Hum. Genet. 46, 285--294 (1979)

© by Springer-Verlag 1979

Origin of Trisomies in Human Spontaneous Abortions Terry Hassold* and Aileen Matsuyama University of Hawaii, John A. Burns School of Medicine, Department of Anatomy and Reproductive Biology, 1960 East-West Road, Honolulu, Hawaii 96822, USA

Summary. Chromosome heteromorphisms of 34 trisomic abortuses and their parents were compared to determine the origin of the extra chromosome. Fourteen of the trisomies were maternal in origin, ten resulting from a firstmeiotic-division error and four from either first- or second-meiotic-division errors. No paternally derived trisomy was identified.

Introduction Analysis of Q- and C-banded chromosome heteromorphisms has been shown to be of considerable value in determining the mechanism of origin of various chromosome abnormalities, including autosomal trisomies, triploidy, and structural rearrangements. Licznerski and Lindsten (1972) were the first to apply this technique, and were able to demonstrate a maternal origin for a case of trisomy 21. Subsequently, several studies aimed at determining the origin of trisomy 21 have been published, and results from over 100 informative families are now available (Bott et al., 1975; H a r a and Sasaki, 1975; Magenis et al., 1977; Mikkelsen et al., 1976; Robinson, 1973; Schmidt et al., 1976; Wagenbichler, 1976). However, as virtually all studies of this nature have used the live-born population, there has been little opportunity to examine the origin of trisomies other than Down's syndrome. Only in two studies of spontaneous abortion (Lauritsen and Friedrich, 1976; Niikawa et al., 1977) have data been collected for any of the other autosomal trisomies. Approximately one-half of all spontaneous abortuses are chromosomally abnormal (Carr, 1977) and of these, close to 40% are trisomic for chromosomes that are frequently heteromorphic. Furthermore, several different types of trisomies are found in high frequency among abortuses, including types that are associated with increasing maternal age (i.e., trisomies 13, 14, 15, 21, and 22), as well as those that are apparently maternal age-independent (i.e., trisomies 4, 9, and 16). Thus the use of spontaneous abortions provides a convenient mechanism for *

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T. Hassold and A. Matsuyama

c o m p a r i n g the origin o f different types of a u t o s o m a l trisomies, a n d in the case o f t r i s o m y 21 at least, for c o m p a r i n g the p a r e n t a l origin o f the extra c h r o m o s o m e in a b o r t e d a n d l i v e - b o r n conceptuses with the same c h r o m o s o m e a b n o r m a l i t y . Since A p r i l 1, 1976, we have been c o n d u c t i n g a cytogenetic survey o f all s p o n t a n e o u s a b o r t i o n s o c c u r r i n g in a large m a t e r n i t y hospital in H o n o l u l u , H a w a i i ( H a s s o l d et al., 1978). One p u r p o s e o f the s t u d y was to d e t e r m i n e the m e c h a n i s m o f origin o f the extra c h r o m o s o m e in a u t o s o m a l trisomies involving a h e t e r o m o r p h i c c h r o m o s o m e . The p r e s e n t r e p o r t discusses o u r results with respect to 34 t r i s o m i e s s t u d i e d in the first two years o f the project.

Materials and Methods Procedures for the collection, culturing, and cytogenetic evaluation of the spontaneous abortions have been described previously (Hassold et al., 1978). Abortuses were selected for further examination if they were trisomic for a heteromorphic chromosome and if the parents were available. All abortuses meeting these two requirements were studied and no selection was made for abortuscs with particularly distinctive heteromorphisms. Thirty-two trisomies and one double trisomy and the parents involved were analyzed. The relevant heteromorphic chromosomes of the trisomic fetuses and the parents were examined by means of either the CBG-banding technique (for trisomies 9 and 16) or the QFQ-banding technique (for trisomies 4, 13, 14, 15, 21, and 22). The chromosome preparations of each abortus and the parents were stained and examined at the same time to minimize technical variation. All observations were made directly on the microscope, and the method of scoring the heteromorphic regions was essentially that described in the Paris Conference, 1971 (Supplement, 1975). All preparations were examined by at least two independent observers and, in the event of any ambiguity, the most conservative result was taken as the final one. For each trisomy, the conditional probabilities of the observations were determined using the methodology of Jacobs and Morton (1977).

