Am J Hum Genet 28:208-212, 1976
A Large Pericentric Inversion of Human Chromosome 8 RIITTA HERVA1
AND
ALBERT
DE LA
CHAPELLE2
INTRODUCTION
Pericentric inversions in human chromosomes have been recognized with increasing frequency [1]. Although most inversion carriers are phenotypically normal, a number of unanswered questions still exist. What is the incidence and distribution of inversions in the human population? Are the break points randomly or preferentially distributed between and within chromosomes? What are the phenotypic consequences in terms of chromosomally unbalanced offspring and fetal wastage? Thorough reporting of human inversions may help investigators answer these questions. This paper reports a previously undescribed type of pericentric inversion of chromosome 8 and its segregation. METHODS
Chromosome investigations were carried out by lymphocyte culture. In addition to conventionally stained cells, G-banded [2] and Q-banded mitoses [3] were studied. Over 20 metaphases per subject were analyzed. CLINICAL AND FAMILY DATA
The proposita was referred to a gynecology clinic for investigation following two spontaneous abortions; she had no children. Karyotypes prepared from her leukocytes and those of her husband [4] revealed an inversion in the husband. The family (fig. 1) was then investigated further. The proposita (III-6) was born in 1947 and her husband (III-5) in 1950; they were married in 1971. She had spontaneous abortions in 1972 and 1973. During the course of this investigation there were two further abortions, one in 1974 and another in 1975. All four miscarriages occurred in the ninth-tenth week of gestation. Histological examination disclosed normally developed placental tissue, but no fetal remnants. Cytogenetic investigation of the aborted material, therefore, could not be performed. Detailed clinical investigation failed to disclose any cause of the abortions. The proband and her husband were normal. The husband asserted that he had a child by another woman conceived before his marriage with the proband. This child could not be approached for paternity check. A study of the husband's sperm was normal. Chromosome investigation of the available family members showed that the inversion occurred in three of the husband's four sibs and in his father. His grandparents and his Received September 18, 1975; revised December 29, 1975. This work was supported by grants from the Finnish National Research Council for Medical Sciences and the Sigrid Jus6lius Foundation. 1 Department of Pathology, University of Oulu, Oulu, Finland. 2Folkhiilsan Institute of Genetics, Helsinki, Finland. @ 1976 by the American Society of Human Genetics. All rights reserved.
208
PERICENTRIC INVERSION OF CHROMOSOME NO. 8 1
1
INVERSION HETEROZYGOTE
2
TM
|N 1 4
3
ill
1
2
-V
1
2
3
209
NORMAL KARYOTYPE MISCARRIAGE
5
N 6
4
1
N7
8
13
FIG. 1.-Pedigree of the family
only paternal aunt (II-1), who had had no children, were dead. His only paternal uncle (II-3), who was unmarried, did not have the inversion. Two older sibs of the husband had the inversion; they were both married, and each had at least one child with the inversion. The younger sibs (III-7 and III-8) were unmarried. No members of the families of the proposita or her husband had any recognized congenital abnormalities. The proposita had three sisters and three brothers. Spontaneous abortions had not occurred in either family. CYTOGENETIC DATA
The inverted chromosome no. 8 was acrocentric but the same length as its homologue (fig. 2). In the short arm, breakage had occurred in band p1I close to the centromere, and in the long arm, in the distal band q24. This had produced an acrocentric chromosome with a tiny lightly staining (G banding) short arm and a long arm consisting proximally of the normal long arm and distally of the material normally situated in the short arm (i.e., bands p12, p21, p22, and p23, respectively). The inversion can be written inv(8)(pl1q24). All other chromosomes were normal. A diagrammatic representation of the inversion is given in figure 3. DISCUSSION
We know of at least three descriptions of inversions in chromosome 8 which have produced an abnormal acrocentric chromosome. In a family described by FergusonSmith [5], the inversion was seen in the mother and grandmother of three malformed children. An unbalanced karyotype was postulated in the third child, but this occurred before the banding era and could not be proved. M. A. FergusonSmith (personal communication, 1975) informed us that the inversion he ascribed to chromosome 10 should now be classified as a chromosome 8 inversion. In addition, banding studies of the mother's karyotype indicate that the inversion is in fact inv(8) (p23ql 1) which suggests that the malformed child was unlikely to have had an unbalanced karyotype due to a single crossover event within the inversion. An identical inversion occurred in seven other unrelated Scottish families (K. E.
