9J Med Genet 1993; 30: 926-931

Types, stability, and phenotypic consequences ofchromosome rearrangements leading to

interstitial telomeric sequences

E Rossi, G Floridia, M Casali, C Danesino, G Chiumello, F Bernardi, I Magnani,L Papi, M Mura, 0 Zuffardi

Biologia Generale eGenetica Medica,Universita di Pavia,CP 217, 1-27100 Pavia,Italy.E RossiG FloridiaM CasaliC DanesinoO Zuffardi

Clinica Pediatrica,Ospedale SanRaffaele, Universita diMilano, Milano, Italy.G Chiumello

Laboratorio diGenetica, PoliclinicoBorgo Roma, Verona,Italy.F Bernardi

Dipartimento diBiologia e Genetica,Universita di Milano,Milano, Italy.I Magnani

Genetica Medica,Universita di Firenze,Italy.L Papi

Anatomia Patologica,Ospedale Niguarda CaGranda, Milano, Italy.M Mura

Correspondence toDr Zuffardi.

Received 19 May 1993.Accepted 22 June 1993.

AbstractUsing in situ hybridisation, we identifiedinterstitial telomeric sequences in seven

chromosomal translocations present innormal and in syndromic subjects. Telo-meric sequences were also found at thecentromeric ends of a 4p and a 4q causedby centric fission of one chromosome 4.We found that rearrangements leading tointerstitial telomeric sequences were ofthree types: (1) termino-terminal re-

arrangements with fusion of the telo-meres of two chromosomes, of which we

report one case; (2) rearrangements inwhich an acentric fragment of one chro-mosome fuses to the telomere of anotherchromosome. We describe four cases ofPrader-Willi syndrome with the 15ql-qter transposed to the telomeric repeatsof different recipient chromosomes; (3)telomere-centromere rearrangements inwhich telomeric sequences of one chro-mosome fuse with the centromere ofanother chromosome. We describe twoexamples of these rearrangements inwhich not only telomeric sequences butalso remnants of alphoid sequences were

found at the fusion point.Instability at the fusion point of the

derivative chromosome was found in thePrader-Willi translocations but we were

unable to correlate this instability withculture conditions. The two subjects withthe termino-terminal rearrangementand the centric fission respectively havenormal phenotypes. The two patientswith telomere-centromere fusions were

unbalanced for the short arm of an acro-

centric chromosome and had failure tothrive; one of them also had dysmorphicfacies. We postulate that these pheno-

types could be the result of uniparentaldisomy.(J Med Genet 1993;30:926-31)

Linear chromosomes contain two telomeres,one at each end of the molecule, consisting ofshort, tandemly repeated DNA sequences

which are loosely conserved in eukaryotes.'There are, however, several examples in ver-

tebrates of non-telomeric sites of the telomericsequences. In some species, including our

own, the interstitial location of telomeric se-

quences is a fixed characteristic of some chro-mosome pairs,2- in others it is the conse-quence of rearrangements found in exceptionalcases.6 In at least one case, that of humanchromosome 2, the interstitial telomere se-

quences map in the same region as a folatesensitive fragile site.7 This coincidence indic-ates that interstitial telomeric sequences maycause fragility, in other words that some fragilesites are such because they are constituted bytelomeric sequences. We report seven ex-

amples of human constitutional chromosomeabnormalities involving the presence of inter-stitial telomeric sequences and associated withdifferent phenotypes. In some of these casesthe sites of the interstitial telomere coincidewith a fragile site. We also investigated a case

of familial centric fission to find out whethernew telomere sequences were present at thetwo broken ends of the fission chromosome.

Case reports and methodsThe major symptoms and cytogenetic data ofthe subjects are shown in table 1. Cell linesfrom all cases but case 5 are available. Five ofthe cases have been described previously, as

indicated in table 1.Studies on fragile site expression were

Table 1 Karyotypes and phenotypes of the eight subjects.