Results O f the 33 a b o r t u s e s studied, t r i s o m y 16, with ten cases, was the m o s t frequent. The r e m a i n i n g a b o r t u s e s consisted o f three cases o f t r i s o m y 4, one o f t r i s o m y 9, two o f t r i s o m y 13, two o f t r i s o m y 14, five o f t r i s o m y 15, one o f t r i s o m y 21, eight o f t r i s o m y 22, a n d one d o u b l e t r i s o m y (+21+22). Tables 1 a n d 2 s u m m a r i z e the p a r e n t a l ages, c y t o g e n e t i c o b s e r v a t i o n s a n d c o n d i t i o n a l p r o b a b i l i t i e s o f these o b s e r v a t i o n s for the f o u r possible m e c h a n i s m s o f origin for each case. In one t r i s o m y (K494) o n l y the m o t h e r was available for cytogenetic study. F o r each case we have a s s u m e d t h a t the t r i s o m y c o u l d have arisen f r o m one o f f o u r p o s s i b l e m e c h a n i s m s , i.e., first- or s e c o n d - m e i o t i c - d i v i s i o n errors in either p a r e n t . T h u s we have n o t c o n s i d e r e d the possibilities o f m o s a i c i s m in a p a r e n t o r a p o s t zygotic n o n d i s j u n c t i o n a l event that w o u l d be indistinguishable f r o m a secondm e i o t i c - d i v i s i o n n o n d i s j u n c t i o n . A d d i t i o n a l l y we have a s s u m e d that no crossingover o c c u r r e d b e t w e e n the c e n t r o m e r e a n d the h e t e r o m o r p h i c region in question. C h i a s m a t a have o n l y o c c a s i o n a l l y been o b s e r v e d in these regions in m a l e meiosis ( H u l t e n , 1974), so t h a t the a s s u m p t i o n o f no crossing-over s h o u l d h o l d for all b u t a very small p r o p o r t i o n o f the cases.

Table 1. Origin o f the extra c h r o m o s o m e in 14 trisomies involving c h r o m o s o m e s 4, 9, or 16 Trisomy

Case no.

K365

Paternal

Maternal Heteromorphisms

C o n d i t i o n a l probability

age

age

Father

M o t h e r Fetus

~ I

(~ II

~ I

~ II

30

32

ab

aa

0

1/2

1/2

1/2

aaa

K542

32

29

aa

aa

aaa

1

1

1

1

K567

26

22

aa

ab

aab

1/2

1/2

1

0

9

K399

44

38

ab

aa

aab

1

0

1/2

1/2

16

K23~

38

36

ab

cd

acd

0

0

1

0

K242

22

21

ab

aa

aab

1

0

1/2

1/2

K257

29

23

ab

ac

abc

1/2

0

1/2

0

K286

26

23

ab

ac

abc

1/2

0

1/2

0

K31~

24

26

aa

bc

abc

0

0

1

0

K355

24

27

aa

aa

aaa

1

1

1

1

K424

31

28

ab

ac

abc

1/2

0

1/2

0

K432

35

32

aa

aa

aaa

1

1

1

1

K494

--

22

--

aa

aaa

1

1

1

1

K529

35

34

aa

aa

aaa

1

1

1

1

Parental origin d e t e r m i n e d Table 2. Origin o f the extra c h r o m o s o m e in 20 trisomles involving acrocentric c h r o m o s o m e s Trisomy

13

14

15

21

22

a

Case no.

Paternal

Maternal Heteromorphisms

C o n d i t i o n a l probability

age

age

Father

M o t h e r Fetus

~ I

K431

34

26

aa

aa

aaa

K435 ~

23

26

ab

cd

acd

(~ II

~ I

Q II

1

1

1

1

0

0

1

0

K30!

