8

Cytogenetic Study of the Offspring of Atomic Bomb Survivors, Hiroshima and Nagasaki

A.A.AWA1, T.HONDA2, S.NERIISHI3, T.SUFUNI1,4, H.SHIMBA1, K.OHTAKI1, M.NAKANO1, Y.KODAMA1, M.ITOH2, and H.B.HAMILTON5

1 Introduction

A cytogenetic study of the children born to atomic bomb survivors in Hiroshima and Nagasaki and children born to unexposed parents was initiated in 1967 (Awa 1975; Awa et al. 1968). The study was expanded in 1976 as a part of the Genetic Platform Research Program at RERF (Radiation Effects Research Foundation), and has been continued to the present time in conjunction with the ongoing mortality study and biochemical genetics survey on the F1 progeny (RERF Research Protocol 1975).

The main objective of the present study is to evaluate the radiation sensitivity of human germ-cell chromosomes by measuring the frequency of children with chromosome changes in structure or number induced by radiation in the germ cells of exposed parents. It is expected that stable chromosome aberrations, if induced in the germ cells, would be most likely transmitted to the offspring. Although there is no evidence of chromosome aneuploidy being induced by radiation exposure in humans, it is difficult to exclude the possibility that abnormalities, such as XYY and XXX, would be induced in the offspring.

The present chapter describes the results of somatic chromosome analysis of 8,322 children born to A-bomb survivors in Hiroshima and Nagasaki and 7,976 children born to parents who had received less than 1 rad (distally exposed) or were not in the cities (NIC) at the time of the bomb (ATB). Chromosome analyses were based mostly on nonbanded preparations throughout the study.

Because of the recent, extensive reassessment of A-bomb dosimetry by a US Japan team of experts (1st and 2nd US-Japan Joint Workshop 1983, 1984), the present study samples have been divided into exposed and control groups based on the T65DR system that has been routinely used until recently at RERF (Milton and Shohoji 1968). The data base for the new DS86 dose system has been entered into the RERF

1

Radiation Effects Research Foundation, 5–2 Hijiyama Park, Minami-ward Hiroshima 732, Japan

2

Department of Radiobiology, Nagasaki, Japan

3

Department of Clinical Studies, Nagasaki, Japan

4

Biological Safety Research Center, National Institute of Hygienic Sciences, Tokyo, Japan

5

RERF Consultant

Reproduced, with permission, from Cytogenetics, ed. by G.Obe and A.Basler, © Springer-Verlag, Berlin-Heidelberg, 1987.



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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study 8 Cytogenetic Study of the Offspring of Atomic Bomb Survivors, Hiroshima and Nagasaki A.A.AWA1, T.HONDA2, S.NERIISHI3, T.SUFUNI1,4, H.SHIMBA1, K.OHTAKI1, M.NAKANO1, Y.KODAMA1, M.ITOH2, and H.B.HAMILTON5 1 Introduction A cytogenetic study of the children born to atomic bomb survivors in Hiroshima and Nagasaki and children born to unexposed parents was initiated in 1967 (Awa 1975; Awa et al. 1968). The study was expanded in 1976 as a part of the Genetic Platform Research Program at RERF (Radiation Effects Research Foundation), and has been continued to the present time in conjunction with the ongoing mortality study and biochemical genetics survey on the F1 progeny (RERF Research Protocol 1975). The main objective of the present study is to evaluate the radiation sensitivity of human germ-cell chromosomes by measuring the frequency of children with chromosome changes in structure or number induced by radiation in the germ cells of exposed parents. It is expected that stable chromosome aberrations, if induced in the germ cells, would be most likely transmitted to the offspring. Although there is no evidence of chromosome aneuploidy being induced by radiation exposure in humans, it is difficult to exclude the possibility that abnormalities, such as XYY and XXX, would be induced in the offspring. The present chapter describes the results of somatic chromosome analysis of 8,322 children born to A-bomb survivors in Hiroshima and Nagasaki and 7,976 children born to parents who had received less than 1 rad (distally exposed) or were not in the cities (NIC) at the time of the bomb (ATB). Chromosome analyses were based mostly on nonbanded preparations throughout the study. Because of the recent, extensive reassessment of A-bomb dosimetry by a US Japan team of experts (1st and 2nd US-Japan Joint Workshop 1983, 1984), the present study samples have been divided into exposed and control groups based on the T65DR system that has been routinely used until recently at RERF (Milton and Shohoji 1968). The data base for the new DS86 dose system has been entered into the RERF 1 Radiation Effects Research Foundation, 5–2 Hijiyama Park, Minami-ward Hiroshima 732, Japan 2 Department of Radiobiology, Nagasaki, Japan 3 Department of Clinical Studies, Nagasaki, Japan 4 Biological Safety Research Center, National Institute of Hygienic Sciences, Tokyo, Japan 5 RERF Consultant Reproduced, with permission, from Cytogenetics, ed. by G.Obe and A.Basler, © Springer-Verlag, Berlin-Heidelberg, 1987.

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study computer; however, calculations of the individual dose estimates for each survivor are now in progress, but are not available at this time. For this reason, no attempt has been made to analyze the present data in terms of parental radiation doses. 2 Materials and Methods The sample subjects of the present survey were selected primarily from the RERF F1 mortality study cohort (Kato et al. 1966). This cohort includes children born between 1 May 1946 and 31 December 1958 to parents, one or both of whom were the residents of Hiroshima and Nagasaki ATB. The samples were later expanded to include children who were born after 1959 through the end of 1972. The contribution of the extended samples was about 10% of the total. In this analysis, the exposed group consists of children born to parents, one or both of whom were located within 2000 m from the hypocenter and who had T65DR dose estimates of more than 1 rad. The control group consisted of children born to parents (1) one or both of whom were exposed distally (2500 m or more from the hypocenter) with estimated doses of less than 1 rad, or (2) were not present in the city ATB. About 40% of the total individuals in the original samples were not included in this study, because they had died (5%), or migrated outside the contactable areas of both cities (35%). Of the remaining individuals, approximately 74% agreed to participate in this study. Thus, the participation rate of this survey was 45% of the total original sample. After obtaining consent from the F1 participants and, if necessary, their parents, they were invited to visit the RERF clinic. At that time they were interviewed by nurses to obtain medically-related information and a blood sample was drawn. If requested, a physical examination was performed. Heparinized blood specimens, 1 to 2 ml per person, collected from each participant, were cultured for 2 days, and then harvested for chromosome preparations using the conventional Giemsa staining methods, the details of which have been described elsewhere (Awa et al. 1978). In each case, ten well-spread metaphases were examined directly under the microscope, and three of them were photographed for detailed karyotype analysis. Cases with less than ten scorable metaphases were regarded as culture failure. The rate of failure was about 0.1% of the total blood samples in the two cities. When an abnormality was suspected, 100 or more cells were examined. In addition to the conventional stain, both Q- and C-band preparations (Caspersson et al. 1971; Sumner 1972) were used as a routine procedure. The G-banding method of Seabright (1971) was also applied to cases suspected of having abnormality. When family studies were performed on probands with structural rearrangements, high resolution banding techniques (Yunis et al. 1978; Pai and Thomas 1980) were employed for the precise identification of breakpoints of the chromosomes involved in the aberrations. A description of the type of chromosome abnormalities was made following the standardized nomenclature of ISCN (1978, 1981, 1985).

