pericentric inversion in human chromosome 1 and the risk ... · journal of medical genetics 1987,...

Journal of Medical Genetics 1987, 24, 325-334

Pericentric inversion in human chromosome 1and the risk for male sterilityANN C CHANDLEY, S McBEATH, R M SPEED, L YORSTON, ANDT B HARGREAVE*From the MRC Clinical and Population Cytogenetics Unit; and *University of Edinburgh, Department ofSurgery (Urology), Western General Hospital, Edinburgh EH4 2XU.

SUMMARY A pericentric inversion in chromosome 1 of a severely oligospermic human male isreported. Pachytene analysis in microspread preparations shows an absence of full loopformation in the inversion bivalent and only the rare occurrence of a partial loop. The majority ofcells exhibit extensive asynapsis across the inverted segment, or a normal looking synaptonemalcomplex indicative of heterologous pairing along the length of the inversion. Crossing over isreduced in the No 1 bivalent with only a rare chiasma being seen in the inverted region atmetaphase I. Males heterozygous for a pericentric inversion in chromosome 1 appear to beat severe risk for infertility brought about by spermatogenic disturbance. The dearth of full loopsat prophase in this patient, and in other pericentric inversion cases studied both in man and otherspecies, raises the question of whether recombinant offspring might be rarer than anticipated on atheoretical basis owing to asynapsis or early heterologous synapsis across inverted segments.

An extensive search of human cytogenetic publica-tions since 1970 has revealed 20 published cases ofpericentric inversion in chromosome 1, of whichnine have been found in adult males. Of these, eighthave been ascertained through male sterility withassociated oligo- or azoospermia (table 1).Ascertainment of pericentric inversions in man in

general is not made through male sterility but by thebirth of a child with congenital malformations orspontaneous abortion resulting from a duplication-deficiency product from the carrier parent.Pericentric inversion in chromosome 1 thus appearsto carry a special risk for male infertility throughspermatogenic impairment, and this holds trueregardless of breakpoint positioning.A further case of pericentric inversion in chromo-

some 1 is now reported in an oligospermic man.Meiotic analyses at prophase and metaphase I showsevere disruption of pairing in the inversion bivalenttogether with associated synaptic disturbance inother members of the complement. The reportcorroborates and extends previous meiotic analysesmade on human male inversion 1 heterozygotes.

Received for publication 26 January 1987.Accepted for publication 30 February 1987.

Case report

Patient WSM 213, aged 31 years, was referred to themale infertility clinic of the Western General Hos-pital, Edinburgh, in November 1985. He and hiswife had been trying for a child for the last 18months of a five year marriage. He was phenotypi-cally normal. No abnormality which might accountfor the failure to conceive could be traced to hiswife. Tests indicated spontaneous regular ovulationand normal tubal patency and anatomy.

PHYSICAL EXAMINATIONThe patient's height was 177 cm and weight 73-5 kg.The testes were small (mean volume 14 cc, normalrange for Caucasians 15 to 45 cc), but the penis andscrotum were normal. A small varicocele waspresent on the left side.

SEMINAL ANALYSISTwo semen samples, analysed in the autumn of1985, showed severe oligospermia. The best samplegave a count of 1x 106 per ml and a motility of 80%normal.

HORMONE INVESTIGATIONS

Raised levels of LH and FSH were recorded: LH325

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Pericentric inversion in human chromosome I and the risk for male sterility

11-8 U/i (normal range 1 to 6-5 U/i), FSH 6-4 U/i(normal range 1 to 6 U/i). Testosterone (27-2 ng/ml)was within the normal range (10 to 30 ng/ml).

TESTICULAR HISTOLOGYA testicular biopsy was taken from the right side inApril 1986. The seminiferous tubules were ofnormal diameter and no thickening of the tunicapropria was seen. Spermatogenic activity was pre-sent in all tubules, but there was a deficiency ofspermatids and a severe paucity of spermatozoa inthe lumina. Leydig cells were well represented andthere were no inflammatory or vascular abnormali-ties.

CYTOGENETIC METHODSConventional techniques were used to perform asomatic chromosome analysis on blood lymphocytesof WSM 213, cells being prepared by G and Cbanding techniques.8 9 Analysis at meiotic meta-phase I (MI) was carried out on air dried cells,"'stained with carbol fuchsin," or by C banding.'2Microspread preparations of prophase spermato-cytes were made according to methods previouslydescribed'3 and examined at electron microscope(EM) level.

Results

BLOOD LYMPHOCYTE ANALYSISA total of 10 G banded cells showed WSM 213to have a large pericentric inversion in chromo-some 1, with breakpoints at p31 and q43 (fig la).C banding showed the changed position of thelarge centromeric block of heterochromatin in theabnormal chromosome (fig lb). A repeat bloodsample taken at the time of the testicular biopsyconfirmed the above findings. The inversion is

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shown diagrammatically in fig 2. The karyotype is46,XY,inv(1)(p31q43).