210
HERVA AND DE LA CHAPELLE
FIG. 2.-Trypsin-G-banded karyotype prepared from the proband's husband (III-5). Inverted no. 8 is to the right of its normal homologue.
FiG. 3.-Diagram of normal no. 8 (left) and its inverted homologue (right). Arrows indicate points of breakage.
PERICENTRIC INVERSION OF CHROMOSOME NO. 8
211
Buckton, personal communication, 1975). Three of these have been described in detail [6]; the break points (p23ql 1) have also been reported [7]. The inversion in these eight Scottish families appeared to be identical to the one described by us when conventional staining is used. However, banding discloses that they were entirely dissimilar; the Scottish type comprised most of the short and very little of the long arm, while the Finnish one involved little of the short but virtually all of the long arm. Thus, comparisons should not be made between structural rearrangements unless they are adequately defined. Moreover, it seems that the type of inversion so common in Scotland is not necessarily widespread elsewhere. An inversion 8 producing an acrocentric chromosome has been described but not further specified [8]. In a familial pericentric inv(8) recently reported [9], the break points (p23q22) are nearly equidistant from the centromere and hence do not cause a clear-cut alteration in the position of the centromere. Such inversions must have been overlooked during the prebanding era and could occur in many chromosomes [1, 10]. The frequency of some of them, such as inv(9), may be very high, perhaps as great as 17o in the general population [1]; even higher frequencies have been proposed [11]. The true incidence can be determined only after adequate banding techniques have been applied to large population samples. It is uncertain whether the inversion described in this report has had any clinical consequences. Heterozygotes for the inversion are themselves phenotypically normal; both male and female carriers are fertile and have not produced chromosomally unbalanced offspring. It is uncertain, therefore, whether the four consecutive abortions sustained by the proband are related to her husband's inversion. The proband was examined and her husband's inversion detected because patients with repeated miscarriages are routinely karyotyped at the clinical unit in question. We have shown previously that the great majority of such patients have normal karyotypes; a causal association with a segregating reciprocal (7; 14) translocation found in a family of one patient could not be established [12]. In view of the ascertainment bias, an association between the proband's abortions and her husband's inv(8) is unlikely when the spouses of other male carriers (II-4 and III-2) have not had abortions. We conclude that in the present family the inversion does not have any obvious consequences for carriers; it is even doubtful whether it is related to the proband's miscarriages. If it were, we hypothesize that additional deleterious factors would have to be present in the proband's husband but not in his father. This inversion resembles other pericentric inversions seen in our laboratories [1] and by others [6, 13, 14]; such inversions may be regarded as examples of structural chromosomal polymorphism that do not cause infertility. Finally, because the inversion described by us is large, the length of the inverted segment is not necessarily related to its potential for clinical consequences. SUMMARY
A large pericentric inversion, inv(8) (pllq24), was ascertained in a male investigated because his wife had had repeated miscarriages. The inversion segregated in
212
HERVA AND DE LA CHAPELLE
3 generations of the family, and no chromosomally unbalanced offspring were detected. The miscarriages and the inversion could not be causally related. REFERENCES 1.
CHAPELLE A, SCHR6DER J, STENSTRAND K, FELLMAN J, HERVA R, SAARNI M, ANTTOLAINEN I, TALLILA I, TERVILX L, HUSA L, TALLQVIST G, ROBSON EB, COOK PJL, SANGER R: Pericentric inversions of human chromosomes 9 and 10. Am J Hum
DE LA
Genet 26:746-766, 1974 2. SEABRIGHT M: A rapid banding technique for human chromosomes. Lancet 2:971-
972, 1971 3. CASPERSSON T, ZECH L, JOHANSSON C, MODEST EJ: Identification of human chromosomes by DNA-binding fluorescent agents. Chromosoma 30:215-227, 1970 4. JARVINEN PA, KOKKONEN J: Etiology and treatment of failed pregnancies. Int J Fertil 17:81-85, 1972 5. FERGUSON-SMITH MA: Clinical cytogenetics, in Proceedings 3d International Con6. 7.
