mosaicism translocation: autoradiographic fluorescent ... · journalofmedicalgenetics (1972). 9,...

Journal of Medical Genetics (1972). 9, 280.

Mosaicism with Translocation: Autoradiographic andFluorescent Studies of an Inherited Reciprocal

Translocation t(2q+;14q-)JACOB A. REISS, HERMAN E. WYANDT, R. ELLEN MAGENIS,

EVERETT W. LOVRIEN, and FREDERICK HECHTFrom the Division of Medical Genetics, Department of Pediatrics and Genetics Clinic, Crippled Children's

Division, University of Oregon Medical School, Portland, Oregon 97201, USA

Translocation mosaicism is an extremely rareoccurrence. We have briefly reported the findingin different families of 2 patients with transloca-tion mosaicism (Magenis et al, 1970). One patientis reported here.

Case ReportThe propositus was born on 12 July 1970 after a full-

term gestation. The father was 26. The mother was21 years old; she had previously had 3 consecutive first-trimester spontaneous abortions. The amniotic fluidand the baby were both meconium stained. The um-bilical cord was tightly coiled around his neck, and he re-quired vigorous resuscitation. The Apgar score was4 at 1 minute. At birth his weight was 2A4 kg, length46 cm, head circumference 33 cm, chest circumference33-5 cm. Dolichocephalic head, small palpebral fissures,right exotropia, retrocessed ears, increased nasolabialdistance, upturned nares, cleft soft palate, large mouth,and micrognathia were noted (Fig. 1). Redundant skinwas present over the lateral and posterior aspect of theneck. Flexion contractures of the proximal inter-phalangeal joints of the 3rd and 4th fingers were presentbilaterally. The dermal ridges were hypoplastic. Thedermatoglyphic patterns differed from his parents. Hehad 6 arches while his mother had one tented arch andhis father had no arches. The fingernails were small.The pelvis was small and the hips were tight to abduc-tion. No testis was palpable on the left and on the rightit was felt in the inguinal canal. A left inguinal herniawas present. The infant had a weak, hoarse cry and hadgeneralized hypertonia and hyperreflexia.During the first month of life intermittent episodes of

tachypnoea, tachycardia, and cyanosis occurred. Agrade III/VI harsh pansystolic murmur was heard. Heartfailure was present and digitalis was administered untilhe was 4 months. At that time an electrocardiogram

Received 27 October 1971.

showed right ventricular hypertrophy and radiologyshowed a small heart. Tetralogy of Fallot was diag-nosed. Early in the neonatal period there was alsointermittent distention of the abdomen due to rectalstenosis. This was successfully treated by rectaldilatation.Growth and development have been consistently re-

tarded. At age 10 months his weight was 3-8 kg, length56-5 cm, head circumference 40 3 cm; all these values arebelow the 3rd centile. He could not sit without sup-port. There was head lag when he was pulled to a sittingposition. Only occasionally would he bear weight onhis legs. He had no verbalization, failed to reach forobjects, followed sporadically with his eyes, and smiledrarely. His estimated development age was 2 months.

Chest radiographs revealed hypoplastic 12th ribs.Nuclear projections were demonstrated in increasednumbers in his neutrophils. Starch gel haemoglobinelectrophoresis was normal with 0-8% fetal haemoglobinat 10 months ofage.

Family DataA partial pedigree of the family is shown in Fig. 2.

The father of the propositus had 3 normal sisters, one ofwhom had a son (IV.8) with Hirschsprung's disease (con-genital aganglionic megacolon). The child developednormally and had no other congenital abnormalities,but died at 9 months from bronchopneumonia and toxicenterocolitis. A deceased paternal great uncle (II.2)had been mentally retarded, but reportedly had no mal-formations. Both of the paternal grandparents werePortuguese; the paternal great grandparents (I.1 andI.2) were born in the Azores. Consanguinity betweenthe parents was denied.

Chromosome StudiesChromosome Studies of the Propositus.

