Editorial A CLOSER LOOK AT CHROMOSOMAL INVERSIONS
Human genetics once had the reputation of being inordinately concerned with rare, esoteric, untreatable diseases. A similar attitude is sometimes seen in the dismissal of the rare cytogenetic phenomena observable in human populations. It is now appreciated that inversions in humans are not uncommon but only rarely contribute to disorders. These generalizations are consistent with the expanding body of published evidence resulting from wide use of chromosome banding techniques. This view of inversions as polymorphisms which seldom cause clinical defects needs confirmation, and more importantly, any exceptions need to be precisely clarified. Two papers which appear in this issue are noteworthy, not for the novelty of findings, but because they represent the present state of our understanding of inversions [1, 2]. Inversion incidence as high as 1%o [3, 4] and even 2.8% [5] have been reported; however prebanding studies yielded rates as low as .007%0 [6]. Further studies of large unselected populations may place these new results in better perspective. Jacobs et al. [7] state: "There is no data relating to the reproductive fitness of a substantial body of individuals with either an inversion or an extreme variant. It is clear that much more data, collected in a systematic and unbiased way, on . . . [this] . . . will be necessary before their effect can be established
with precision." Although the ability to detect and characterize inversions exists, limitations or bias of the techniques may not be fully appreciated at present. Even with banding, there is a preponderance of pericentric inversions over paracentrics. While this may be based on biological factors, it probably reflects a technical limitation. Only nine bands define the long arm of chromosome no. 7, and less than half of all chromosome arms of the human karyotype are of a similar or greater length. Thus detection of paracentric inversions is now possible but difficult. The highly preferential involvement of chromosome no. 9 in the inversions observed so far is widely confirmed and unlikely to be related to artifact. A concentration of inversion polymorphisms within one chromosome is not uncommon, occurring in certain Drosophila species. With the exceptions of position effect and partial infertility, there is no theoretical basis for an inversion affecting the phenotype of the carrier. In published reports on inversions, however, ascertainment of a carrier is most frequently because of clinical defects in the individual or near relatives. Further, doubt may exist as to cytological interpretation; is one dealing with a subtle duplication-deficiency chromosome rather than the inversion? In the study by Vine et al. [1] the exclusion of any intrinsic clinical significance for homozygosity and for heterozygosity per se is conclusive. The clinically abnormal propositus, an inversion homozygote 294
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of a no. 9 pericentric inversion, has a brother with a similar constellation of defects, although this brother is a heterozygote. A final nicety is that a sister of the propositus is free of any physical defect but is also heterozygous for the inversion. For a particular pericentric inversion only two types of recombinants can result from any uneven number of crossovers within the inversion. Each of the two products will be characteristic, both for phenotype and morphology of the recombinant chromosome. Evidence from the few reports which do correlate inversion heterozygosity with progeny maldevelopment and an unbalanced chromosome have been most convincing. A unique duplication-deficiency chromosome 3 syndrome was described by comparing similar anomalies in several children; in all of these children, only one of the two possible recombinants was present [8]. The general likelihood of duplication-deficiency being compatible with life may be extremely low and thus account for the rarity of such classic examples. An estimate of 26%o sperm carrying either of the two types of duplication-deficiency chromatids was made using C banding and an ingenious approach to interpretation of diakinesis figures in material from a pericentric no. 4 inversion [9]. Inversion heterozygosity should produce considerable infertility, but generally this has not been seen. Herva and de la Chapelle [2] conclude that the apparent infertility of their propositus is only coincidental with the fact that the husband of the propositus is heterozygous for a large pericentric inversion of no. 8. The propositus had four spontaneous