8. 9.
10. 11. 12. 13. 14.
gress of Human Genetics, Chicago, 1966, edited by CROW JF, NEEL JV, Baltimore, Johns Hopkins Press, 1967, pp 69-75 JACOBS PA, CRUICKSHANK G, FAED MJW, ROBSON EB, HARRIS H, SUTHERLAND I: Pericentric inversion of a group C autosome: a study of three families. Ann Hum Genet 31 :219-230, 1967 JACOBS PA, BUCKTON KE, CUNNINGHAM C, NEWTON M: An analysis of the break points of structural rearrangements in man. J Med Genet 11:50-64, 1974 BREG WR, ALLDERDICE PW, MILLER DA, MILLER OJ: Quinacrine fluorescence patterns and terminal DNA labelling of human C group chromosomes. Nature [New Biol] 236:76-78, 1972 FUJIMOTO A, WILSON MG, TOWNER JW: Familial inversion of chromosome no. 8. An affected child and a carrier fetus. Humangenetik 27:67-73, 1975 LEONARD C, HAZEL-MASSIEUX P. BOCQUET L, LARGET-PIET L, BOUE J: Inversion pericentrique inv(2)(plq13) dans des familles non apparentees. Humangenetik 28: 121-128, 1975 MCKENZIE WH, LUBs HA: Human Q and C chromosomal variations: distribution and incidence. Cytogenet Cell Genet 14:97-115, 1975 DE LA CHAPELLE A, SCHRODER J, KOKKONEN J: Cytogenetics of recurrent abortion or unsuccessful pregnancy. Int J Fertil 18:215-219, 1973 BHASIN MK, FOERSTER W, FUHRMANN W: A cytogenetic study of recurrent abortion. Humangenetik 18:139-148, 1973 BETZ A, TURLEAU C, DE GROUCHY J: Heterozygotie et homozygotie pour une inversion pericentrique du 3 humain. Ann Genet (Paris) 17:77-80, 1974
A Large Pericentric Inversion of Human Chromosome 8 RIITTA HERVA1
AND
ALBERT
DE LA
CHAPELLE2
INTRODUCTION
Pericentric inversions in human chromosomes have been recognized with increasing frequency [1]. Although most inversion carriers are phenotypically normal, a number of unanswered questions still exist. What is the incidence and distribution of inversions in the human population? Are the break points randomly or preferentially distributed between and within chromosomes? What are the phenotypic consequences in terms of chromosomally unbalanced offspring and fetal wastage? Thorough reporting of human inversions may help investigators answer these questions. This paper reports a previously undescribed type of pericentric inversion of chromosome 8 and its segregation. METHODS
Chromosome investigations were carried out by lymphocyte culture. In addition to conventionally stained cells, G-banded [2] and Q-banded mitoses [3] were studied. Over 20 metaphases per subject were analyzed. CLINICAL AND FAMILY DATA
The proposita was referred to a gynecology clinic for investigation following two spontaneous abortions; she had no children. Karyotypes prepared from her leukocytes and those of her husband [4] revealed an inversion in the husband. The family (fig. 1) was then investigated further. The proposita (III-6) was born in 1947 and her husband (III-5) in 1950; they were married in 1971. She had spontaneous abortions in 1972 and 1973. During the course of this investigation there were two further abortions, one in 1974 and another in 1975. All four miscarriages occurred in the ninth-tenth week of gestation. Histological examination disclosed normally developed placental tissue, but no fetal remnants. Cytogenetic investigation of the aborted material, therefore, could not be performed. Detailed clinical investigation failed to disclose any cause of the abortions. The proband and her husband were normal. The husband asserted that he had a child by another woman conceived before his marriage with the proband. This child could not be approached for paternity check. A study of the husband's sperm was normal. Chromosome investigation of the available family members showed that the inversion occurred in three of the husband's four sibs and in his father. His grandparents and his Received September 18, 1975; revised December 29, 1975. This work was supported by grants from the Finnish National Research Council for Medical Sciences and the Sigrid Jus6lius Foundation. 1 Department of Pathology, University of Oulu, Oulu, Finland. 2Folkhiilsan Institute of Genetics, Helsinki, Finland. @ 1976 by the American Society of Human Genetics. All rights reserved.
