of the family.The authors wish to thank Dr. S. Silberman for

typing the haptoglobins, Miss S. Busch and Mr. M.Behzad for typing the blood groups, Mr. J. DeBruin forthe photography, and Mr. B. Berg for the medicalIllustrations.

REFEENcEs

Chicago Conference (1966). Standardization in Human Cyto-genetics. Birth Defects, Original Article Series, II: 2. TheNational Foundation March of Dimes, New York.

Court-Brown, W. M., Buckton, K. E., Jacobs, P. A., Tough, I. M.,Kuenssberg, E. V., and Knox, J. D. E. (1966). Chromosome4

studies on adults. Eugenics Laboratory Memoirs No. XLII,p. 23. Cambridge University Press, London.

Dekaban, A. S. (1966). Transmission of a D/D reciprocal trans-location in a family with high incidence of mental retardation.Amer. J. hum. Genet., .18, 288.

Engel, E., McGee, B. J., Hartmann, R. C., and Engel-de Montmollin,M. (1965). Two leukemic peripheral blood stemlines duringacute transformation of chronic myelogenous leukemia in a D/Dtranslocation carrier. Cytogenetics, 4, 157.

German, J. L. (1964). The pattern of DNA synthesis in the chro-mosomes of human blood cells. J. Cell Biol., 20, 37.

Giannelli, F. (1965). Autoradiographic identification of theD (13-15) chromosome responsible for D1 trisomic Patau's syndrome.Nature (Lond.), 208, 669.-, and Howlett, R. M. (1966). The identification of the chromo-

somes of the D group (13-15) Denver: An autoradiographic andmeasurement study. Cytogenetics, 5, 186.

de Grouchy, J., Mlynarski, J. C., Matoteaux, P., Lamy, M., Deshaies,G., Benichou, C., and Salmon, C. (1963). Syndrome poly-dysspondylique par translocation 14-15 et dyschondrosteose,chez un meme sujet. Segregation famiLiale. C. R. Acad. Sci.(Paris), 256, 1614.

Hamerton, J. L., Giannelli, F., and Carter, C. 0. (1963). A familyshowing transmission of a D/D reciprocal translocation and a caseof regular 21-trisomic Down's syndrome. Cytogenetics, 2, 194.

Jagiello, G. M. (1963). Familial 13-15 translocation abnormality(Denver Classification) associated with one case of cerebral palsy.Preliminary report. New Engl. J. Med., 269, 66.

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210 Krmpotic, Ramanathan, and Grossman

. w..: ... z..

I :: ..

FIG. 3. Autoradiographic labelling of groups 1-3, 13-15, and X chromosomes from 4 karyotypes (Nos. 10, 17, 29, and 41 in Table III).Upper row: labelled chromosomes. Lower row: the same chromosomes after grain reduction. Asterisk points to translocation chromosome.

Lejeune, J., Turpin, R., and Decourt, J. (1960). Aberrationschromosomiques et maladies humaines. Syndr6me de KlinefelterXXY a 46 chromosomes par fusion centromerique T-T. C. R.Acad. Sci. (Paris), 250, 2468.

Moorhead, P. S., Nowell, P. C., Mellman, W. M., Battips, D. M.,and Hungerford, D. A. (1960). Chromosome preparations ofleukocyte cultures from human peripheral blood. Exp. Cell Res.,20, 613.

Richards, B. W., and Stewart, A. (1965). D/D translocation.Lancet, 1, 1076.

Tiepolo, L., Fraccaro, M., Hult&n, M., and Lindsten, J. (1967).

Double aneuploidy [46, XXY, D-, D-, t(DqDq) +]. Ann.Gbdnt., 10, 114. f

Walker, S., and Harris, R. (1962). Familial transmission of atranslocation between two chromosomes of the 13-15 group(Denver Classification). Ann. hum. Genet., 26, 151.

Yunis, J. J., Alter, M., Hook, E. B., and Mayer, M. (1964). FamilialD-D translocation. Report of pedigree and DNA replicationanalysis. New Engl.J. Med., 271, 1133.

Zergollern, L., Hoefnagel, D., Benirschke, K., and Corcoran, P. A.(1964). A patient with trisomy 21 and a reciprocal translocationin the 13-15 group. Cytogenetics, 3, 148.

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A family with D-D translocation.

E Krmpotic, K Ramanathan and A Grossman

doi: 10.1136/jmg.5.3.2051968 5: 205-210 J Med Genet 

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