abortions in 5 years, each at 9 to 10 weeks gestation, yet all male and female carriers were evidently fertile and phenotypically normal. Reports in which an association between infertility and inversion was found are few. In one study, [10] nine unrelated families with the same pericentric 9 inversion showed reduced fertility, but none of several affected progeny were recombinants. That the aneusomic products arising from this inversion are invariably arrested so early in development that fertilization is unrecognized is suggested, and alternatively it is speculated that some property of the inverted constitutive heterochromatin of the 9qh region interferes with normal development or with local crossing over [10]. Apart from a possible relation to preferential sites of breakreunion, an understanding of the significance of specialized regions, such as lqh, 9qh, 16qh, would have important implications for clinical cytogenetics. One is somewhat uncomfortable in assigning no significance for fetal development to the presence of a "variant" chromosome. Apropos of this Schinzel et al. [11] and Bowen et al. [12] each have reported a case of lymphocyte mosaicism for trisomy 9 in a malformed infant who had inherited a maternal pericentric inversion. The inversion in each case had one break point in the 9qh region and in both children the trisomic cells had two inverted 9's. Nondisjunctional events associated with inversions have very rarely been reported, and considering the frequency of inversion, they may be coincidental. Knowledge of the particulars of human meiosis is obviously essential for understanding the clinical implications of structural rearrangements. Extrapolations based on other organisms may be faulted by differences in spindle mechanisms. In
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Chironomus the number of inversion loops at meiosis in heterozygotes is regularly less than the number formed in the polytene chromosomes. In Drosphila there is no crossing over in males and dicentric formation in paracentric inversion recombination causes a spindle orientation which excludes abnormals from the progeny. Happily the correspondence between human pachytene chromomere patterns and the major mitotic chromosome bands provides an independent means for confirming interpretation of meiotic configurations. We remain dependent on tables of empiric risk in dealing with prognosis for human inversion, as with other structural rearrangements. An inherent problem is that inversions are treated as an homogenous class. New findings on human cytogenetic mechanisms and their variations may provide the discrimination needed. PAUL S. MOORHEAD
University of Pennsylvania
Philadelphia REFERENCES 1. VINE DT, YARKONI S, COHEN MM: Inversion homozygosity of chromosome no. 9 in a highly inbred kindred. Am J Hum Genet 28:203-207, 1976 2. HERVA R, DE LA CHAPELLE A: A large pericentric inversion of human chromosome 8. Am J Hum Genet 28:208-212, 1976 3. DE LA CHAPELLE A, SCHR6DER J, STENSTRAND K, FELLMAN J, HERVA R, SAARNI M, ANTTOLAINEN I, TALLILA I, TERVILX L, HuSA L, TALLQVIST PJL, SANGER R: Pericentric inversions of human chromosomes 9 and 10. Am J Hum Genet 26:746-766, 1974 4. MCKENZIE WH, LUBs HA: Q and C chromosomal variations: distribution and incidence. Cytogenet Cell Genet 14:97-115, 1975 5. MADAN K, BOBROW M: Structural variation in chromosome 9. Ann Genet (Paris) 17:81-86, 1974 6. DUTRILLAUX B: Les aberrations chromosomiques transmissibles. J Parisiennes Pediatr, 1972, pp 13-21 7. JACOBS P, FRAcKIEwIcz A, LAW P, HILDITCH CJ, MORTON NE: The effect of structural aberrations of the chromosomes on reproductive fitness in man. II. Results. Clin Genet 8:169-178, 1975 8. ALLDERDICE PW, BROWNE M, MURPHY DP: Chromosome 3 duplication q21 -* qter deletion p25 -- pter syndrome in children of carriers of a pericentric inversion inv(3) (p25q21). Am J Hum Genet 27:699-718, 1975 9. VAN DER LINDEN AGJ, PEARSON PL, VAN DE KAMP JJP: Cytological assessment of meiotic exchange in a human male with pericentric inversion of chromosome no. 4. Cytogenet Cell Genet 14:126-139, 1975 10. BoUt J, TAILLEMITE JC, HAZAEL-MASSIEUX P, LEONARD C, BOUt A: Association of pericentric inversion of chromosome 9 and reproductive failure in ten unrelated families. Humangenetik 30:217-224, 1975 11. SCHNIZEL A, HAYASHI K, SCHMID W: Mosaic-trisomy and pericentric inversion of chromosome 9 in a malformed boy. Humangenetik 25:171-177, 1974 12. BOWEN P, YING KL, CHUNG GSH: Trisomy 9 mosaicism in a newborn infant with multiple malformations. J Pediatr 85:95-97, 1974 13. MARTIN J: Meiosis in inversion heterozygotes in Chironomidae. Can J Genet Cytol 9:255-268, 1967