Case no Karyotype Main symptoms(age at lastobservation, y)

1 (1) 45,XX,ter rea(17;22)(p;q)de novo Normal phenotype, normal psychomotor development. Chromosome abnormalitydetected when her mother requested amniocentesis for advanced age (42 years)

2 (21) 45,XX, - 5, - 15, + der(5)t(5;15)(qter;ql3)de novo Neonatal hypotonia, obesity, mental retardation. See Rivera et al,8 case 23 (11) 45,XX, - 15,- 18, + der(18)t(15;18)(ql3;qter)/ Neonatal hypotonia, obesity, severe mental retardation. See Rivera et al,' case 1

45,X, - X, - 15, + der(X)t(X;1 5)(qter;ql3)de novo4 (12) 45,XX, - 12,- 15, + der(12)t(12;15)(qter;qll.1)de novo Neonatal hypotonia, obesity, mental retardation5 (27) 45,XY, -9,- 15, + der(9)t(9;15)(qter;qll.1)de novo Neonatal hypotonia, mild mental retardation, slight obesity, cryptorchidism. See

Fraccaro et al96 (12) 45,XX, -2, - 22, + der(2)t(2;22)(qter;cen)de novo Dysmorphic facial features, failure to thrive, slight mental retardation. See Di Lernia

et al'° and Magnani et al"7 (5) 45,XY, - 5,- 13, + der(5)t(5;13)(pter;cen)/46,XY, Failure to thrive. Very thin build

- 5, - 13, + der(5)t(5;13)(pter;cen), + i(13p)de novo8 (52) 47,XX, -4, + 4p, + 4q Aunt of a child with trisomy 4p. See Dallapiccola et al'2

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Types, stability, and phenotypic consequences of chromosome rearrangements leading to interstitial telomeric sequences

Table 2 Chromosome fragility at the fusion points ofthe rearranged chromosomes from cases I to 7.

RPMI RPMI RPMI RPMI RPMI Totals-FA +DA + Aph + BrdU

Case 1 0/72 0/202 0/71 0/126 - 0/471Case 2 0/100 0/100 1/50* - - 1/250Case 3 0/100 1/79t 0/100 - - 1/279Case 4 0/161 - 2,100 1/50 - 3/311Case 5 2/60+ 1/106+ 2/60 1/98§ 1/102+ 7/426Case 6 0/100 0/100 - - - 0/200Case 7 0/100 - - - - 0/100* Chromosome break (fig ID).t Deletion of 15ql-qter both from the der(18) and from theder(X) (fig IE).$ Chromatid breaks (fig 1A,B).§ Transposition of 15ql-qter to 6q (46,XY, -6, + der(6),t(6;15)(qter-ql 1.1)).FA = folic acid, DA = distamycin A, Aph = aphidicolin, BrdU= bromodeoxyuridine.

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Figure 1 Partial metaphases from case 5 showing chromatid breaks (A, B) andchromosome gap (C) at the fusion point of the der(9). (D) Partial metaphase fromcase 2 showing break at the fusion point of the der(5). (E) Metaphases from case 3showing deletion of 15ql-qter both from the der(18) andfrom the der(X). Longarrow indicates the normal chromosome 15. Open arrows and short arrows indicate thetwo X chromosomes and the two chromosomes 18 respectively.

undertaken in cultured lymphocytes from allcases but case 7. Standard cultures were estab-lished in RPMI-1640 medium supplementedwith 10% FBS and 0-8% L-glutamine andwere processed at 72 hours. For the expressionof folate sensitive fragile sites, cultures fromcases 1, 2, 3, 5, and 6 were established inmodified RPMI-1640 without folic acid (FA)(Irvine Scientific), supplemented with 10%FBS, and were processed at 96 hours. Induc-tion of distamycin A (DA) fragile sites wasstudied in cases 1 to 5 with the addition ofDA(100 gg/ml) for the last 48 hours." Cultureswere processed at 72 hours. BrdU induciblefragile sites were studied in case 5. BrdU(40 mg/l) was added six hours before harvest at72 hours.'4 For the expression of aphidicolininducible fragile sites, blood cultures fromcases 1, 4, and 5 were supplemented with0-2 imol/l aphidicolin (Aph) after 70 hours ofculture and processed at 96 hours.'5