208
PERICENTRIC INVERSION OF CHROMOSOME NO. 8 1
1
INVERSION HETEROZYGOTE
2
TM
|N 1 4
3
ill
1
2
-V
1
2
3
209
NORMAL KARYOTYPE MISCARRIAGE
5
N 6
4
1
N7
8
13
FIG. 1.-Pedigree of the family
only paternal aunt (II-1), who had had no children, were dead. His only paternal uncle (II-3), who was unmarried, did not have the inversion. Two older sibs of the husband had the inversion; they were both married, and each had at least one child with the inversion. The younger sibs (III-7 and III-8) were unmarried. No members of the families of the proposita or her husband had any recognized congenital abnormalities. The proposita had three sisters and three brothers. Spontaneous abortions had not occurred in either family. CYTOGENETIC DATA
The inverted chromosome no. 8 was acrocentric but the same length as its homologue (fig. 2). In the short arm, breakage had occurred in band p1I close to the centromere, and in the long arm, in the distal band q24. This had produced an acrocentric chromosome with a tiny lightly staining (G banding) short arm and a long arm consisting proximally of the normal long arm and distally of the material normally situated in the short arm (i.e., bands p12, p21, p22, and p23, respectively). The inversion can be written inv(8)(pl1q24). All other chromosomes were normal. A diagrammatic representation of the inversion is given in figure 3. DISCUSSION
We know of at least three descriptions of inversions in chromosome 8 which have produced an abnormal acrocentric chromosome. In a family described by FergusonSmith [5], the inversion was seen in the mother and grandmother of three malformed children. An unbalanced karyotype was postulated in the third child, but this occurred before the banding era and could not be proved. M. A. FergusonSmith (personal communication, 1975) informed us that the inversion he ascribed to chromosome 10 should now be classified as a chromosome 8 inversion. In addition, banding studies of the mother's karyotype indicate that the inversion is in fact inv(8) (p23ql 1) which suggests that the malformed child was unlikely to have had an unbalanced karyotype due to a single crossover event within the inversion. An identical inversion occurred in seven other unrelated Scottish families (K. E.
210
HERVA AND DE LA CHAPELLE
FIG. 2.-Trypsin-G-banded karyotype prepared from the proband's husband (III-5). Inverted no. 8 is to the right of its normal homologue.
FiG. 3.-Diagram of normal no. 8 (left) and its inverted homologue (right). Arrows indicate points of breakage.
PERICENTRIC INVERSION OF CHROMOSOME NO. 8
211
Buckton, personal communication, 1975). Three of these have been described in detail [6]; the break points (p23ql 1) have also been reported [7]. The inversion in these eight Scottish families appeared to be identical to the one described by us when conventional staining is used. However, banding discloses that they were entirely dissimilar; the Scottish type comprised most of the short and very little of the long arm, while the Finnish one involved little of the short but virtually all of the long arm. Thus, comparisons should not be made between structural rearrangements unless they are adequately defined. Moreover, it seems that the type of inversion so common in Scotland is not necessarily widespread elsewhere. An inversion 8 producing an acrocentric chromosome has been described but not further specified [8]. In a familial pericentric inv(8) recently reported [9], the break points (p23q22) are nearly equidistant from the centromere and hence do not cause a clear-cut alteration in the position of the centromere. Such inversions must have been overlooked during the prebanding era and could occur in many chromosomes [1, 10]. The frequency of some of them, such as inv(9), may be very high, perhaps as great as 17o in the general population [1]; even higher frequencies have been proposed [11]. The true incidence can be determined only after adequate banding techniques have been applied to large population samples. It is uncertain whether the inversion described in this report has had any clinical