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Table 1. Number of F1 children examined   Number of cases     Males Females Total Number of parental couples Hiroshima Control   2,477 2,635 5,112 4,242   Exposed: Father 638 636 1,274 968   Mother 1,348 1,490 2,838 2,018   Both 274 330 604 467   Total 2,260 2,456 4,716 3,453 Nagasaki Control   1,205 1,659 2,864 2,231   Exposed: Father 543 623 1,166 802   Mother 912 1,123 2,035 1,305   Both 199 206 405 263   Total 1,654 1,952 3,606 2,370 Total Control   3,682 4,294 7,976 6,473   Exposed: Father 1,181 1,259 2,440 1,770   Mother 2,260 2,613 4,873 3,323   Both 473 536 1,009 730   Total 3,914 4,408 8,322 5,823 3 Results 3.1 Characteristics of the Study Sample As shown in Table 1, the total number of children examined was 16,298 in the two cities; 9,828 in Hiroshima (4,716 exposed and 5,112 controls), and 6,470 in Nagasaki (3,606 exposed and 2,864 controls). The number of females predominated over males in both cities as well as in both the exposed and control groups. The exposed group was further divided into three categories by parental exposure status; i.e., children born to parents in which only the father was exposed, only the mother was exposed, or both parents were exposed. Since efforts were made to collect as many cases as possible in the exposed group, the number of children per parental couple is considerably higher in the exposed group than in the controls (Table 1); 1.4 children per couple (or 8,322 in 5,823) in the exposed, and 1.2 per couple (or 7,976 in 6,473) in the controls, when the two cities were combined. The mean age of the participants at examination was 24 in Hiroshima, and 23 in Nagasaki with a range between 12 and 38.

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Table 2. Overall frequency of F1 children with chromosome abnormalities (per 1,000)   Rearrangements     Sex chromosomes Balanced Unbalanced Trisomy Total No. of cases examined Hiroshima Control   17 (3.33) 16 (3.13) 0 0 33 (6.46) 5,112   Exposed: Father 4 (3.14) 5 (3.92) 2 (1.57) 1 (0.78) 12 (9.42) 1,274   Mother 5 (1.76) 7 (2.47) 1 (0.35) 0 13 (4.58) 2,838   Both 3 (4.97) 2 (3.31) 0 0 5 (8.28) 604   Total 12 (2.54) 14 (2.97) 3 (0.64) 1 (0.21) 30 (6.36) 4,716 Nagasaki Control   7 (2.44) 9 (3.14) 2 (0.70) 0 18 (6.28) 2,864   Exposed: Father 3 (2.57) 3 (2.57) 1 (0.86) 0 7 (6.00) 1,166   Mother 4 (1.97) 0 1 (0.49) 0 5 (2.46) 2,035   Both 0 1 (2.47) 0 0 1 (2.47) 405   Total 7 (1.94) 4 (1.11) 2 (0.55) 0 13 (3.61) 3,606 Total Control   24 (3.01) 25 (3.13) 2 (0.25) 0 51 (6.39) 7,976   Exposed: Father 7 (2.87) 8 (3.28) 3 (1.23) 1 (0.41) 19 (7.79) 2,440   Mother 9 (1.85) 7 (1.44) 2 (0.41) 0 18 (3.69) 4,873   Both 3 (2.97) 3 (2.97) 0 0 6 (5.95) 1,009   Total 19 (2.28) 18 (2.16) 5 (0.60) 1 (0.12) 43 (5.17) 8,322 Newborn infantsa   127 (2.23) 110 (1.93) 34 (0.60) 82 (1.44) 353 (6.20) 56,952 a Cited from Hook and Hamerton (1977). 3.2 Types and Frequencies of Chromosome Abnormalities The results of the cytogenetic observations are shown in Table 2, and every abnormal case is fully described in the Appendix Table (see pp. 181–183). Chromosome abnormalities are classified into the following three groups; (1) sex chromosome abnormalities, (2) autosomal structural rearrangements, and (3) autosomal trisomics. 3.2.1 Sex Chromosome Abnormalities As shown in Table 3, there were 43 cases with sex chromosome anomalies; 19 of 8,322 in the exposed group (2.28 per 1,000) and 24 of 7,976 in the controls (3.01 per 1,000). No increased frequency of sex chromosome abnormalities, ascribable to parental radiation exposure, was observed. The majority of the abnormalities was due to sex chromosome aneuploidy, mostly XYY and XXY in males and XXX in females, which constituted 75% of the total sex