28

28

ab

aa

aaa

0

1/2

1/2

I/2

K346 ~

29

26

ab

cd

acd

0

0

1

0

K244a

47

41

ab

cc

acc

0

0

1

1

K274

41

40

ab

ac

aac

0

1/4

1/2

0

S 11~

42

44

ab

cd

acd

0

0

1

0

K419"

30

32

ab

cc

acc

0

0

1

1

K587"

26

19

ab

cd

acd

0

0

1

0

K392

40

37

ab

ac

abc

1/2

0

1/2

0

K425

42

32

ab

ac

abc

1/2

0

1/2

0

K220 a

33

36

aa

bc

abc

0

0

1

0

K282"

39

37

ab

cd

acd

0

0

1

0

K324 a

33

34

ab

cd

acd

0

0

1

0

K351

30

28

aa

ab

aaa

1/2

1/2

0

1/2

K358

33

32

aa

ab

aab

1

0

1/2

1/2

K392~

40

37

ab

cc

acc

0

0

1

1

K414"

43

37

aa

bb

abb

0

0

1

1

K544

35

32

ab

ac

abc

1/2

0

1/2

0

K586"

43

33

ab

cd

acd

0

0

1

0

Parental origin d e t e r m i n e d

288

T. Hassold and A. Matsuyama

Table 1 summarizes the findings for the three nonacrocentric trisomies studied, +4, +9, and + 16. Based on the combined findings of several surveys of spontaneous abortions (Creasy et al., 1975; Lauritsen, 1976; Hassold et al., 1978; T. Kajii, personal communication), trisomy 16 appears to have little, if any relationship to increasing maternal age. Too few data are available on either trisomy 4 or trisomy 9 to evaluate their possible association with advancing age of the mother. Table 2 lists the results for trisomies 13, 14, 15, 21, and 22. Trisomies 13 and 21 are known to be associated with increasing maternal age from studies of the live-born population (Hamerton, 1970), and studies of spontaneous abortions have shown the same to be true for D- and G-group trisomies in general (Bou~ and Bou6, 1975; Lauritsen, 1976; Creasy et al., 1975; Hassold et al., 1978). In 9 of the 14 nonacrocentric trisomies the heteromorphisms of the parental homologues were not identical, so that some information could be obtained with respect to the origin of the extra chromosome. While we were unable to determine the origin precisely in any of the cases of trisomy 4 or 9, in three instances we were able to rule out at least one of the possible mechanisms. In two of the abortuses with trisomy 16 it was possible to specify an exact mechanism of origin, and in both cases the trisomy resulted from a maternal first-meioticdivision error. The parental and fetal chromosomes 16 from one of these cases (K312) are shown in Figure 1. In the remaining eight cases of trisomy 16, we excluded both paternal and maternal second-division errors in three and a

Fig. 1. C-banded chromosomes 16 from K312 and parents, showing a maternal first-meioticdivision error

Origin of Trisomles in Human Spontaneous Abortions

289

paternal second-division in one, and in four instances the heteromorphisms were uninformative. In none of the cases of trisomy 4, 9, or 16 were we able to exclude as impossible a maternal I error. In 12 of the 20 acrocentric trisomies the parental origin of the extra chromosome was determined. Eight of the trisomies--one case of trisomy 13, one of trisomy 14, two of trisomy 15 and four of trisomy 22--were the result of a maternal first-meiotic-division error. Additionally, in two cases of trisomy 15 and two of trisomy 22 the additional chromosome was maternal although it was not possible to distinguish between a first- or second-division error. In seven of the remaining eight cases in which the parental origin could not be determined, we were still able to rule out one or more of the possible mechanisms of origin. Only in one case of trisomy 13 were the heteromorphisms completely uninformative. K392 was the only double trisomy in our series, +21+22. For the purpose of analysis we have assumed that the two trisomies were independent; however, it is interesting to note that if their occurrence was in fact related, the only mechanism possible for both the extra 21 and the extra 22 would have been a maternal I error. K425 and K586 are consecutive spontaneous abortions occurring to the same couple. In the first instance the trisomy could have arisen as a result of either a maternal I or a paternal I error, while in the second case the trisomy resulted from a maternal I error.

