Hum. Genet. 31, 93--96 (1976) © by Springer-Veriag 1976

Four Familial Translocations Ascertained through Spontaneous Abortions D a v i d H. Cart a n d Milan M. Gedeon DeparSment of Anatomy, MeMaster University, Hamilton, Ontario, Canada I~eeeived August 11, 1975 / September 29, 1975

Summary. In a study of 514 spontaneous abortions, 194 were found to have a chromosome anomaly. Of these, 4 (2.1~o) were unbalanced translocations. Three of the transloeations were Robertsonian (13q14q) and one was reciprocal. Each translocation was ascertained independently and each was associated with a balanced rearrangement in a carrier parent. The m a j o r i t y of chromosome anomalies f o u n d in s p o n t a n e o u s abortions are sporadic events u n r e l a t e d to d e m o n s t r a b l e chromosome disorder in a parent. I t is k n o w n t h a t p a r e n t s who carry b a l a n c e d translocations have, theoretically at least, a s u b s t a n t i a l l y increased risk of producing ehromosomally a b n o r m a l coneeptuses. The carrier f r e q u e n c y of balanced translocations i n the n e w b o r n population is a b o u t 0.17% (Jaeobs et al., 1974b). The actual frequency of coneeptuses with u n b a l a n c e d chromosome products from t r a n s l o c a t i o n carrier p a r e n t s is uncertain. I t appears to v a r y with the chromosomes i n v o l v e d in the t r a n s l o c a t i o n ( H a m e r t o n , 1970). I n studies of families with repeated abortions, the frequency of translocations in the p a r e n t s is a b o u t 10 times as high as i n n o r m a l n e w b o r n s (Lucas et al., 1972). I t is of interest to k n o w w h a t p r o p o r t i o n of chromosome anomalies a m o n g abortuses are associated with a balanced t r a n s l o e a t i o n in a carrier parent. We report, here, the details of 4 u n b a l a n c e d translocations among 514 s p o n t a n e o u s abortions which we have studied.

Materials and Methods The studies involve three different series of abortuses. The first was a study of 227 unselected consecutive abortuses using a standard chromosome stain (Carr, 1967). The second series of abortuses were selected for study for one of three reasons: the mother had been on oral contraceptives within 6 months of conception of the abortus; the pregnancy was 60 days or less of menstrual age; or the specimen was grossly abnormal. This group of 145 abortuses was also studied by a standard staining technique. The third series of abortuses were selected for study because the specimen was morphologically abnormal. The 142 abortuses in this group were studied by the Q-banding technique and details of the first 27 specimens have been published (~cConnell and Cart, 1975).

Results The results are s u m m a r i z e d in Table 1. There were no translocations detected a m o n g the 50 ehromosomally a b n o r m a l abortuses from the unselected series. One of the abortuses in the second s t u d y showed a t r a n s l o c a t i o n between two chromosomes in group D in a d d i t i o n to 5 free D group chromosomes. This is effectively a t r i s o m y D for one of the m e m b e r s of the group. The specimen was

94

D. H. Carr and M. ~ . Gedeon Table 1. Frequency of translocations in 3 series of spontaneous abortions Chromosomally normal

Total chromosomally abnormal

Translocations

Total

Unselected consecutive Selected, standard technique Fluorescent banding

177 75 68

50 70 74

0 1 3

227 145 142

Totals

320

194

4

514

Table 2. l~eproductive histories of 3 families carrying 13/14 translocations Family