Two cell lines were observed in cultured lympho-cytes (Table I). One contained a translocation

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Mosaicism with Translocation

la lbFIG. 1. The propositus at age 2 weeks. (a) The small palpebral fissures, right exotropia, large mouth, and increased nasolabial dis-

tance are shown. (b) Dolichocephaly, retrocessed ears, upturned nares, and micrognathia are seen here.

involving a chromosome No. 2 and a D chromosome(Fig. 3a) interpreted as 46,XY,t(2q + ;Dq -). Thesecond cell line was identical except for an additionalDq - chromosome (Fig. 3b).

Skin fibroblast cultures harvested after 44 daysin culture also contained both cell lines. Equalnumbers of the 2 cell types were observed in thelymphocyte cultures, while the skin fibroblast cul-tures showed clear predominance of the aneuploidcell line (Table I).

Chromosome Studies of other FamilyMembers. Chromosome analyses were performed

on the other family members as indicated in thepedigree (Fig. 2). The detailed results are shownin Table I. The translocation involving a chro-mosome 2 and a D chromosome was also discoveredin the father (III.7) and paternal grandfather (II.3).All other family members studied had normalkaryotypes.

Autoradiography. Lymphocytes and fibro-blasts cultured from the propositus were studied byautoradiography after continuous late-labelling withtritiated thymidine for 6 hours before harvest, asdescribed by Schmid (1963). The late-labelling

TABLE ICHROMOSOME STUDIES

Number of MetaphasesTissue* With 46 With 47 Interpretation

Chromosomes Chromosomes

IV. 12 Propositus L 43 56 46,XY,t(2q + ;14q -)/47,XY,t(2q + ;14q -),(14q-) +F 2 32 46,XY,t(2q + ;14q -)/47,XY,t(2q + ;14q -),(14q-) +

III.7 Father L 77 46,XY,t(2q+;14q-)F 24 46,XY,t(2q+;14q-)III.8 Mother L 56 46,XX

11.3 Paternal grandfather L 36 46,XY,t(2q + ;14q-)I1.2 Paternal grandmother L 32 46,XX

III.4 Paternal aunt L 22 46,XX

II1.5 Paternal aunt L 39 46,XX

* L = lymphocytes; F = skin fibroblasts.

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Translocation Mosoicism[46 xY, t(2q+; 14q-)/47, xY, t(2q+; 14q-),(14q-)+JTranslocation Carrier46, xY, t (2q+; 14q-)

Normal Karyotype

Not Studied

\_/ %,/\- - .- -6 7 8 9 10 12

FIG. 2. The pedigree of family 1282.

patterns of the D group chromosomes in both the46 and 47 cell lines are illustrated in Fig. 4.

Thirty-seven metaphases were scored for themissing D chromosome. Twenty-one of the 37cells had autoradiographic patterns consistent witha missing chromosome No. 14, 13 of the 37 hadambiguous labelling patterns, and 3 had patternsconsistent with a missing 13 or 15.The autoradiographic patterns of the Dq -

chromosomes themselves were analysed; 34 of 61labelled similarly to chromosome 14; 12 labelledwith ambiguous patterns but were possibly 14;15 labelled with patterns other than chromosome 14.Thus, 74% (46 of 61) of the Dq- chromosomeshad a pattern consistent with that ofchromosome 14.The autoradiographic patterns of the two Dq -

chromosomes in the aneuploid line of cells were alsocompared. Twenty-four cells were scored. Of

these, 15 (63%) showed both Dq - chromosomeswith patterns definitely or possibly consistent withNo. 14; 2 (9%) showed both Dq - chromosomeswith patterns definitely or possibly consistent withNo. 15; and the remaining 7 (29%) showed dis-cordant labelling patterns.