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Table 3. Frequency of F1 children with sex chromosome abnormalities (per 1,000)a   Males Females   XYY XXY Mosaic Other Total X XXX Mosaic Other Total Hiroshima Control   5 (2.02) 4 (1.61) 0 2 (0.81) 11 (4.44) 0 3 (1.14) 3 (1.14) 0 6 (2.28)   Exposed: Father 0 1 (1.57) 1 (1.57) 0 2 (3.13) 0 2 (3.14) 0 0 2 (3.14)   Mother 0 4 (2.97) 0 0 4 (2.97) 0 1 (0.67) 0 0 1 (0.67)   Both 0 1 (3.65) 0 0 1 (3.65) 0 1 (3.03) 1 (3.03) 0 2 (6.06)   Total 0 6 (2.65) 1 (0.44) 0 7 (3.10) 0 4 (1.63) 1 (0.41) 0 5 (2.04) Nagasaki Control   0 5 (4.15) 0 0 5 (4.15) 0 1 (0.60) 0 1 (0.60) 2 (1.21)   Exposed: Father 2 (3.68) 0 0 0 2 (3.68) 0 1 (1.61) 0 0 1 (1.61)   Mother 1 (1.10) 1 (1.10) 0 1 (1.10) 3 (3.29) 0 0 1 (0.89) 0 1 (0.89)   Both 0 0 0 0 0 0 0 0 0 0   Total 3 (1.81) 1 (0.60) 0 1 (0.60) 5 (3.02) 0 1 (0.51) 1 (0.51) 0 2 (1.02) Total Control   5 (1.36) 9 (2.44) 0 2 (0.54) 16 (4.35) 0 4 (0.93) 3 (0.70) 1 (0.23) 8 (1.86)   Exposed: Father 2 (1.69) 1 (0.85) 1 (0.85) 0 4 (3.39) 0 3 (2.38) 0 0 3 (2.38)   Mother 1 (0.44) 5 (2.21) 0 1 (0.44) 7 (3.10) 0 1 (0.38) 1 (0.38) 0 2 (0.77)   Both 0 1 (2.11) 0 0 1 (2.11) 0 1 (1.87) 1 (1.87) 0 2 (3.73)   Total 3 (0.77) 7 (1.79) 1 (0.26) 1 (0.26) 12 (3.07) 0 5 (1.13) 2 (0.45) 0 7 (1.59) Newborn infantsb   35 (0.93) 35 (0.93) 14 (0.37) 14 (0.37) 98 (2.59) 2 (0.10) 20 (1.04) 7 (0.37) 0 29 (1.51) No. of cases   37,779   19,173 a The rates for the sex chromosome abnormalities apply only to the affected sex. b Cited from Hook and Hamerton (1977).

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study anomaly cases. Except for mosaic situations, no female with 45,X was detected in any of the groups studied. When the data from the two cities were combined, there were no significant differences between the frequencies of sex chromosome abnormalities in the exposed group when compared to the controls. The frequency of mosaic cases was higher in females (2 in 4,408 exposed and 3 in 4,294 controls) than in males (1 in 3,914 exposed). Among the mosaics, there was a woman showing a mosaic of 45,X/46,X,r(X) in the Hiroshima controls. A family study revealed that the abnormality was identified as a de novo mutant since both parents showed the normal karyotype. There were three cases with structural rearrangements involving sex chromosomes, all of which belonged to the control group; two unrelated males, each with a pericentric inversion of the Y-chromosome in Hiroshima, and a female with a distally deleted long arm of one of the X-chromosomes in Nagasaki. One unusual observation was made in the Nagasaki series. A male child, born to an exposed mother, was found to have 46 chromosomes with two X-chromosomes (46,XX). 3.2.2 Autosomal Structural Rearrangements 3.2.2.1 Balanced. The majority of structural rearrangements involving autosomes were translocations of the Robertsonian or reciprocal types and pericentric inversions. They would, therefore, result in no loss or gain of chromosome material, and would be genetically balanced without any phenotypic effect. In the present study sample, there were occasionally two or more sibs in a family showing the identical karyotypic abnormality. Among these cases, there were ten children (seven D/D and three D/G) from eight families with Robertsonian translocations in the exposed group, and six children (all D/D) from three families with similar rearrangements in the controls. By the same token, there were seven children from five families in the exposed group, and 13 children from 12 families in the controls with reciprocal translocations. Only one child in the exposed, and six children from five families in the controls had inversions. An examination of Table 4 shows that an unusually high incidence of pericentric inversions was observed in the Hiroshima controls, and in Nagasaki a strikingly high rate of reciprocal translocations was observed in the controls, while no such cases were found in the exposed group. As shown in the Appendix Table, chromosomes 5 and 8 were found to be involved more frequently than the others in the formation of reciprocal translocations. Furthermore, there was a frequent involvement of a chromosome 2 in pericentric inversions in Hiroshima. In Table 5, pooled data on the frequencies of balanced structural rearrangements are tabulated in terms of the number of families in which they are observed as a function of total families included in the study. Although there is no significant difference in the frequencies of families with stable autosomal rearrangements, a relatively low frequency of rearrangements was observed in the exposed group in Nagasaki. The data

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Table 4. Frequency of F1 children with structural rearrangements (per 1,000)   Balanceda Unbalanceda   rob(D/D) rob (D/G) rcp inv Total rob rcp del supern other Total Hiroshima Control 4 (0.78) 0 6 (1.17) 6 (1.17) 16 (3.13) 0 0 0 0 0 0 Exposed:   Father 2 (1.57) 0 3 (2.35) 0 5 (3.92) 0 0 0 1 (0.78) 1 (0.78) 2 (1.57) Mother 3 (1.06) 1 (0.35) 2 (0.70) 1 (0.35) 7 (2.47) 0 0 0 0 1 (0.35) 1 (0.35) Both 0 0 2 (3.31) 0 2 (3.31) 0 0 0 0 0 0 Total 5 (1.06) 1 (0.21) 7 (1.48) 1 (0.21) 14 (2.97) 0 0 0 1 (0.21) 2 (0.42) 3 (0.64) Nagasaki Control 2 (0.70) 0 7 (2.44) 0 9 (3.14) 0 0 0 0 2 (0.70) 2 (0.70) Exposed:   Father 2 (1.72) 1 (0.86) 0 0 3 (2.57) 0 0 0 1 (0.86) 0 1 (0.86) Mother 0 0 0 0 0 0 0 0 0 1 (0.49) 1 (0.49) Both 0 1 (2.47) 0 0 1 (2.47) 0 0 0 0 0 0 Total 2 (0.55) 2 (0.55) 0 0 4 (1.11) 0 0 0 1 (0.28) 1 (0.28) 2 (0.55) Total Control 6 (0.75) 0 13 (1.63) 6 (0.75) 25 (3.13) 0 0 0 0 2 (0.25) 2 (0.25) Exposed:   Father 4 (1.64) 1 (0.41) 3 (1.23) 0 8 (3.28) 0 0 0 2 (0.82) 1 (0.41) 3 (1.23) Mother 3 (0.62) 1 (0.21) 2 (0.41) 1 (0.21) 7 (1.44) 0 0 0 0 2 (0.41) 2 (0.41) Both 0 1 (0.99) 2 (1.98) 0 3 (2.97) 0 0 0 0 0 0 Total 7 (0.84) 3 (0.36) 7 (0.84) 1 (0.12) 18 (2.16) 0 0 0 2 (0.24) 3 (0.36) 5 (0.60) Newborn infantsb (56,952) 40 (0.70) 11 (0.19) 51 (0.90) 8 (0.14) 110 (1.93) 4 (0.07) 7 (0.12) 5 (0.09) 10 (0.18) 8 (0.14) 34 (0.60) a Abbreviations: rob Robertsonian translocation; rcp reciprocal translocation; inv inversion; del deletion; supern supernumerary chromosome. b Cited from Hook and Hamerton (1977).