In situ hybridisation was performed in allcases with the biotinylated telomeric se-quences (TTAGGG)n (P5097-B.5, ONCOR).Hybridisation and posthybridisation washeswere performed according to the manufac-turer's instructions. Detection was done withthe ONCOR detection kit with three amplifi-cation steps. Chromosomes were counter-stained with propidium iodide (1 ig/ml) andbanded with DAPI (0 5 gig/ml). In some cases(cases 6 to 8) in situ hybridisation was alsoperformed with the alphoid probe p82H to testfor the presence of alphoid sequences at thebreakpoint of the rearrangements. p82H isspecific for chromosome 1416 so hybridisationand posthybridisation washes were performedin conditions that allowed all alphoid se-quences to be detected (hybridisation 37°C in50% formamide/2 x SSC, posthybridisationwashes 30% formamide/2 x SSC). In cases 6and 7 p82H was labelled by nick translationwith biotin-16-dUTP. Detection was as forthe telomeric probe. In case 8, p82H waslabelled by nick translation with digoxigenin-1 1-dUTP; detection was with the digoxigenindetection kit according to the manufacturer'sinstructions (Boehringer Mannheim).

In each case a minimum of 20 metaphaseswere analysed in each hybridisation experi-ment.

ResultsThe results of chromosome analyses are givenin table 1. C banding, performed in all cases,showed the presence of a second, inactivecentromere only in case 1 in which the chro-mosome 22 centromere was consistently inac-tive. No remnant of C banding was detected atthe fusion point of the rearrangements of cases6 and 7 although in both cases the chromosomeportion transposed to the telomere of the reci-pient chromosome was broken at the centro-mere. In case 8 both the centromeres of 4p and4q were C positive.

Results of chromosome fragility studies atthe fusion point of the rearrangements fromcases 1 to 7 are given in table 2. In case 5, thefusion point of the der(9) appeared as a gap

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Figure 2 Metaphase from case 1 hybridised with the telomeric probe andcounterstained with propidium iodide. Arrow indicates the ter rea(17;22). Inset:cutout of chromosomes 17, 22, and the ter rea(1 7;22).

(fig 1C) in nearly all the cells, and for thisreason it was not considered among the fragilesites in table 2. The size of the gap excluded itsorigin by fusion of the two G negative bands9q34 and 15q11.1 (fig 1C). In this case, in asingle cell from the aphidicolin treated cul-tures, we also found a der(6) instead of theder(9) and this was entered in table 2 as afragile site. Conversely, in case 3, mitoses withthe der(X) instead of the der(18) were notentered in table 2 since they were consideredconstitutional as they were also found in fibro-blasts.8

FISH analysis showed that all the re-arrangements from cases 1 to 7 contained telo-meric sequences at the fusion point (figs 2, 3,4). In case 8 telomeric sequences were alsofound at the centromeric ends of 4p and 4q(fig 5). In cases 6 and 7, FISH analysis withp82h showed hybridisation signals at thefusion point of both the der(2) and the der(5).However, these signals were much smaller (fig4) than those found at the primary constric-tions of the other chromosomes, and in case 7they were detectable in only four of 20 meta-phases. Conversely in case 8 hybridisationsignals with p82H at 4p and 4q were veryevident.

DiscussionTYPES OF REARRANGEMENTS LEADING TOINTERSTITIAL TELOMERIC SEQUENCES ORCENTRIC FISSIONRearrangements leading to an interstitial loca-tion of telomeric sequences are of two types:those involving two telomeres and those involv-ing one telomeric and one non-telomeric site.Our case 1 is an example of a termino-terminalrearrangement involving the telomeres of twochromosomes. This type of rearrangement isvery unusual among constitutional chromo-some abnormalities and we were unable to finda similar published case. However, the factthat the human chromosome 2 derives fromthe telomeric fusion of two ancestral primatechromosomes3 and the finding of telomericinterstitial sites of hybridisation in some chro-mosome pairs of certain vertebrates245 indic-ates that this type of rearrangement had a rolein the process of karyotype evolution. In addi-tion, telomeric fusions are observed with highfrequency as non-clonal abnormalities in sometumours'7 and in cultured lymphocytes ofpatients with ataxia telangiectasia and related

Figure 3 Partial metaphases from cases 2(A), 3(B), 4(C), and 5(D) after hybridisation with the telomeric probes(top) and after staining with DAPI (bottom).