Abortus studies

Children

Spontaneous abortions

M Ta B

Fetal cyclops Ruptured sac Intact sac - - macerated embryo

5 3 3

3 3 3

ll

9

a Sister of M but independently ascertained in third study. selected for s t u d y because t h e 35 m m fetus was a cyclops (Table 2). The m o t h e r (Mrs. M.) was t h e carrier of a (DqDq) t r a n s l o c a t i o n a n d details h a v e been described elsewhere (Carr et al., 1972). The D chromosomes i n v o l v e d in t h e t r a n s l o c a t i o n were n o t identified. There were 3 t r a n s l o c a t i o n s a m o n g t h e 74 c h r o m o s o m a l l y a b n o r m a l specimens in t h e t h i r d s t u d y . These specimens were all s t a i n e d b y Q - b a n d i n g t e c h n i q u e and, therefore, t h e i n d i v i d u a l chromosomes could be identified. Two of t h e specimens h a d identical k a r y o t y p e s , 4 6 , X Y 0 - - 1 3 , + t (13q14q). The r e p r o d u c t i v e histories a n d means of a s c e r t a i n m e n t of t h e 3 families w i t h (13q14q) t r a n s l o c a t i o n s are shown in T a b l e 2. Mrs. T. was t h e carrier of t h e translocation in her f a m i l y a n d at t h e t i m e of s t u d y it was found t h a t she was t h e sister of Mrs. M. This established r e t r o s p e c t i v e l y t h a t Mrs. M., who was identified t h r o u g h t h e a b o r t i o n of a fetal cyclops in series 2, was a (13q14q) t r a n s l o c a t i o n carrier. I n f a m i l y B., t h e f a t h e r was t h e carrier of t h e (13q14q) translocation. His wife was p r e g n a n t a t t h e t i m e of s t u d y a n d she s u b s e q u e n t l y delivered a t e r m i n f a n t who was n o r m a l p h y s i c a l l y a n d chromosomally. The 3 families carrying (13q14q) translocations, b e t w e e n t h e m p r o d u c e d 11 t e r m pregnancies a n d 9 s p o n t a n e o u s abortions. Only t h e n e o n a t e b o r n to Mrs. B. h a d a chromosome analysis a m o n g t h e 11 p h e n o t y p i c a l l y n o r m a l offspring in t h e 3 families. The p a r e n t s in each f a m i l y were either r e l u c t a n t or definitely unwilling to h a v e t h e i r children s t u d i e d a n d were n o t pressed to change t h e i r minds. The r e m a i n i n g t r a n s l o c a t i o n in series 3, was found t h r o u g h s t u d y of an a b o r t u s consisting of a large i n t a c t e m p t y sac. The chromosome a b n o r m a l i t y was identified as a chromosome 17 w i t h e x t r a m a t e r i a l on t h e long arm. The source of this m a t e r i a l would n o t h a v e been k n o w n if t h e f a m i l y h a d n o t been s t u d i e d p r e v i o u s l y for a n o t h e r reason. U n k n o w n to us a t t h e t i m e t h e a b o r t u s was k a r y o t y p e d , t h e

Translocations in Abortions

95

family had had extensive eytogenetic investigation because of an abnormal and mentally retarded child who was found to have 9p trisomy. The father had a reciprocal transloeation between chromosomes Nos. 9 and 17 (Uchida, personal communication). Discussion

I t has been shown that transloeations, unsuspected by standard techniques, can be identified by chromosome banding (Breg et al., 1972; tIirsehhorn et al., 1973 ; del Solar and Uehida, 1974). All of the 4 unbalanced transloeation products described here could be readily identified by standard staining although the chromosomes involved could not. None of the four was ascertained through prior knowledge of congenital defects or transloeations in the families. Even the two carrier sisters were independently ascertained. I f banding techniques had been available earlier we may have discovered other unsuspected unbalanced translocations in series 1 and 2. However, careful analysis of the 68 apparently normal karyotypes in the banding study has failed to show any additional rearrangements, except for 2 pericentrie inversions of No. 9. The specimen with 17q@ would have been identified as abnormal by standard staining technique, although even with banding, the origin of the extra material would have been uncertain if the family had not already been studied. (DqDq) transloeations were found in 31 of 43558 newborn infants (0.07%) (Jaeobs et al., 1974b). Although the actual D chromosomes involved is not known from these data, it, has been established that the majority of translocations between two members of group D are of the (13q14q) type (Cohen, 1971; Jaeobs et al., 1974a). All 3 of the (DqDq) translocations we identified were between chromosomes 13 and 14. Unbalanced transloeations were identified in only 3 of 43558 consecutive liveborn infants (Jaeobs et al., 1974b). As might be expected, the frequency of unbalanced translocations appears to be much higher among abortuses. Bou6 et al. (1975) found 35 structural anomalies among 921 ehromosomally abnormal abortuses. Of these, only one third were associated with an anomaly in a parent. Further details of the transloeations are not available. Kajii et al. (1973) found 3 translocations among 82 ehromosomMly abnormal specimens bug 2 of them were successive abortions from the same parent. Creasy and Alberman (personal communication) found 7 unbalanced translocations among 287 singleton abortuses Table 3. Frequency of unbalanced translocations in cytogenetic studies of abortuses Reference

Total abortuses

Chromosomally abnormal abortuses

Unbalanced transloe~tions No. anomalies(%)

Kajii et al., 1973 Creasy, M., and Alberman, E. (personal communication, 1975) Present study

152 941

82 287

2a 7

2.4 2.4

514

194

4

2.1

a Three unbalanced translocations were found but 2 were successive abortions from the same parents.