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Table 5. Frequency of autosomal structural rearrangements by parental couples City Groupa No. of parental couples No. of rearrangements Rate (×10-3) Hiroshima E 3453 11 3.19   C 4242 13 3.06   T 7695 24 3.12 Nagasaki E 2370 3 1.27   C 2231 7 3.14   T 4601 10 2.17 Combined E 5823 14 2.40   C 6473 20 3.09   T 12296 34 2.77 Neonatesb   59542 113 1.90 a Abbreviations: E exposed; C control; T total. b Cited from Jacobs (1981). were further compared with the frequencies of the same types of abnormalities derived from cytogenetic surveys on 59,542 consecutive newborn infants (Jacobs 1981). The results obtained in this study of both exposed and control groups were approximately 50% higher than that reported for neonatal surveys. Family studies of abnormal cases were undertaken to determine whether the observed structural rearrangements arose de novo or were inherited from one or the other parent (Table 6). Family studies in all cases were not possible because of death of parents, or because parents did not wish to cooperate in this study. When two or more sibs in a family were found to carry the identical rearrangement, however, their abnormalities were judged to be inherited, even though a family study may not have been done. The ample evidence indicates that the majority of cases with rearrangements are heritable. There were only two de novo mutants identified. Both mutants (one in the exposed and one in the control group) were seen in the Hiroshima group. None have been detected so far in Nagasaki. The gametic mutation rates on structural rearrangements derived from the combined data were estimated as 1.72×10-4 in the exposed group, and 1.40×10-4 in the controls, respectively. These values did not deviate significantly from the value of 1.88×10-4 per gamete per generation in the liveborn infant survey (Jacobs 1981) (see Addendum p. 178). 3.2.2.2 Unbalanced. There were seven abnormal cases which were placed in this category; five in the exposed and two in the controls. All of them were characterized by the presence of an extra-small metacentric element (or elements), termed as “mar” according to the standardized nomenclature system (ISCN 1978, 1981, 1985). The element (or elements) was present either as a “supernumerary” piece of chromosomal

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Table 6. Parental origin of balanced structural rearrangementsa   Hiroshimab Nagasakib H+Nb Neonatesc   E C E C E C   de novo 1 1 0 0 1 1 18 Inherited 5 5 1 5 6 10 73 Father 2 3 1 3 3 6 37 Mother 0 1 0 1 0 2 36 Undetermined 3 1 0 1 3 2 0 Total 6 6 1 5 7 11 91 Not studied 5 7 2 2 7 9 22 Mutation rate (×10-4) 2.65 2.55 — — 1.72 1.40 1.88 a Including reciprocal and Robertsonian translocations and pericentric inversions. b Abbreviations: E exposed; C control. c Cited from Jacobs (1981). material, in addition to the normal chromosome complement in all cells, or was in the form of a mosaic (Table 4, Appendix Table). Five of the cases were mosaics (three exposed and two controls). In one male observed in the Nagasaki controls, three extra minute elements, each of which differed in size and shape, existed as cell lines with different combinations of markers (Itoh et al. 1984). Family studies revealed that most of these abnormal cases of unbalanced type were found to arise as de novo mutants (see Appendix Table). 3.2.3 Autosomal Trisomics There was only one male Downs syndrome case (47,XY,+21) born in 1966 to an exposed father in Hiroshima, whose age at cytogenetic examination was 15. No other trisomic cases, such as D- and E-trisomy, have been observed in the F1 population. A summary of the overall frequencies of cases with abnormalities by parental exposure and by city is shown in Table 7. It can be seen that for sex chromosome abnormalities and structural rearrangements, the frequencies are consistently higher in the controls than in the exposed, and also higher in Hiroshima than in Nagasaki. Yet none of these differences are significantly different. The data from the two cities were combined, regardless of parental radiation exposure, and each of the frequencies was compared with that of corresponding abnormalities in the cytogenetic surveys on 56,952 consecutive liveborn infants (Hook and