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Types, stability, and phenotypic consequences of chromosome rearrangements leading to interstitial telomeric sequences

Figure 4 Partial metaphases from case 6 (A,B) and 7(C,D) hybridised with the telomeric probe (A,C) andwith p82H (B,D). The same metaphases stained withDAPI are shown on the right. Arrows indicate thederivative chromosomes.

syndromes.'8 Thus it seems likely that some

genetic conditions may predispose to telomerefusion. The same holds true for ring chromo-somes that have been found, as recurrentevents, in various haematological and solidtumours.'9 Some of the ring chromosomes,either constitutional or acquired, appear tooriginate through telomere-telomere fusions.This mechanism was shown in three cases ofconstitutional ring chromosome, in which itwas possible to detect not only the telomericsequences but also the telomere associatedones.20 Thus it seems that termino-terminalrearrangements occur not only between thetelomeres of two chromosomes but alsobetween the distal ends of the same chromo-some. Cases 2, 3, 4, 5, 6, and 7 are all examplesof rearrangements involving one telomeric andone non-telomeric site. The first four cases are

patients with the Prader-Willi syndrome. Inthese cases the rearrangements involve most ofthe chromosome 15 long arm that is transposedto the very terminal region of a recipientchromosome. The presence of telomeric se-

quences at the fusion point of similar Prader-Willi translocations was suspected8 for severalreasons: (1) 15ql-qter is always transposed tothe distal portion of the recipient chromosomeand in some cases it jumps from one chromo-some to another in different cells of the same

subject, and (2) the reciprocal product ofthe translocation, when present, is not theexpected 15pter-ql but an inv dup(15ql). Insitu hybridisation with telomere sequencesshowed that in cases 2, 3, 4, and 5 the recipientchromosome maintained its telomere. Thesame finding has been reported in three casesof Prader-Willi translocations.6 2' Thus itseems likely that in most Prader-Willi translo-cations, 15ql-qter is transposed to the telo-meric sequences of the recipient chromosome.Since it is unlikely that the entire 1 to 1 5 MbPrader-Willi chromosome region (PWCR) hasaffinity for the telomere, there must be uniqueor repeated sequences with this characteristicalong it. In two translocation patients in whommolecular studies have been done, the chro-mosome 15 breakpoint is distal to TD189-1and proximal to IRIO- 1.22 Thus sequence(s)prone to attach to telomeres could be presentinside this region. Sequences with affinity forthe telomeres are not exclusive to the PWCRas shown by similar rearrangements involvingother chromosomes .6The rearrangements found in cases 6 and 7

are also instances of fusion between telomericand non-telomeric sequences but in these casesthe non-telomeric sequences are part of thecentromere as indicated by the finding of rem-nants of alphoid sequences at the fusion pointof both the der(2) and the der(5). In case 7 weare confident that the breakpoint of chromo-some 13 is at the centromere, since its recipro-cal product is an i(l3p). In case 6, a 2;22translocation, the absence of an i(22p) does notexclude a breakpoint in the chromosome 22short arm, but the presence at the fusion pointof the der(2) of a very small domain of alphoidDNA and its banding pattern do indeedsuggest that it derives from telomere-centro-mere fusion. The existence of this type ofrearrangement, that is, breakage of the centro-mere of one chromosome, transposition of oneof its arm to the telomere of another chromo-some, and duplication of the other arm to forman isochromosome, was postulated by Auriasand Dutrillaux,23 who reviewed several cases inwhich this rearrangement could have hap-pened. Our finding that alphoid and telomeresequences were both present at the fusionpoint does not in itself indicate that telomeresequences actually stick to the alphoid ones,since centromeres contain several classes ofrepetitive DNA.24