AIR DRIED MEIOTIC ANALYSISAnalysis of 329 dividing cells in the carbol fuchsinstained testicular suspension gave a distributioncount of: spermatogonial mitosis (16%), MI (78%),MIT (6%). This indicated an arrest in developmentfor many spermatocytes between the first andsecond meiotic divisions. Severe degenerativechanges affected a high proportion of MI cells, but atotal of 65 healthy cells in this stage was found in ascan of six slides. More than half (39/65 or 60%)showed failure of X and Y attachment, one of thesecells also showing a pair of small autosomal univa-lents. A further cell, with attached sex chromo-somes, showed three small pairs of autosomalunivalents. This indicates a high degree of synapticdisturbance in the non-inverted portion of thegenome. Autosomal univalents are usually extreme-ly rare in human male meiotic material,'4 15 while Xand Y univalents are found with a mean frequencyof about 20% in our material.'5 Chiasma counts for20 cells gave a mean of 55-2 (range 47 to 63) per cell,a figure within the normal range.Although it was not always possible to identify

unambiguously the inversion bivalent in the carbolfuchsin preparations, about two-thirds of the 65 MI

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divisions scanned did show a large bivalent whichlacked chiasmata over an extensive interstitial seg-ment (fig 3a). This was interpreted as the No 1bivalent. A single cell showed total failure ofchiasma formation over a large segment whichresulted in a bivalent held together by chiasmata atonly one end, the arms freely diverging at the other(fig 3b). Pale gaps in this bivalent indicated thepericentromeric regions, these being seen to lie inasymmetrical positions across the bivalent, as ex-pected for an inversion. Unequivocal evidence ofasymmetrical positioning of the centromeres in theinversion bivalent was obtained, however, from theC banded preparations (fig 3c). A total of 19 MIdivisions was analysed over four thoroughly scannedC banded slides. Chiasma counts for the inversion

bivalent showed them to have two chiasmata (n=8),three chiasmata (n=9), or four chiasmata (n=2).The mean chiasmata frequency for the inversionbivalent was 2*68 compared with a normal mean of3 90 for the normal No 1 bivalent. 14 Only in one cell(fig 3d) was evidence found of chiasma formationwithin the inverted segment of bivalent No 1.

MEIOTIC PROPHASE ANALYSIS BY

MICROSPREADINGA total of 122 spread prophase cells was found on 23grids examined at EM level. A high proportion(55/122 or 45%) showed changes in the synapto-nemal complexes (SC) indicative of degeneration,principle features being fragmentation of the axes orpairing disturbance or both over a major part of the

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complement (fig 4). For the remaining 67 healthylooking prophases, the results of the SC analysis aregiven in table 2. Each cell was classified according toXY pairing stage, by the scheme of Solari,16 whichrecognises six prophase stages (types O-V). It wasobvious that few cells with paired sex chromosomeaxes had progressed beyond early pachytene, onlythree cells being classified as types III and IV (latepachytene) and none being classed as type V(diplotene). In normal meiotic preparations ap-proximately 65% of all prophase spermatocytes areusually found among the types III to V categories. 13For 21 cells showing separated X and Y axes (31-3%of the total analysed), thickening and condensation

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of the sex chromosome axes was a characteristicfeature, as previously noted.'3 The recorded inci-dence of separated X and Y axes in normal prophasematerial prepared by spreading in our laboratory is0.9% .13 Asynapsis affecting both the autosomes andsex pair at prophase of meiosis was thus a markedfeature of the inversion heterozygote.For the majority of prophase cells, no problem

was encountered in recognising one long anomalousSC which was interpreted as corresponding to theinversion bivalent. In general, this showed a regionof moderate to extensive interstitial asynapsis whichwas complete (fig 5a) or with a twist in the axes (figSb), suggestive in some cells of an attempt to initiatesynapsis at one point (fig Sc). The twists, however,were seen somewhat randomly positioned along theunpaired segment, sometimes being closer to thelonger paired distal SC (interpreted as homolo-gously paired distal lp) (for example, fig Sb), and atother times being closer to the shorter paired distalsegment of lq (for example, fig Sc). Configurationsof this type were recorded in 50-7% of all cells andare classified in table 2 under category A. Thicken-ing and the presence of excrescences characterisedthe unpaired lateral elements. In fig Sd, an exampleis shown of asynapsis extending not only over theinverted segment, but also to the telomeres of onearm. This produced two extensive and free lyinglateral elements. A total of 11/67 cells (16.4%)belonged in this, category B (table 2). It is probablethat a prophase configuration of this type couldprogress to the kind of MI cell shown in fig 3b,chiasma formation being restricted to one distallypaired segment, probably being the longer distal lp.This, however, was the only MI cell out of 65

TABLE 2 Prophase analysis by microspreading. Classification of cells (n=67) by XY pairing stage and inversionconfiguration.