consequences. Heterozygotes for the inversion are themselves phenotypically normal; both male and female carriers are fertile and have not produced chromosomally unbalanced offspring. It is uncertain, therefore, whether the four consecutive abortions sustained by the proband are related to her husband's inversion. The proband was examined and her husband's inversion detected because patients with repeated miscarriages are routinely karyotyped at the clinical unit in question. We have shown previously that the great majority of such patients have normal karyotypes; a causal association with a segregating reciprocal (7; 14) translocation found in a family of one patient could not be established [12]. In view of the ascertainment bias, an association between the proband's abortions and her husband's inv(8) is unlikely when the spouses of other male carriers (II-4 and III-2) have not had abortions. We conclude that in the present family the inversion does not have any obvious consequences for carriers; it is even doubtful whether it is related to the proband's miscarriages. If it were, we hypothesize that additional deleterious factors would have to be present in the proband's husband but not in his father. This inversion resembles other pericentric inversions seen in our laboratories [1] and by others [6, 13, 14]; such inversions may be regarded as examples of structural chromosomal polymorphism that do not cause infertility. Finally, because the inversion described by us is large, the length of the inverted segment is not necessarily related to its potential for clinical consequences. SUMMARY
A large pericentric inversion, inv(8) (pllq24), was ascertained in a male investigated because his wife had had repeated miscarriages. The inversion segregated in
212
HERVA AND DE LA CHAPELLE
3 generations of the family, and no chromosomally unbalanced offspring were detected. The miscarriages and the inversion could not be causally related. REFERENCES 1.
CHAPELLE A, SCHR6DER J, STENSTRAND K, FELLMAN J, HERVA R, SAARNI M, ANTTOLAINEN I, TALLILA I, TERVILX L, HUSA L, TALLQVIST G, ROBSON EB, COOK PJL, SANGER R: Pericentric inversions of human chromosomes 9 and 10. Am J Hum
DE LA
Genet 26:746-766, 1974 2. SEABRIGHT M: A rapid banding technique for human chromosomes. Lancet 2:971-
972, 1971 3. CASPERSSON T, ZECH L, JOHANSSON C, MODEST EJ: Identification of human chromosomes by DNA-binding fluorescent agents. Chromosoma 30:215-227, 1970 4. JARVINEN PA, KOKKONEN J: Etiology and treatment of failed pregnancies. Int J Fertil 17:81-85, 1972 5. FERGUSON-SMITH MA: Clinical cytogenetics, in Proceedings 3d International Con6. 7.
8. 9.
10. 11. 12. 13. 14.
gress of Human Genetics, Chicago, 1966, edited by CROW JF, NEEL JV, Baltimore, Johns Hopkins Press, 1967, pp 69-75 JACOBS PA, CRUICKSHANK G, FAED MJW, ROBSON EB, HARRIS H, SUTHERLAND I: Pericentric inversion of a group C autosome: a study of three families. Ann Hum Genet 31 :219-230, 1967 JACOBS PA, BUCKTON KE, CUNNINGHAM C, NEWTON M: An analysis of the break points of structural rearrangements in man. J Med Genet 11:50-64, 1974 BREG WR, ALLDERDICE PW, MILLER DA, MILLER OJ: Quinacrine fluorescence patterns and terminal DNA labelling of human C group chromosomes. Nature [New Biol] 236:76-78, 1972 FUJIMOTO A, WILSON MG, TOWNER JW: Familial inversion of chromosome no. 8. An affected child and a carrier fetus. Humangenetik 27:67-73, 1975 LEONARD C, HAZEL-MASSIEUX P. BOCQUET L, LARGET-PIET L, BOUE J: Inversion pericentrique inv(2)(plq13) dans des familles non apparentees. Humangenetik 28: 121-128, 1975 MCKENZIE WH, LUBs HA: Human Q and C chromosomal variations: distribution and incidence. Cytogenet Cell Genet 14:97-115, 1975 DE LA CHAPELLE A, SCHRODER J, KOKKONEN J: Cytogenetics of recurrent abortion or unsuccessful pregnancy. Int J Fertil 18:215-219, 1973 BHASIN MK, FOERSTER W, FUHRMANN W: A cytogenetic study of recurrent abortion. Humangenetik 18:139-148, 1973 BETZ A, TURLEAU C, DE GROUCHY J: Heterozygotie et homozygotie pour une inversion pericentrique du 3 humain. Ann Genet (Paris) 17:77-80, 1974