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Hamerton 1977). Here again, the frequencies of both sex abnormalities and rearrangements were somewhat higher in the children included in this study as compared to the neonates. In contrast, the incidence of autosomal trisomics was strikingly decreased in our samples. Table 7. Frequency of cases with chromosome abnormalities in the F1 population (per 1,000)   Exposed Control Hiroshima Nagasaki Combined Neonatesa No. of cases 8,322 7,976 9,828 6,470 16,298 56,952 Abnormalities:   Sex chromosomes 2.28 3.01 2.95 2.16 2.64 2.23 Autosomal rearrangement   Balanced 2.16 3.13 3.05 2.01 2.64 1.93 Unbalanced 0.60 0.25 0.31 0.62 0.43 0.60 Autosomal trisomy 0.12 0 0.10 0 0.06 1.44 Total 5.17 (43) 6.39 (51) 6.41 (63) 4.79 (31) 5.77 (94) 6.20 (353) a Cited from Hook and Hamerton (1977). 3.2.3.1 Heteromorphic Variants. In the course of the present screening, there was a variety of heterochromatic variants as detected with the conventional staining method. Some of these cases were reanalyzed by the application of C-, Q-, and other banding techniques, and the results have been already reported elsewhere (Sofuni et al. 1978, 1980; Sofuni and Awa 1982). Of the heteromorphic variants observed, cases with inv(9p+q-), 1qh+, 9qh+, 16qh+, (C-band variants at the constitutive heterochromatic regions), Dp+, Gp+, Dps+, Gps+, DP-, Gp- (Q-band variants either deleted or enlarged satellites and/or short arms of acrocentric chromosomes) were identified with high frequency. 4 Discussion As mentioned previously, the main objective of this study was to demonstrate whether there is any measurable increase in the frequency of children with chromosome abnormalities that might be associated with A-bomb radiation exposure of parental germ-cell chromosomes. This cytogenetic evaluation was conducted by comparing the frequencies of children born to A-bomb survivors with chromosome abnormalities, especially structural rearrangements, with children born to nonexposed parents. The present results show that there are no statistically significant increases in the frequency of chromosome abnormalities among the children of the exposed. In fact, the frequency of both sex chromosome aneuploidy and structural rearrangements was higher in the controls than in the exposed.

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study This does not imply that genetic effects ascribable to parental A-bomb exposure have not occurred. It simply indicates that such effects have not been detectable by the current cytogenetic methods used. The reason for the absence of cytogenetic effects of A-bomb radiation on the children of the survivors remains unresolved. One of the possible interpretations is that germ cells with chromosome damage could have been eliminated either in the course of gametogenesis or in the very early period of gestation as “unrecognized” spontaneous abortions. Extensive cytogenetic surveys on consecutive liveborn infants, undertaken as international collaborative studies in several European and North American countries, have provided very useful and relevant information on the natural incidence of various types of constitutional chromosome abnormalities in the human population (Sergovich et al. 1969; Lubs and Ruddle 1970; Friedrich and Nielsen 1973; Jacobs et al. 1974; Hamerton et al. 1975; Nielsen and Sillesen 1975; Walzer and Gerald 1977; also refer to Hook and Hamerton 1977 for review). Cytogenetic data based on these surveys were compared with our present findings (Tables 2 to 4, and 7). It is apparent that the frequencies of both sex chromosome abnormalities and balanced rearrangements are slightly higher in our study than in the neonatal surveys. The situation is reversed when one compares unbalanced rearrangements and autosomal trisomics. It is known that most, but not all, situations where autosomal trisomy as well as unbalanced rearrangements are associated with physical malformations, are incompatible with life. Since the mean age of our study subjects was 24 years at examination, it is conceivable that most conceptions with these abnormalities do not survive for 2 or 3 decades even if they survived to term. Recently, attempts have been made to reevaluate cytogenetic surveys of neonates using banding techniques in order to obtain more precise information on the frequency of abnormalities associated with structural chromosomal changes in the general human population (Lin et al. 1976; Buckton et al. 1980; Hansteen et al. 1982; Nielsen et al. 1982). The results obtained in such studies are discordant. Some studies indicated an increase in the frequency of reciprocal translocations (Hansteen et al. 1982), and inversions (Hansteen et al. 1982; Nielsen et al. 1982), or an increase in the Q-band variants (Lin et al. 1976). In contrast, the frequency of all types of chromosome abnormalities detected when G-banding techniques were used have been found to be similar to that observed previously when conventional stain preparations were used (Buckton et al. 1980). In our experience, there seemed to be no difference in the detectability of structural rearrangements between conventional stain and G- and Q-banding methods, although the latter were found to be more efficient in detecting heteromorphic variants than the conventional method. Maeda et al. (1978) reported the results of a cytogenetic survey on 2,626 consecutive liveborn infants in Japan. They found nine cases with sex chromosome abnormalities (0.30%) and ten autosomal abnormalities, including five with Robertsonian translocation of the balanced type (0.19%), one with 13-trisomy associated with Robertsonian translocation (0.04%), one with a supernumerary marker (0.04%), and three with 21-trisomy (0.11%). Although the sample size of this survey was rather small, the results agreed to-a certain extent with our findings with respect to the frequency of sex chromosome abnormalities and types and patterns of autosomal abnormalities.

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Table 8. Frequency of autosomal structural rearrangements City Groupa No. of children No. of rearrangements Rate (×10-3) Hiroshima E 4716 14 2.97   C 5112 16 3.13   T 9828 30 3.05 Nagasaki E 3606 4 1.11   C 2864 9 3.14   T 6470 13 2.01 Combined E 8322 18 2.16   C 7976 25 3.13   T 16298 43 2.64 Neonatesb   59542 113 1.90 a Abbreviations: E exposed; C control; T total. b Cited from Jacobs (1981). The origin and cytogenetic features of an additional marker chromosome, often designated as a supernumerary chromosome, have been studied extensively (refer to Buckton et al. 1985). This marker chromosome is chracterized by a small metacentric element. Often it has a satellite (or satellites) at one or both distal ends. With regard to the presence of cases in the F1 carrying such a marker, it was interesting to observe that (1) the supernumerary was seen in all cells or existed in the form of a mosaic, and (2) the majority of the supernumeraries were do novo mutants without any phenotypic change. This finding led to the presumption that the origin of the markers in our cases might arise from a product of a Robertsonian translocation between the short arms of the D- and G-chromosomes. There has been discrepancy concerning a possible association between maternal radiation and trisomy-21 (Uchida et al. 1961; Schull and Neel 1962; Uchida 1977). In the A-bomb exposed population, Schull and Neel (1962) reported that the frequency of children with Down syndrome born to exposed mothers (fathers not exposed) was 0.54 per 1,000 (3 in 5,579), and 1.27 per 1,000 (12 in 9,440) in children born to nonexposed mothers. These results suggest that no association exists between Down syndrome and maternal radiation. The present results do not indicate an increase in children with 21-trisomy or aneuploidy involving any other chromosome. Finally, when the new A-bomb radiation dosimetry system (DS86) becomes available for estimating the dose for individual survivors, the present data will be reanalyzed to determine the relationship between the frequency of chromosome abnormalities observed in children as a function of parental gonadal dose.