Human genetics once had the reputation of being inordinately concerned with rare, esoteric, untreatable diseases. A similar attitude is sometimes seen in the dismissal of the rare cytogenetic phenomena observable in human populations. It is now appreciated that inversions in humans are not uncommon but only rarely contribute to disorders. These generalizations are consistent with the expanding body of published evidence resulting from wide use of chromosome banding techniques. This view of inversions as polymorphisms which seldom cause clinical defects needs confirmation, and more importantly, any exceptions need to be precisely clarified. Two papers which appear in this issue are noteworthy, not for the novelty of findings, but because they represent the present state of our understanding of inversions [1, 2]. Inversion incidence as high as 1%o [3, 4] and even 2.8% [5] have been reported; however prebanding studies yielded rates as low as .007%0 [6]. Further studies of large unselected populations may place these new results in better perspective. Jacobs et al. [7] state: "There is no data relating to the reproductive fitness of a substantial body of individuals with either an inversion or an extreme variant. It is clear that much more data, collected in a systematic and unbiased way, on . . . [this] . . . will be necessary before their effect can be established
with precision." Although the ability to detect and characterize inversions exists, limitations or bias of the techniques may not be fully appreciated at present. Even with banding, there is a preponderance of pericentric inversions over paracentrics. While this may be based on biological factors, it probably reflects a technical limitation. Only nine bands define the long arm of chromosome no. 7, and less than half of all chromosome arms of the human karyotype are of a similar or greater length. Thus detection of paracentric inversions is now possible but difficult. The highly preferential involvement of chromosome no. 9 in the inversions observed so far is widely confirmed and unlikely to be related to artifact. A concentration of inversion polymorphisms within one chromosome is not uncommon, occurring in certain Drosophila species. With the exceptions of position effect and partial infertility, there is no theoretical basis for an inversion affecting the phenotype of the carrier. In published reports on inversions, however, ascertainment of a carrier is most frequently because of clinical defects in the individual or near relatives. Further, doubt may exist as to cytological interpretation; is one dealing with a subtle duplication-deficiency chromosome rather than the inversion? In the study by Vine et al. [1] the exclusion of any intrinsic clinical significance for homozygosity and for heterozygosity per se is conclusive. The clinically abnormal propositus, an inversion homozygote 294
EDITORIAL
295
of a no. 9 pericentric inversion, has a brother with a similar constellation of defects, although this brother is a heterozygote. A final nicety is that a sister of the propositus is free of any physical defect but is also heterozygous for the inversion. For a particular pericentric inversion only two types of recombinants can result from any uneven number of crossovers within the inversion. Each of the two products will be characteristic, both for phenotype and morphology of the recombinant chromosome. Evidence from the few reports which do correlate inversion heterozygosity with progeny maldevelopment and an unbalanced chromosome have been most convincing. A unique duplication-deficiency chromosome 3 syndrome was described by comparing similar anomalies in several children; in all of these children, only one of the two possible recombinants was present [8]. The general likelihood of duplication-deficiency being compatible with life may be extremely low and thus account for the rarity of such classic examples. An estimate of 26%o sperm carrying either of the two types of duplication-deficiency chromatids was made using C banding and an ingenious approach to interpretation of diakinesis figures in material from a pericentric no. 4 inversion [9]. Inversion heterozygosity should produce considerable infertility, but generally this has not been seen. Herva and de la Chapelle [2] conclude that the apparent infertility of their propositus is only coincidental with the fact that the husband of the propositus is heterozygous for a large pericentric inversion of no. 8. The propositus had four spontaneous abortions in 5 years, each