Discussion Most of the cytological information on the origin of human trisomies has come from studies of trisomy 21 in the live-born population. However there are now enough data from spontaneous abortions to make it worthwhile to compare these results with those from the live-born studies. Table 3 summarizes the cytogenetic results from the three studies of spontaneous abortions and the pooled findings from eight reports on live-born subjects with trisomy 21. For each group of data m a x i m u m likelihood estimates have been determined by the methodology of Jacobs and Morton (1977). Only in the studies of Niikawa et al. (1977) and Robinson (1973) were all cases reported, and only in the later study were all cytogenetic observations unambiguously presented. Therefore, in calculating the m a x i m u m likelihood estimates it was usually necessary to reconstruct the mating types observed, and this was done by assuming the simplest possible mating type involving the fewest heteromorphisms consistent with the observed cytogenetic result. The study most directly comparable to ours is that of Niikawa et al. (1977). These authors presented data on 33 abortuses with trisomies 13, 14, 15, 21, or 22, and in 11 instances were able to identify the parental origin of the extra chromosome. Their findings and ours are in close agreement, as they also found only maternally derived trisomies, almost all of which were the result of a maternal I error. Maximum likelihood estimates based on their data and our own are not significantly different (Z~ = 1.77). In the only other study that utilized spontaneous abortions, Lauritsen and Friedrich (1976) also found a preponderance of maternal

Spontaneous abortions

Live-born population

Lauritsen and Friedrich (1976)

Bott et al. (1975)

Present study

Robinson (1973) Schmidt et al. (1976) Wagenbichler et al. (1976)

Mikkelsen et al. (1976)

Spontaneous abortions

Spontaneous abortions

Niikawa et al. (1977)

Hara and Sasaki (1975) Licznerski and Lindsten (1972) Magenis et al. (1977)

Source of material

Report

4, 9, 13, 14, 15, 16, 21,22

21

16

13, 14, 15, 21,22

Trisomy(ies)

34

266

16

33

12

2

4I

12

1 2

--

10

63

7

9

d~II 6 ' I 9 I or II

--

12

1

1

4

5

--

1

9II ?I or II

No. of Mechamsm of origin cases

Table 3. Summary of reports on the origin of trisomies in spontaneous abortions and trisomy 21 in the live-born population

9II

0.050 0.001 0.938 0.011

0.187 0.055 0.587 0.172

0.1440.015 0.759 0.081

0.111 0.006 0.834 0.048

d~I ~ I I ~ I

Maximum likelihood estimates for:

>

Q

m

Origin of Trisomies m Human Spontaneous Abortions

291

I errors in their analysis of trisomy 16. Furthermore, the difference in maximum • • likelihood estimates based on their findings and ours is not si gmficant 0(22 = 4.52). However their study differs from ours in at least two respects: they identified three cases of paternally derived trisomy 16 while we found none, and their rate of success in determining the parental origin of the extra 16 was very much higher than was ours (i.e., 11 of 16 cases compared to 2 of 10 cases). As the number of cases analyzed in both Lauritsen's and Friedrich's study and in our own was rather small, the difference in success rate may be merely coincidental, or it may reflect a real difference in the frequency of chromosome 16 heteromorphisms in the two populations studied. Maternal first-meiotic-division errors are also apparently the most common mechanism leading to live-born trisomy 21, as evidenced by the pooled data from the eight studies listed in Table 3. There are, however, certain important differences between the data obtained from abortuses and data obtained from live-born individuals, namely a substantial increase in both paternal and second-division errors among the live-born trisomics. These differences are reflected in the m a x i m u m likelihood data: estimates for maternal meiosis I errors range from 0.76 to 0.94 in the spontaneous abortion studies, while for the liveborn the corresponding value is only 0.59. Moreover, the difference in the maximum likelihood estimates between the data obtained from the live-born studies and ours is highly significant (Z2 = 79.86). The reasons for these differences are not altogether clear, but they are probably due, at least in part, to the manner in which the data were reported. With the exception of Robinson's study, none of the reports of live-born individuals listed in Table 3 gave information on all cases studied. In comparison, of the three studies using spontaneous abortions, only Lauritsen and Friedrich reported just those cases in which a determination of the parental origin had been made. At the very least, such incomplete reporting results in the loss of information; more importantly, by considering only cases informative for a specific mechanism of origin, a bias toward second-division errors is introduced (Langenbeck et al., 1976). The fact that most of the studies of live-born individuals have been biased in precisely this manner suggests that the frequency of seconddivision errors in these data may well be artificially inflated relative to the abortion studies. Alternatively, the disparity between the two sets of data may be partially due to real biological differences between the live-born and aborted trisomic conceptuses. Warburton et al. (1978) recently suggested that the level of mosaicism among spontaneously aborted and live-born trisomics may be much higher than is currently believed. Since trisomies resulting from postzygotic nondisjunction are indistinguishable cytologically from second-division errors, the presence of undetected mosaicism will increase the frequency of apparent second-division errors. Assuming that, on average, such mosaic trisomic conceptuses have a better chance of surviving to term than do complete trisomics, the effect of mosaicism on the frequency of second-division errors will presumably be more pronounced in the data obtained from live-born subjects than in those from abortuses. In spite of the differences between the data obtained from abortuses and liveborn individuals, two general facts are clear from Table 3: first, trisomies can result from any of the four possible meiotic mechanisms, as evidenced by the identifica-