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Table 9. Parental origin of balanced structural rearrangementsa   Hiroshima Nagasaki H+N Neonatesb   E C E C E C   de novo 1 1 0 0 1 1 18 Inherited 8 8 2 7 10 15 73 Father 2 4 2 4 4 8 37 Mother 0 1 0 1 0 2 36 Undetermined 6 3 0 2 6 5 0 Total 9 9 2 7 11 16 91 (Not studied) (5) (7) (2) (2) (7) (9) (22) Gametic mutation rate (×10-4) 1.65 1.74 — — 0.98 0.98 1.88 a Including reciprocal and Robertsonian translocations plus pericentric inversions. b Cited from Jacobs (1981). Abbreviations: E exposed; C control; H Hiroshima; N Nagasaki. Addendum. In the test, we computed the gametic mutation rates of structural rearrangements of balanced type in our population in terms of the frequency of families with abnormality as a function of total families studied. However, it seems more appropriate to estimate the chromosomal mutation rate using the following formula: For the gametic mutation rate, the value derived from the above formula is further divided by 2 (Jacobs 1981). The gametic mutation rates on structural rearrangements derived from the combined data in Tables 8 and 9 were estimated as 0.98×10-4 in the exposed, and 0.98×10-4 in the controls, respectively. These values were much lower than the value of 1.88×10-4 per gamete per generation in the liveborn infant survey (Jacobs 1981). Acknowledgments. We are grateful to the Hiroshima and Nagasaki citizens for their willingness to voluntarily participate in this survey. Without their cooperation this study would not have been possible. Our thanks are due also to the following RERF staff members for their continued support throughout this survey: Drs. M.Otake and S.Fujita, Department of Statistics, Dr. Y.Shimizu, Department of Epidemiology, for sample selection and statistical advices; Drs. T.Amano, M.Soda, R.Hazama, and their associaes in the Nursing Section, Department of Clinical Studies, for their clinical assistance; public health nurses and clinical contactors in the Department of Research Support who obtained consent of the participants and arrangements for their visit to RERF. We are very much indebted to Messrs. S.Iida, K.Tanabe, Mrs. Y.Urakawa, and their colleagues in the Cytogenetics Laboratories in Hiroshima and Nagasaki for their continued technical support including blood cultures, chromosome preparations, microscope and karyotype analysis, and photographic works. We wish to thank Dr. C.W.Edington, Vice-Chairman of RERF, for his encouragement and for going through the manuscript.

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study References Awa AA ( 1975) Review of thirty years study of Hiroshima and Nagasaki atomic bomb survivors. II Biological effect. B Genetic effects. 2 Cytogenetic study. J Radiat Res16 (Suppl): 75–81 Awa AA, Bloom AD, Yoshida MC, Neriishi S, Archer PG ( 1968) Cytogenetic study of the offspring of atom bomb survivors. Nature (London)218:367–368 Awa AA, Sofuni T, Honda T, Itoh M, Neriishi S, Otake M ( 1978) Relationship between the radiation dose and chromosome aberrations in atomic bomb survivors of Hiroshima and Nagasaki. J Radiat Res19:126–140 Buckton KE, O'Riordan ML, Ratcliffe S, Slight J, Mitchell M, McBeath S, Keay AJ, Barr D, Short M ( 1980) A G-band study of chromosome in liveborn infants. Ann Human Genet43:227–239 Buckton KE, Spowart G, Newton MS, Evans HJ ( 1985) Forty four probands with an additional “marker” chromosome. Human Genet69:353–370 Caspersson T, Lomakka G, Zech L ( 1971) The 24 fluorescence pattern of the human metaphase chromosomes—distinguishing characters and variability. Hereditas67:89–102 Friedrich U, Nielsen J ( 1973) Chromosome studies in 5,049 consecutive newborn children. Clin Genet4:333–343 Hamerton JL, Canning N, Ray M, Smith S ( 1975) A Cytogenetic survey of 14069 newborn infants. I Incidence of chromosome abnormalities. Clin Genet8:223–243 Handsteen I-L, Varslot K, Steen-Johnsen, Langard S ( 1982) Cytogenetic screening of a newborn population. Clin Genet21:309–314 Hook EB, Hamerton JL ( 1977) The frequency of chromosome abnormalities detected in consecutive newborn studies—differences between studies—results by sex and by severity of phenotypic involvement. In: Hook EB, Porter IH (eds) Population cytogenetics—Studies in humans. Academic Press, London New York, pp 63–79 ISCN ( 1978) An international system for human Cytogenetic nomenclature (1978) In: Lindsten JE, Klinger HP, Hamerton JL (eds) Birth defects: original article series, vol 14 (8). Natl Found, New York; also in: Cytogenet Cell Genet21:309–404 ISCN ( 1981) An international system for human Cytogenetic nomenclature (1981) High resolution banding. In: Harnden DG, Lindsten JE, Buckton KE, Klinger HP (eds) Birth defects: original article series, vol 17 (5). March of Dimes, Birth Defects Found, New York; also in: Cytogenet Cell Genet31:1–28 ISCN ( 1985) An international system for human Cytogenetic nomenclature (1985) In: Harnden DG, Klinger HP (eds) published in collaboration with Cytogenet Cell Genet ( Karger, Basel 1985); also in: Birth defects: original article series, vol 21 (1). March of Dimes Birth Defects Found , New York Itoh M, Soda M, Honda T ( 1984) Unstable behavior and mosaicism of extra minute chromosome in man . Nagasaki Med J59:441–445 Jacobs PA ( 1981) Mutation rates of structural chromosome rearrangements in man. Am J Human Genet33:44–54 Jacobs PA, Melville M, Ratcliffe S, Keay AJ, Syme J ( 1974) A Cytogenetic survey of 11680 newborn infants. Ann Human Genet37:359–376 Kato H, Schull WJ, Neel JV ( 1966) A cohort-type study of survival in the children of parents exposed to atomic bombings. Am J Human Genet18:339–373 Lin CC, Gedeon MM, Griffith P, Smink WK, Newton DR, Wilkie L, Sewell LM ( 1976) Chromosome analysis on 930 consecutive newborn children using quinacrine fluorescent banding technique. Human Genet31:315–328 Lubs HA, Ruddle FH ( 1970) Chromosomal abnormalities in the human population: Estimation of rates based on New Haven newborn study. Science169:495–497 Maeda T, Ono M, Takada M, Kato Y, Nishida M, Jobo T, Adachi H, Taguchi A ( 1978) A cytogenetic survey of consecutive liveborn infants—incidence and type of chromosome abnormalities. Jpn J Hum Genet23:217–224 Milton RC, Shohoji T ( 1968) Tentative 1965 radiation dose (T65D) estimation for atomic bomb survivors ; Hiroshima and Nagasaki. ABCC Teech Rep1–68