XY type* Prophase stage A B C D E F Totalcells

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or c SCs

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-diploteneX+Y, 4 6 5 3 () O 3 21% 5(0-7 16-4 11-9 1-5 3-0 16-4

Total no of cells analysed=67

*Classification of Solari.t(tX and Y present as separated axes.

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analysed to be seen in the air dried preparations,suggesting selective elimination of the majority ofsuch cells between pachytene and MI.

Fig 6a, b, and c shows representative cells incategories C, D, and E, respectively. In category Ccells (11-9%), synapsis had occurred at the approxi-mate midpoint of the inversion, the flanking axes

remaining, however, asynapsed (fig 6a). A singlecell in category D showed total asynapsis over thedistal segments (fig 6b). The cell in fig 6c (categoryE) was one of only two cells in which loop formationhad been achieved, but even in these cells the loopwas incompletely formed and segments of asynapsisremained. No evidence of association between theinversion bivalent and XY bivalent was found in anycell.

Finally, it was noted that 16-4% of all prophasecells analysed showed normal looking SCs with no

hint of the inversion bivalent (fig 7) (category F).Such cells must be presumed to have undergonenon-homologous pairing along the inverted segmentof chromosome 1. According to XY type, they were

distributed across zygotene and all pachytene stagesand were not exclusively seen at the late pachytenestage to which heterolo ous 'adjusted' synapsis isthought to be confined.

Discussion

Our pericentric inversion chromosome 1 wouldappear to be behaving at prophase of meiosis in a

similar way to those described by Gabriel-Robez eta15 and Batanian and Hult6n.7 Extensive disturb-ance of synapsis across the inverted region is seenin most cells, with complete loop formation beingachieved in only a minority. The inversion in our

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o.FIG 7 EM spread at late pachytene in which all synaptonemal complexes appear normal.

patient remains asynapsed along most of its length ina high proportion of prophase cells, with extensiveasynapsis even surrounding those segments whichhave managed to achieve partial loop formation.Chiasma frequency at MI is reduced for the inver-sion bivalent as a whole, crossing over and chiasmaformation being rare within the inverted segmentitself. The combined prophase observations ofasynapsis and heterologous synapsis across theinversion seen in cells as early as the zygotene stagewould account for this lack of crossing over.

Since testicular biopsies for meiotic chromosomeanalysis are usually obtained from infertility pa-tients, studies in human pericentric inversion casesare limited. Nevertheless, where a pachytene analy-sis has previously been made, albeit mostly on airdried preparations which give only limited resolu-tion, the occurrence of loops has been reported tobe 'frequent' in a case of inversion 4,18 but 'rare' or

'absent' for individual cases of inversion 7,19 inver-sion 3,2() and inversion 13.21 Moreover, the rarity offull loop formation in pericentric inversions ofanimals, although based only on a limited number ofspecies, has been noted for the sand rat (Psam-

momys obesus),22 deer mouse (Peromyscusmaniculatus23 and Peromyscus sitkensis24), anddomestic fowl (Gallus domesticus).25 Studies madein the deer mouse23 24 and fowl25 show the vastmajority of cells forming normal looking SCs overthe whole genome, the inversions having pairedheterologously over their entire lengths. The generalassumption made on classical grounds, that loopsare invariably present at meiotic prophase in inver-sion heterozygotes, would thus seem to be chal-lenged by these observations. The clinical implica-tions of loop formation versus lack of loops areextremely important in man, for only when loopsare formed can crossing over within an inversiontake place. Extensive asynapsis or early hetero-synapsis in an inversion bivalent would obviouslyminimise the opportunities for exchange and theproduction of recombinant offspring. The problemof genetic counselling of inversion carriers andestimation of risks have been considered by anumber of authors in the past'8 19 26 27 and somegeneral predictions have been made concerning theprobability for exchange within the loop formed byan inverted segment, for example, depending on