292

T. Hassold and A. Matsuyama

tion of paternal first- and second-division errors and maternal second-division errors in trisomies 16 and 21, and second, by far the most common mechanism leading to trisomy is nondisjunction in the first meiotic division in the mother. This seems to hold regardless of whether the conceptus is aborted or live-born and, more importantly, regardless of the chromosome involved. Maternal I errors predominate among the trisomy 16 abortuses, the only trisomy that has been studied in any numbers which has little or no association with increasing maternal age, as well as a m o n g those trisomies that are known to be maternal agedependent. Furthermore, for this latter type of trisomy, data from both the liveborn population (Magenis et al., 1977) and the spontaneously aborted population indicate that maternal I errors are the most c o m m o n mechanism of origin a m o n g younger women as well as older women. In our own study, 12 of the 20 acrocentric trisomies that we examined involved women under 35 and, of these, in each of the five cases where we could determine an exact origin, the error was at maternal meiosis I. The fact that maternal meiosis I errors predominate both in age-related trisomies and in an apparently age-independent trisomy, and in both younger and older women, suggests that there are at least two mechanisms affecting nondisjunction at maternal meiosis I - - o n e type restricted primarily to older women and certain chromosomes and another that is maternal age-independent. At least three mechanisms have been proposed to account for trisomies arising from maternal first-division errors. Evans (1967) suggested that the persistence of nucleoli in older oocytes or as a result of viral infection might prevent normal disjunction of half-bivalents sharing the same nucleolus. There has been little evidence in man either for or against this claim; however, the occurrence of both age-related trisomies (e.g., trisomy 18, Hamerton, 1970) and age-unrelated trisomies (e.g., trisomy 16) involving chromosomes without nucleolar organizing regions limits the general applicability of this explanation. Henderson and Edwards (1968) found declining chiasma frequencies and increases in univalents in aging mouse oocytes, and suggested that random segregation of such univalents at meiosis I could account for the excess of trisomies in older women. Subsequent studies in mouse (Luthardt et al., 1973; Polani and Jagiello, 1976; Speed, 1977) and in man (Luthardt, 1977) have confirmed most of their original findings with respect to decreasing chiasma frequency with age. However, Polani and Jagiello (1976) did not observe the expected association between univalents at meiosis I and hyperhaploidy at meiosis II, and both they and Speed (1977) suggested that, in the mouse at least, other mechanisms may be more frequently responsible for trisomy. There is, therefore, little experimental evidence supporting the notion that either of these mechanisms contributes substantially to trisomy in man. Moreover, even assuming that either or both of these mechanisms, or nondisjunction resulting from exogenous factors such as maternal irradiation (Uchida, 1977), accounts for a proportion of age-related trisomy, none can satisfactorily explain the maternal age-independent event. A possible mechanism for this latter type of abnormality may be spindle degeneration as a result of intrafollicular aging (Mikamo, 1968). Experimental studies on induced preovulatory delay in Xenopus (Witschi and Laguens, 1963; Mikamo, 1968) and in rat (Butcher and Fugo, 1967; Mikamo and Hamaguchi, 1975) have demonstrated increases in both triploidy and trisomy. In