Fluoromicroscopy. Metaphases from thepatient, his father, and his paternal grandfather werestained with quinacrine mustard (Caspersson,Zech, and Johansson, 1970a) and photographed witha Zeiss Photomicroscope II equipped with a Plana-chromat oil immersion lens, HB200 mercury lightsource, BG12 excitation filter, and 530 nm barrierfilter. The resultant 35 mm negatives were printedon Kodabromide F-5 and for greater contrast onBrovira Agfa grade 6 photographic paper. Thesame metaphases were then restained with Giemsa

TABLE IIGENETICS MARKER STUDIES

Date of MNS P Rhesus Lewis (Le) Duffy (Fy) Kidd (Jk) Acid Secre- Aiy-Birth a b a b a b P~hos-; PGM LP tor laae

11.3 Grandfather 1.3.'14 NN5 + DCcee - - - + + - B 2-2 - Se A/AII.4 Grandmother 4.13.'18 NNss - DCcee - - + + - + B 2-1 + Se A'AIII.4 Aunt 5.31.'48 NNss + DCCee - - + _ + + B 2-1 - Se A/A111.5 Aunt 9.7.'48 NN§§ - DCcee + - + + + + B 2-2 - 9,6 A/A1II.7 Father* 3.4.'44 NN§§ + dccee - - + + + + B 2-1 - Se A/A111.8 Mother 9.8.'48 MNS5 + DCcee - - - + + + BA 1-1 - Se A/ABIV.12 Propositus* 7.12.'70 MNS§ + DCcee + - - + + + BA 1-1 - Se

* Family members with the translocation.All family members had the following in common: Al; Lu(a -); K(K -,k +); Dia(-); Tf(C); Hp(2-2); E,(A); E,(U); AK(1-1); 6PGD(A);Lan(+); Xga(+); PTC(+); Gc(2-1); Gm(1-, 2-12+).

I

HI

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;a.

b

FIG. 3. Partial karyotypes of the two cell lines. (a) 46 count cell line, 46,XY,t(2q + ;Dq-) and (b) 47 count cell line, 47,XY,t(2q +;Dq - ),(Dq -) +. The arrows indicate the chromosomes involved in the translocation. The translocation (in a) was found in the fatherand paternal grandfather of the propositus.

and rephotographed by conventional light micro-scopy.A representative metaphase spread and partial

karyotypes of 4 cells prepared with quinacrine mus-tard are shown in Fig. 5. Pairs of morphologicallynormal chromosomes were seen with the fluorescentpatterns associated with chromosomes 13 and 15(Caspersson et al, 1970b). However, only onemorphologically normal chromosome 14 was ob-served, and the Dq - chromosome(s) had a patternconsistent with the proximal portion of chromosome14.Normally, chromosome No. 2 shows decreasing

fluorescence over the distal (telomeric) part of thelong arm, and chromosome No. 14 normally a regionof relative negative-fluorescence just proximal to themore brightly fluorescent telomeric region. Themorphologically normal chromosome No. 2 andchromosome No. 14 from the patient, his father, andpaternal grandfather showed these patterns.The region of gradually diminishing fluorescence

was missing from the telomeric portion of the 2q +chromosome. Conversely, the region of relativenegative-fluorescence located just proximal to themore brightly fluorescent telomeric region associ-ated with chromosome No. 14 was missing from the14q - chromosome, but was observed on the distal

portion of the long arm of 2q +. We interpretthese findings as consistent with a reciprocal trans-location between 2q and 14q. Specifically, we be-lieve that the findings speak against a one-way in-sertional translocation of material from No. 14 intothe long arm of No. 2.

Genetic Marker StudiesRed cell antigens, red cell enzymes, plasma pro-

teins, and saliva factors were investigated for geneticpolymorphisms by standard techniques. The re-sults are listed in Table II.The propositus is Le (a +,b -) and a secretor.