96

D.H. Carr and M. M. Gedeon

with chromosome anomalies (2.4%). The present paper reports 4 u n b a l a n c e d translocations a m o n g 194 chromosomally a b n o r m a l abortuses, all i n d e p e n d e n t l y ascertained a n d all associated with a balanced p a r e n t a l translocation. The d a t a from the latter three studies are s u m m a r i z e d in Table 3. The frequency of unbalanced products among t o t a l specimens studied varies because of differences in m e t h o d of ascertainment. However, the frequency of u n b a l a n c e d translocations as a proportion of chromosomally a b n o r m a l specimens only varies from 2.1 to

24% I t is clear t h a t the m a j o r i t y of chromosomally a b n o r m a l conceptuses are aborted spontaneously, whether sporadic or arising in a family with a translocation. I n m o n i t o r i n g pregnancies of k n o w n carriers b y amniocentesis the frequency of abnormalities m a y have been reduced b y prior miscarriage. The frequency of the e v e n t among t r a n s l o c a t i o n carriers is still u n c e r t a i n a n d c o n t r a d i c t o r y evidence exists (Hamerton, 1970). I n a n y case, s p o n t a n e o u s abortion, if it is to occur, would almost certainly do so before the time of amniocentesis at 15 to 16 weeks.

Acknowledgements. The authors would like to thank Dr. Irene Uchida for helpful information and suggestions in the preparation of this paper. We also sincerely thank the staff of St. Josephs and Henderson Hospitals in Hamilton whose co-operation made this study possible. The work was supported by a grant from the Medical Research Council of Canada. References Bout, J., Bou4, A., Lagar, 1). : The epidemiology of human spontaneous abortions with chromosomal anomalies. Aging Gametes. Int. Syrup. Seattle, 1973, pp. 330--348. Basel: Karger 1975 Breg, W. R., Miller, D. A., Allderdice, 1). W., Miller, O. J. : Identification of translocation chromosomes by quinacrine fluorescence. Amer. J. Dis. Child. 123, 561--564 (1972) Carr, D. H.: Chromosome anomalies as a cause of spontaneous abortion. Amer. J. Obstet. Gynec. 97, 2 8 3 4 9 3 (1967) Carr, D. H., Law, E. M., Ekins, J. G. : Chromosome studies in selected spontaneous abortions IV. Unusual cytogenetic disorders. Teratology 5, 49--56 (1972) Cohen, iV[.M. : The chromosomal constitution of 165 human transloeations involving D group chromosomes identified by autoradiography. Ann. G@n4t. 14, 87--96 (1971) del Solar, C., Uchida, I, A. : Identification of chromosomal abnormalities by quinacrine staining technique in patients with normal karyotypes by conventional analysis. J. 1)ediat. 84, 534--538 (1974) Hamerton, J. L. : gobertsonian translocations. In: ~Iuman population cytogenetics (eds. 1), A. Jacobs, W. H. 1)rice, 1). Law), pp. 63--80. Edinburgh: University 1)ress 1970 Hirschhorn, K., Lucas, M., Wallace, I. : 1)recise identification of various chromosomal abnormalities. Ann. hum. Genet. 36, 375--377 (1973) Jacobs, 1). A., Buckton, K. E., Curmingham, C., Newton, M. : An analysis of the break points of structural re-arrangements in man. J. reed. Genet. 11, 50--64 (1974a) ~acobs, P. A., Melville, M., Ratcliffe, S., Keay, A. J., Syme, J.: A cytogenetic survey of 11,680 newborn infants. Ann. hum. Genet. 87, 359--376 (1974b) Kajii, T., 0hama, K., Niikawa, N., Ferrier, A., Avirachan, S. : Banding analysis of abnormal karyotypes in spontaneous abortion. Amer. J. hum. Genet. 25, 539--547 (1973) Lucas, M., Wallace, I., I-Iirschhorn, K. : Recurrent abortions and chromosome abnormalities. J. Obstet. Gynaec. Brit. Cwlth 79, 1119--1127 (1972) McConnell, H. D., Carr, D. H. : Recent advances in the cytogenetic study of human spontaneous abortions. Obstet. and Gynec. 45, 547--552 (1975) Dr. D. H. Carr

Department of Anatomy McMaster University Hamilton, Ontario, Canada LSS 4J9