at 9 to 10 weeks gestation, yet all male and female carriers were evidently fertile and phenotypically normal. Reports in which an association between infertility and inversion was found are few. In one study, [10] nine unrelated families with the same pericentric 9 inversion showed reduced fertility, but none of several affected progeny were recombinants. That the aneusomic products arising from this inversion are invariably arrested so early in development that fertilization is unrecognized is suggested, and alternatively it is speculated that some property of the inverted constitutive heterochromatin of the 9qh region interferes with normal development or with local crossing over [10]. Apart from a possible relation to preferential sites of breakreunion, an understanding of the significance of specialized regions, such as lqh, 9qh, 16qh, would have important implications for clinical cytogenetics. One is somewhat uncomfortable in assigning no significance for fetal development to the presence of a "variant" chromosome. Apropos of this Schinzel et al. [11] and Bowen et al. [12] each have reported a case of lymphocyte mosaicism for trisomy 9 in a malformed infant who had inherited a maternal pericentric inversion. The inversion in each case had one break point in the 9qh region and in both children the trisomic cells had two inverted 9's. Nondisjunctional events associated with inversions have very rarely been reported, and considering the frequency of inversion, they may be coincidental. Knowledge of the particulars of human meiosis is obviously essential for understanding the clinical implications of structural rearrangements. Extrapolations based on other organisms may be faulted by differences in spindle mechanisms. In
EDITORIAL
296
Chironomus the number of inversion loops at meiosis in heterozygotes is regularly less than the number formed in the polytene chromosomes. In Drosphila there is no crossing over in males and dicentric formation in paracentric inversion recombination causes a spindle orientation which excludes abnormals from the progeny. Happily the correspondence between human pachytene chromomere patterns and the major mitotic chromosome bands provides an independent means for confirming interpretation of meiotic configurations. We remain dependent on tables of empiric risk in dealing with prognosis for human inversion, as with other structural rearrangements. An inherent problem is that inversions are treated as an homogenous class. New findings on human cytogenetic mechanisms and their variations may provide the discrimination needed. PAUL S. MOORHEAD
University of Pennsylvania
Philadelphia REFERENCES 1. VINE DT, YARKONI S, COHEN MM: Inversion homozygosity of chromosome no. 9 in a highly inbred kindred. Am J Hum Genet 28:203-207, 1976 2. HERVA R, DE LA CHAPELLE A: A large pericentric inversion of human chromosome 8. Am J Hum Genet 28:208-212, 1976 3. DE LA CHAPELLE A, SCHR6DER J, STENSTRAND K, FELLMAN J, HERVA R, SAARNI M, ANTTOLAINEN I, TALLILA I, TERVILX L, HuSA L, TALLQVIST PJL, SANGER R: Pericentric inversions of human chromosomes 9 and 10. Am J Hum Genet 26:746-766, 1974 4. MCKENZIE WH, LUBs HA: Q and C chromosomal variations: distribution and incidence. Cytogenet Cell Genet 14:97-115, 1975 5. MADAN K, BOBROW M: Structural variation in chromosome 9. Ann Genet (Paris) 17:81-86, 1974 6. DUTRILLAUX B: Les aberrations chromosomiques transmissibles. J Parisiennes Pediatr, 1972, pp 13-21 7. JACOBS P, FRAcKIEwIcz A, LAW P, HILDITCH CJ, MORTON NE: The effect of structural aberrations of the chromosomes on reproductive fitness in man. II. Results. Clin Genet 8:169-178, 1975 8. ALLDERDICE PW, BROWNE M, MURPHY DP: Chromosome 3 duplication q21 -* qter deletion p25 -- pter syndrome in children of carriers of a pericentric inversion inv(3) (p25q21). Am J Hum Genet 27:699-718, 1975 9. VAN DER LINDEN AGJ, PEARSON PL, VAN DE KAMP JJP: Cytological assessment of meiotic exchange in a human male with pericentric inversion of chromosome no. 4. Cytogenet Cell Genet 14:126-139, 1975 10. BoUt J, TAILLEMITE JC, HAZAEL-MASSIEUX P, LEONARD C, BOUt A: Association of pericentric inversion of chromosome 9 and reproductive failure in ten unrelated families. Humangenetik 30:217-224, 1975 11. SCHNIZEL A, HAYASHI K, SCHMID W: Mosaic-trisomy and pericentric inversion of chromosome 9 in a malformed boy. Humangenetik 25:171-177, 1974 12. BOWEN P, YING KL, CHUNG GSH: Trisomy 9 mosaicism in a newborn infant with multiple malformations. J Pediatr 85:95-97, 1974 13. MARTIN J: Meiosis in inversion heterozygotes in Chironomidae. Can J Genet Cytol 9:255-268, 1967