Normally Le (a +) individuals are non-secretors.This discrepancy is probably due to his age; if so hewill be Le (a -,b +) when he is older. His paternalaunt (III.5) is Le (a + ,b -) and a non-secretor. Allothers listed in Table II are secretors and probablyLe (a -,b +) but since they are A1 at the ABO locus,Leb cannot be detected with our antiserum.The Duffy blood group system is interesting in

this family. III.4 is apparently FyaFyx. She re-ceived the Fyx from her father (1I.3) who is pre-sumed to be FyxFyb (Chown, Lewis, and Kaita,1965). Further studies are being conducted toconfirm this finding.There was no evidence from the genetic marker

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studies for chimerism in the propositus, for non- aneuploid cefl line, which contains an extra versionpaternity, or for linkage between any of the informa- of 1 of the 2 translocation chromosomes. Thetive marker gene loci and the translocation. severe growth and developmental retardation and

Discussion malformations in the propositus presumably are

The propositus has the famifial reciprocal tranrelated to the presence of the cefl hne with the extra

s- chromosome. This ceR line is trisomic for thelocation in balanced fonn. In addition, he has an short arm, centromere and a large portion of the'..: '.% -:-...:':::.".':..:..A:-.:-:.-.--.-::!::- "%.....::.:.:..:,:...:..:...........................:%.::....:.. .::'::X. ...... ............................ ..:, :,:.: nroximal part of the long arm of chromosome 14,.:.:..-.--.-.-...--.-.-:.-:.-..-.-.-..-..-..-.-.%....::....:..!::........:..:.::..............................................:....:.::....:!%...,...:,..:":: .::::: ...... .lw':::..::.'.: """""'...-::.::..:".,...:..::&:..-:"'"""'"'. :....::.:.:.,........:.:..:::;.:::,:...... ::.:.... ...::.:...-....:%: ....... ..:.....: .:......::.:::..:..,.:::..'*.,:...,.,;&i.,.l::..:..:.: .:....".

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:' ........:......::....:..:.:..:.:.. :'.............:...:...%.....................-.-:.':-...-.-:.'..-.- .....:: .":.,:::..:.,.:..::,:..:-..:::.:..'..:.-. .'-"'::::::, .,:..:.::: .. ........;-. ..:: ...%.....:..:..:.:.....'.'..'-.... ...:.-::*'..::-'.:: :.:: .:. ...: -..-..:.:.:.:.....:........,..:%.:....%.-..:..of the mosaicism observed the pro-

.:.....4.:..... ...............:.... ...............:-:-..:.-..:.....:...... .............................. .:::.. ... ... ... ..: ..",.: .:-::i.:.!.:...-'.." ..%:.::.::.:!.:.,:::::,.!,: '::x;-:'--':: -:-k:%:::-;.--.:..: ..::.:.. .:: ..:.: :......:.:::. ......-...-....::...!: " .............:..: ", ,,.m-:%-.%1-:................... .'..

V..':' ::,: ": "'.....' -'...::..: ...:......O.. ...!:...:: .:....::. .: .:,..... -_-.-_- ..... 1-$i!i'-" _.!.--ii,-, ..:!:...: "-- :i ..1'.'.!:i!'1-'1!:'-2'1-'1 .-!!'-'.-'.'L-!.':. presence orpho-...............................%..........:..:....: .:..:.:..:%.:...:.:...%.:...:....:....::..;:!::::. positus is urtkno'.'.:.:,..,.:%.: :...-.-. '.: %:N...............

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FIG. 5. (left) Fluorescent metaphase spread, 47,XY,t(2q + ;14q -), (14q -) +, from the propositus. (right) Fluorescent staining of theD group and the chromosome 2 pairs from 4 cells. Both cell lines are represented. The arrows indicate the comparable banding patterns

of the portions of chromosomes involved in the translocation, t(2q + ;14q -).

congenital cataracts (Renwick and Lawler, 1963).Kamaryt, Adamek, and Vrba (1971) have suggestedthat human serum amylase (Amy2) and the un-coiler region of chromosome 1 are tightly linked,and very recent work has demonstrated probablelinkage of human serum amylase with the Duffyblood group (Hill, Rowe, and Lovrien, 1972).Close linkage, therefore, presumably exists for theloci Fy, Cae, and AmY2 and these loci are probablyin close proximity to the uncoiler region of chromo-some 1.

SummaryA rare translocation, t(2q + ;Dq -), is reported.

The translocation was ascertained through aninfant with multiple malformations and psycho-motor retardation in whom 2 cell lines were dis-covered. Both lines contained the translocation,one cell line being balanced with 46,XY,t(2q +;14q -), whereas the other line was aneuploid with47,XY,t(2q + ,14q - ),(14q -) +.