332

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absolute size of the inversion,27 or its occurrence in amale or female carrier.'8 26 27 Rarely, however, hasconsideration been given to the possibility that loopsmay not be formed or may not be complete atmeiotic prophase, when crossing over is expected tooccur. To date, no meiotic studies have been madeon oocytes of human female inversion hetero-zygotes, but the general dearth of evidence for loopformation in males should clearly be taken intoaccount when risk figures are being estimated.Recombinant offspring may well be rarer thanexpected. Further investigations at meiosis in car-riers are required before a complete assessment ofthe situation with regard to pairing across invertedregions can be made.The question of how and why a pericentric

inversion in chromosome 1 in man should lead tosterility of the male carrier has been discussedelsewhere.7 The disturbance in spermatogenesis hasbeen suggested principally to arise out of theasynapsis observed, not only within the inversionbivalent itself, but also in other members of thecomplement, these perhaps arising as a secondaryconsequence of the primary anomaly. The pairingproblem in the No 1 bivalent could arise initially outof the large heterochromatic blocks on proximal lq,such blocks tending to delay or inhibit synapsis inmeiotic cells. 16 28 Thus, the male sterilising effects ofchromosome 1 inversions in the human male couldbe accommodated on models which link germ cellmaturation impairment to failure of synapsis.29 30The survival of some germ cells in our patient maybe related to the ability of a proportion of cells toestablish heterologous pairing across the length ofthe inversion. We have noted that cells with anextensive region of asynapsis along most of the No 1axis at meiotic prophase (category B cells) are rarelyto be found at the MI stage, and this could indicateelimination of such cell types from the germ line.Similarly, cells with unpaired X and Y axes, withunpaired autosomes, or with other degrees ofpairing failure within the inverted segment ofchromosome 1 might be selectively eliminated.3"Heterologous pairing along the inversion bivalentcould, however, allow for survival, and such germcells might therefore proceed through meiosis andspermiogenesis, pairing requirements having beensatisfied. There seems no evidence, however, in ourown case or in the inv(1) cases of Gabriel-Robez eta15 and Batanian and Hulten7 to link germ cell deathwith association between the inversion bivalent andthe XY pair,3' 32 as no such contacts were seen inany of these cases.

It has previously been suggested that pairinginitiates within the inv(l) bivalent at the midpoint ofthe inverted segment,4 5 7 but our own observations

do not entirely support this. Possible synapticinitiation points seemed, in our material, to occur atsomewhat random positions along the inversion,and were by no means always found at the midpoint.Moreover, we do not agree with Giuchaoua et al' orGabriel-Robez et a15 that heterologous pairing alongthe inversion occurs only at the late prophase stageswhen synaptic adjustment is occurring.' Cells show-ing 23 normal looking SCs were recorded in our caseat all stages of prophase from zygotene (type 0 ofSolari"6) to late pachytene (type IV) and did notincrease in frequency at late prophase. It is ourbelief, therefore, that non-homologous synapsisacross the inverted segment of bivalent No 1 can beestablished from the earliest stage of prophase whenpairing first begins. We have argued in a previouspublication for the establishment of heterologouspairing at zygotene citing a number of examplesfrom a variety of species, and it has recently beenshown in the deer mouse (Peromyscus sitkensis)24that inverted segments proceed directly to hetero-synapsis without an intervening homosynapticphase. Moreover, Saadallah and Hult6n21 noted theoccurrence of heterosynapsed inv(13) bivalents "inthe earliest pachytene substage", in a substantialproportion of cells studied at prophase. They arguedfor the conversion of other bivalents showingasynapsis and excrescences at early prophase intofully paired bivalents at late prophase. We do notfavour their interpretation of events. Our belief isthat cells showing asynapsis and the development ofexcrescences along unpaired lateral elements will beeliminated from the germ line. This could offer analternative explanation for the decline in frequencyof such cells noted by them towards the end ofprophase.A final point of interest arises out of the fact that

some male sterile No 1 inversions in man have beeninherited from a carrier mother3 6 who is herselffertile. Oogenic development might nevertheless beimpaired in such women. Data from the mouse showthat in the female carriers of a variety of malesterilising chromosome anomalies, oocyte numbers,ovarian size, and reproductive lifespan may all bereduced.3" 3 There could therefore be a notice-able shortening of reproductive life and an earlymenopause for the heterozygous mothers recordedin these cases of inversion 1 in man, and possibly forhuman female carriers of male sterilising anomaliesin general. Few reports are available in humancytogenetics publications, but a pericentric inversionin the X chromosome has been reported in twosisters, both showing premature menopause.36 Asecond report of inversion X describes irregularmenses in a female heterozygote of 36 years.37 Suchcases would support the idea of oogenic impairment

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and depletion in oocyte numbers in such subjects.Premature menopause may perhaps be foundamong the causes of ascertainment in other femaleinversion heterozygotes.

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1982;19:303-5.3 Rivera H, Alvarez-Arratia MC. Moller M. Diaz M. Cantu JM.

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4 Guichaoua MR, Delafontaine D, Taurelle R, Taillemite JL,Morazzani MR, Luciani JM. Loop formation and synapticadjustment in a human male heterozygous for two pericentricinversions. Chromnoso,na 1985:93:313-21).

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Correspondence and requests for reprints to Dr AChandley, MRC Clinical and Population Cytogene-tics Unit, Western General Hospital, Crewe Road,Edinburgh EH4 2XU.

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