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m a n Bou6 a n d Bou6 (1975) p r e s e n t e d e p i d e m i o l o g i c a l d a t a relating the a p p a r e n t d a y o f o v u l a t i o n to the c h r o m o s o m e c o n s t i t u t i o n o f 126 n o r m a l , trisomic, a n d p o l y p l o i d a b o r t u s e s . W h i l e no significant difference was n o t e d between the t r i s o m i c a n d n o r m a l a b o r t u s e s with relation to the d a y o f o v u l a t i o n , m o r e trisomic t h a n n o r m a l a b o r t u s e s were f o u n d in cases where o v u l a t i o n p r e s u m a b l y h a d o c c u r r e d after d a y 18 of the m e n s t r u a l cycle. M o r e o v e r , as p r e o v u l a t o r y d e l a y w o u l d be expected to be related to only a certain p r o p o r t i o n o f the trisomics, the analysis o f trisomies as a single g r o u p w o u l d have tended to m a s k the effect o f a n y such p r e o v u l a t o r y overripeness. As direct e x p e r i m e n t a l evidence on this subject is difficult to o b t a i n f r o m h u m a n s , further e p i d e m i o l o g i c a l investigation into this a r e a w o u l d be very i n f o r m a t i v e a n d should be relatively easy to o b t a i n f r o m s p o n t a n e o u s abortions.

Acknowledgements. We are extremely grateful to Ms. Shirley Yee of the Population Genetics Laboratory, University of Hawaii, for her help with the statistical analysis. This work was supported by grant No. 6-47 from the National Foundation March of Dimes and a Public Health Service Research Fellowship from the National Institutes of Health.

References Bott, C. E., Sekhon, G. S., Lubs, H. A.: Unexpected high frequency of paternal origin oftrisomy 21. Am. J. Hum. Genet. 27, 20A (1975) Bou6, J., Bou6, A., Lazar, P.: Retrospective and prospective epidemlological studies of 1500 karyotyped spontaneous human abortions. Teratology 12, 11--26 (1975) Butcher, R. L., Fugo, N. W.: Overripeness and mammalian ova. II. Delayed ovulation and chromosome anomalies. Fertil. Steral. 18, 297--302 (1967) Carr, D. H., Gedeon, M.: Population cytogenetics of human abortuses. In: Population cytogenetics, E. B. Hook, I. H. Porter, eds., pp. 1--9. New York: Academic Press 1977 Creasy, M. R., Crolla, J. A., Alberman, E. D.: A cytogenetic study of human spontaneous abortions using banding techniques. Hum. Genet. 31, 177--196 (1976) Evans, H. J.: The nucleolus, virus infection, and trisomy in man. Nature 214, 361--363 (1967) Hamerton, J. L.: Human cytogenetics, Vol. II: Clinical cytogenetics. New York: Academic Press 1971 Hara, Y., Sasakl, M.: A note on the origin of extra chromosomes in trisomies 13 and 21. Proc. Jpn. Acad. 51, 295--299 (1975) Hassold, T. J., Matsuyama, A., Newlands, I. M., Matsuura, J. S., Jacobs, P. A., Manuel, B., Tsuei, J.: A cytogenetlc study of spontaneous abortions m Hawaii. Ann. Hum. Genet. 41, 443--454 (1978) Henderson, S. A., Edwards, R. G.: Chiasma frequency and maternal age in mammals. Nature 218, 22--28 (1968) Hulten, M.: Chiasma distribution at diakinesis m the normal human male. Hereditas 76, 55--78 (1974) Jacobs, P. A., Morton, N. E.: Origin of human trisomics and polyploids. Hum. Hered. 27, 59--72 (1977) Langenbeck, U., Hansmann, I., Hinney, B., Honig, V.: On the origin of the supernumerary chromosome in autosomal trisomies--with special reference to Down's syndrome. Hum. Genet. 33, 89--102 (1976) Lauritsen, J. G.: Aetiology of spontaneous abortion. Acta Obstet. Gynecol. Scand. Suppl. 52 (1976) Lauritsen, J. G., Friedrich, J.: Origin of the extra chromosome m trisomy 16. Clin. Genet. 10, 156--160 (1976) Licznerski, G., Lindsten, J.: Trisomy 21 in man due to maternal non-disjunction during the first meiotic division. Hereditas 70, 153--154 (1972)

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Received August 24, 1978 / September 25, 1978

Origin of trisomies in human spontaneous abortions.

Hum. Genet. 46, 285--294 (1979) © by Springer-Verlag 1979 Origin of Trisomies in Human Spontaneous Abortions Terry Hassold* and Aileen Matsuyama Uni...
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