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Nielsen J, Sillesen I ( 1975) Incidence of chromosome aberrations among 11148 newborn children. Humangenetik30:1–12 Nielsen J, Wohlert M, Faaborg-Andersen J, Hansen KB, Hvidman L, Klag-Olsen B, Moulvad I, Videbech P ( 1982) Incidence of chromosome abnormalities in newborn children. Comparison between incidences in 1969–1974 and 1980–1982 in the same area. Human Genet61:98–101 Pai GS, Thomas GH ( 1980) A new R-banding technique in clinical cytogenetics. Human Genet54: 41–45 RERF Research Protocol ( 1975) Research plan for RERF studies of the potential genetic effects of atomic radiation; Hiroshima and Nagasaki. RERF RP 4–75 Schull WJ, Neel JV ( 1962) Maternal radiation and mongolism. Lancet1:537–538 Seabright M ( 1971) A rapid banding technique for human chromosomes. Lancet2:971–972 Sergovich FR, Valentine GH, Chen ATL, Kinch RAH, Smout MS ( 1969) Chromosome aberrations in 2159 consecutive newborn babies. New Engl J Med280:851–855 Sofuni T, Awa AA ( 1982) Chromosome heteromorphisms in the Japanese. III Frequency of C-band variants. RERF Tech Rep4–82 Sofuni T, Tanabe K, Awa AA ( 1978) Chromosome heteromorphisms in the Japanese. I Banding patterns of Dp+ and Gp+ by Q- and C-staining methods. RERF Tech Rep8–78 Sofuni T, Tanabe K, Awa AA ( 1980) Chromosome heteromorphisms in the Japanese. II Nucleolus organizer regions of variant chromosomes in D and G groups. Human Genet55:265–270 Sumner AT ( 1972) A simple technique for demonstrating centromeric heterochromatin. Exp Cell Res75:304–306 Uchida IA ( 1977) Maternal radiation and trisomy 21. In: Hook EB, Porter IH (eds) Population cytogenetics—Studies in humans. Academic Press, London New York, pp 285–299 1st US-Japan joint Worksh Reassessment of atomic bomb radiation dosimetry in Hiroshima and Nagasaki. Radiation Effects Research Foundation, Hiroshima, 1983 2nd US-Japan joint Worksh Reassessment of atomic bomb radiation dosimetry in Hiroshima and Nagasaki. Radiation Effects Research Foundation, Hiroshima, 1984 Walzer S, Gerald PS ( 1977) A chromosome survey of 13751 male newborns. In: Hook EB, Porter IH (eds) Population cytogenetics—studies in humans. Academic Press, London New York, pp 45–61 Yunis JJ, Sawyer JR, Ball DW ( 1978) The characterization of high resolution G banded chromosomes of man . Chromosoma67:293–307

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study Appendix Table. Family studies of abnormal cases of the unbalanced type   Age at birth   Case No. Sex Age ATE Year of birth Mo Fa Exposure status Type of abnormality Remarks   Hiroshima   FH3321 M 28 1948 32 38 C A1. 47,XYY   FH4305 M 22 1956 30 38 C ” ”   FH4998 M 29 1949 25 29 C ” ”   FH7308 M 17 1964 28 32 C ” ”   FH9913 M 15 1969 25 27 C ” ”   FH0757 M 17 1953 26 34 Mo A2. 47,XXY   FH0801 M 22 1948 23 27 Fa ” ”   FH0815 M 13 1957 31 48 B ” ”   FH4223 M 22 1956 34 31 Mo ” ”   FH4727 M 29 1949 33 38 Mo ” ”   FH5953 M 26 1953 21 24 C ” ”   FH6415 M 30 1950 32 40 C ” ”   FH6662 M 28 1952 27 31 C ” ”   FH8632 M 24 1958 24 28 Mo ” ”   FH8718 M 33 1949 35 41 C ” ”   FH8454 M 17 1965 25 30 Fa A3. 46,XY/47,XYY 46:48 cells, 47:152 cells FH6505 M 24 1956 32 38 C A4. 46,X,inv(Y)(p11.2q11.2)   FH7417 M 23 1958 33 31 C ” 46,X,inv(Y)(p11.2q11.23)pat   FH0492 F 21 1948 25 29 Fa A6. 47,XXX   FH1870 F 15 1957 34 33 B ” ”   FH3886 F 30 1947 25 27 C ” ”   FH5852 F 21 1958 30 36 Mo ” ”   FH8291 F 24 1958 23 27 Fa ” ” F2: one (liveborn) FH8912 F 16 1967 37 39 C ” ” Sib (dizygotic co-twin)—normal FH9339 F 15 1967 28 30 C ” ”   FH0092 F 18 1949 33 36 B A7. 45,X/47,XXX 45:95 cells, 47:4 cells FH3033 F 22 1954 33 38 C ” ” 45:82 cells, 47:15 cells FH8020 F 24 1957 24 28 C ” ” 45:44 cells, 47:49 cells. F2 :one (liveborn), also pregnant at examination FH8590 F 33 1948 25 38 C ” 45,X/46,X,r(x)§ §de novo mutant. 45:141 cells, 46:59 cells