The D chromosome involved was determined tobe No. 14 by autoradiography and by quinacrinefluoromicroscopy. Quinacrinefluoromicroscopycon-firmed loss of material from a No. 14 chromosomeand added material on 2q indicating a reciprocaltranslocation between the distal portions of 2qand 14q.

Six, of 26 genetic loci investigated in the family,were informative; there was no evidence for linkagewith the breakpoints of 2q or 14q.

J.A.R. and R.E.M. were postdoctoral researchfellows on a National Institute of Health genetics train-ing grant NICHD 00165. The work was supported byNIH grants AMCA 13173 and HD 05082 and by a grantfrom the Children's Bureau for a genetics programme.

REFERENCESCaspersson, T., Zech, L., and Johansson, C. (1970a). Analysis ofhuman metaphase chromosome set by aid of DNA-bindingfluorescent agents. Experimental Cell Research, 62, 490-492.

Caspersson, T., Zech, L., Johansson, C., and Modest, E. J. (1970b).Identification of human chromosomes by DNA-binding fluores-cent agents. Chromosoma, 30, 215-227.

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286 Reiss, Wyandt, Magenis, Lovrien, and Hecht

Chown, B., Lewis, M., and Kaita, H. (1965). The Duffy bloodgroup system in Caucasians: Evidence for a new allele. AmericanJournal ofHuman Genetics, 17, 384-389.

Donahue, R. P., Bias, W. B., Renwick, J. H., and McKusick, V. A.(1968). Probable assignment of the Duffy blood group locus tochromosome 1 in man. Proceedings of the National Academy ofSciences, 61, 949-955.

Hill, C., Rowe, S., and Lovrien, E. (1972). Probable linkage betweenhuman serum amylase (Amy2) and Duffy blood group. Nature,235, 162-163.

Kamaryt, J., Adamek, R., and Vrba, M. (1971). Possible linkagebetween uncoiler chromosome UN 1 and amylase polymorphismAmY2 loci. Humangenetik, 11, 213-220.

Magenis, R. E., Wyandt, H., Reiss, J., and Hecht, F. (1970).Mosaicism occurring with ring, translocation, and deletion chro-

mosomes. (Abstr.) American Journal ofHuman Genetics, 22, lOa-1 ia.

Miller, 0. J. (1970). Autoradiography in human cytogenetics. InAdvances in Human Genetics, Vol. 1, Chap. 2, p. 70, ed. by H.Harris and K. Hirschhorn. Plenum Press, New York.

Murken, J. D., Bauchinger, M., Palitzsch, D., Pfeifer, H., Suschke,J., and Haendle, H. (1970). Trisomie D2 bei einem 21 jahrigenMadchen (47,XX,14 +). Humangenetik, 10, 254-268.

Renwick, J. H. and Lawler, S. D. (1963). Probable linkage betweena congenital cataract locus and the Duffy blood group locus.Annals ofHuman Genetics, 27, 67-84.

Schmid, W. (1963). DNA replication patterns of human chromo-somes. Cytogenetics, 2, 175-193.

Weiss, L. and Wolf, C. B. (1968). Familial C/G translocation caus-ing mitotic nondisjunction. American Journal of Diseases ofChildren, 116, 609-614.

AddendumSyndrome of Pigmentary Retinal Degeneration,

Cataract, Microcephaly, and Severe Mental Retar-dation by S. Ali Mirhosseini, Lewis B. Holmes, andDavid S. Walton, June 1972, vol. 9, pp. 193-196.An additional disorder, similar in some respects

to the patients discussed, of nerve deafness, eyeanomalies, and Marfanoid habitus has been described(Walker, 1971).

REFERENCEWalker, A. B. (1971). A syndrome of nerve deafness, eye anomaliesand Marfanoid habitus with autosomal dominant inheritance. InBirth Defects: Original Article Series, VMI, 4, pp. 137-139. NationalFoundation-March of Dimes, New York.



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