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study   Age at birth   Case No. Sex Age ATE Year of birth Mo Fa Exposure status Type of abnormality Remarks FH0381 M 18 1951 21 30 Fa B1. 45,XY,t(DqDq)     FH1988 F 16 1956 27 32 Mo ” 45,XX,t(DqDq) Sibs FH2443 F 21 1952 23 28 Mo ” 45,XX, ”     FH4989 M 28 1951 29 39 Mo ” 45,XY,t(13q14q)     FH6456 M 30 1949 24 27 C ” 45,XY,t(13q14q) Sibs FH6664 F 29 1951 26 29 C ” 45,XX, ”     FH6757 F 26 1954 29 32 C ” 45,XX, ”     FH6538 F 30 1950 20 23 C ” 45,XX,t(14q15q)     FH8096 F 16 1966 30 35 Fa ” 45,XX,t(13q14q)     FH3496 F 22 1954 26 34 Mo B2. 45,XX,t(14q21q)     FH0405 F 18 1951 29 43 Fa B3. 46,XX,t(5;11)(q13;p15) Sibs FH8076 M 33 1949 27 41 Fa ” 46,XY, ”     FH2209 F 26 1947 34 36 B ” 46,XX,t(5;17)(p13;q25)§   §de novo mutant FH2210 F 26 1947 23 29 B ” 46,XX,t(5;8)(q22;p11.2)pat     FH2690 M 17 1957 23 27 Fa ” 46,XY,t(5;8)(q22;p11.2)pat     FH4493 M 29 1949 32 34 C ” 46,XY,t(6;12)(q15;q22)     FH4595 M 23 1955 27 30 C ” 46,XY,t(1;6)(q21;p21)     FH6611 F 29 1951 27 32 Mo ” 46,XX,t(3;8)(q21;q24.1) Sibs FH6771 M 26 1954 30 35 Mo ” 46,XY,     FH7342 F 32 1949 27 36 C ” 46,XX,t(12;13)(q21.32;p12.3)§   §de novo mutant FH9219 M 25 1957 25 31 C B3. 46,XY,t(5;7)(q15;p21)pat     FH9876 F 13 1970 29 30 C ” 46,XX,t(5;8)(q22;p11.2)pat     FH9922 M 13 1971 25 30 C ” 46,XY,t(6;8)(q13;q22)     FH1705 F 25 1946 34 35 C B4. 46,XX,inv(2p+q—)     FH5672 M 32 1947 27 32 C ” 46,XY,inv(18)(p11.32q11.2)mat     FH6099 M 27 1953 27 38 Mo ” 46,XY,inv(2)(p11.2q13)     FH7331 F 16 1964 27 33 C ” 46,XX,inv(2)(p11.2q13)pat Sibs FH7333 F 14 1966 29 34 C ” 46,XX, ”     FH9118 M 35 1948 39 45 C ” 46,XY;inv(2)(p11.2q14.2)     FH9254 M 34 1949 27 34 C ” 46,XY,inv(5)(p15.3q13)     FH7361 F 24 1957 24 25 Fa B8. 47,XX,+mar*§ (*minute)   §de novo mutant. F2 :one (liveborn) FH6169 F 23 1956 28 28 Mo B9. 46,XX/47,XX,+mar* (*minute)   46:9 cells, 47:91 cells FH8980 M 14 1969 25 28 Fa ” 46,XY,del(18)(p11.1)/46,XY,i(18q)   del(18p): 181 cells, i(18q): 7 cells FH7594 M 15 1966 25 25 Fa C1. 47,XY,+21§   §de novo mutant

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THE CHILDREN OF ATOMIC BOMB SURVIVORS: A Genetic Study   Nagasaki   FN0217 M 13 1956 37 33 Mo A1. 47,XYY     FN0486 M 21 1948 30 35 Fa ” ”     FN0970 M 19 1951 26 28 Fa ” ”     FN1717 M 26 1948 31 39 C A2. 47,XXY     FN2696 M 18 1957 27 27 C ” ”     FN4025 M 30 1948 27 31 Mo ” ”     FN4171 M 25 1953 22 19 C ” ”     FN4317 M 28 1951 40 45 C ” ”     FN6865 M 14 1970 25 29 C ” ”     FN3338 M 21 1956 25 30 Mo A4. 46,XX   [XX male] FN3252 F 22 1955 24 27 Fa A6. 47,XXX     FN4237 F 31 1947 20 24 C ” ”     FN2120 F 18 1956 26 24 Mo A7. 46,XX/47,XXX   46:3 cells, 47:96 cells FN3202 F 21 1956 33 37 C A8. 46,XXq-     FN4935 F 32 1948 32 46 C B1. 45,XX,t(13q14q)pat Sibs FN4936 F 28 1952 36 50 C ” 45,XX,     FN5837 M 13 1969 32 34 Fa ” 45,XY,t(13q14q)pat Sibs FN5859 F 17 1965 29 31 Fa ”45,XX,     FN0870 M 18 1952 23 31 B B2. 45,XY,t(DqGq)     FN6530 F 14 1969 29 36 Fa ” 45,XX,t(14q21q)     FN1638 M 24 1950 21 22 C B3. 46,XY,t(Cq-;17q+)pat     FN3068 F 28 1948 40 44 C ” 46,XX,t(18q+;20q-)     FN3948 M 21 1957 33 41 C ” 46,XY,t(1p–;12q+)mat     FN4419 F 32 1947 22 28 C ” 46,XX,t(2p–;8p+) Sibs FN4891 F 31 1949 24 30 C ” 46,XX,     FN4724 M 29 1951 24 29 C ” 46,XY,t(Bq–;Cq+)pat     FN5049 F 29 1951 28 35 C ” 46,XX,t(2q–;13q+)     FN2357 F 26 1949 23 46 Fa B8. 47,XX,+mar* mat (*minute)     FN3990 M 22 1957 40 37 C B9. 46,XY/47,XY,+mar*§ (*minute)   §de novo mutant. 46:18 cells, 47:31 cells FN4121 M 30 1948 20 29 Mo ” 46,XY/47,XY,+mar*§ (*minute)   §de novo mutant. 46:21 cells, 47:9 cells FN6023 M 31 1951 23 24 C ” 46,XY/47,XY,+mar/48,XY,+mar×2§   §de novo mutant. Complex mosaic consisting of cell lines with 2 or 3 different minute markers of varying combinations. [Abbreviations] ATE: At the time of examination. Age at birth: Parental age. Mo: Mother. Fa: Father. Exposure status: B-Both parents exposed. Fa=Father exposed. Mo-Mother exposed. C=Control.

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