In case 8 a fission of chromosome 4 ispresent and is found in other members of thefamily.12 As was the case with chromosome 13in case 7, in situ hybridisation showed thatalphoid sequences were present at both of thebroken ends of chromosome 4. In this case thetwo portions of chromosome 4 are stable and,unlike those of chromosome 13 in case 7, areneither prone to stick to telomeres of otherchromosomes nor to form an isochromosome.The reason for this stability is the presence oftelomere sequences at each of the two brokenends. It is not obvious why chromosomesbroken at the centromere can alternativelygenerate a new telomere, stick to telomeres ofother chromosomes, or form an isochromo-

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Figure 5 Partial metaphases from case 8 hybridised with the telomeric probe(A,B,C) and with p82H (D). Arrows indicate the two derivatives 4p and 4qoriginating from the centric fission (A,B,D). In (C) only 4q is shown. DAPI staof metaphases is shown on the right.

some. The only difference we noticed betsthe two broken chromosomes was inamount of alphoid DNA, which was minin the long arm of chromosome 13 joined ti

telomere of 5p and larger in 4p and 4q.finding that broken chromosomes can be s

lised by de novo formation of telomeres iznew. In Tetrahymena it has been shown25telomerase can add telomeric repeats dironto the ends of germline fragmented chrcsomes that lack any pre-existing telonDNA. Similarly, in Ascaris lumbricoides.newly formed ends of the reduced sonchromosomes carry new tandem repealtelomeric sequences.26 At least two examplhealing of a truncated chromosome byaddition of telomeric repeats havereported in humans.2728

ARE INTERSTITIAL TELOMERES FRAGILE SITE

There is general agreement that interstelomeres can be sites of chromosome f

lity.'7 The evidence that in human chromosome2 the fusion point of two ancestral chromo-somes maps to the same band of the rare folicacid sensitive fragile site fra2B suggests that,similarly to what was found at fraXA, in some

, subjects the expansion of interstitial telomererepeats may result in a folic acid sensitivefragile site. However, the demonstration thattelomeric repeats do coincide with fra2B is stilllacking. In our cases 1 to 7 chromosome breaksat the fusion point were seen only in thePrader-Willi translocations (cases 2 to 5),mainly as chromatid breaks (fig 1). From ourexperiments, chromosome fragility in the fourPrader-Willi translocations seems to be inde-pendent of the culture conditions. A similarinstability was described in another Prader-Willi translocation2' and in a telomeric translo-cation 6;19.29 In cases 1, 6, and 7 no fragilitywas found in any of the derivative chromosomealthough case 1 was extensively investigated indifferent culture conditions.

In conclusion, interstitial telomeric se-quences can be considered in some cases asnon-functional elements analogous to the inac-tivated centromeres.6 In other cases, the telo-meric sequences seem to maintain some oftheir function and are prone to breakage. Thejumping phenomenon of the Prader-Willitranslocations8 shows that the internal telo-mere repeats maintain part of the telomerefunction of preventing fusion with other chro-mosomes.

PATIENTS PHENOTYPEThe phenotypes of cases 1 to 5 and 8 are asexpected. Cases 1 and 8 carry balanced re-arrangements and are completely normal,while cases 2 to 5 have the Prader-Willi syn-drome. The severity of the condition variesconsiderably from case 3 with severe obesityand mental retardation to case 4 showing slight

tining obesity and very mild mental retardation. Thisphenotypic variation could be because of thevarying size of the chromosome 15 deletion ordifferences in the parental origin of the trans-

ween location or both. In fact some phenotypicthe differences were found between Prader-Willi

Limal patients with the deletion and those witho the uniparental maternal disomy.30The Cases 6 and 7 have chromosome imbalancestabi- involving the short arms of acrocentric chro-s not mosomes and should have a normal pheno-that type. However, both failed to thrive and case 7ectly also had a dysmorphic face. We cannot exclude)mo- the possibility that these abnormalities are theneric result of an undetected chromosome instability, the leading to mosaic monosomy for 22q (case 6)natic and 13q (case 7), but they could be the result ofts of uniparental disomy for one of the chromo-les of somes involved in the rearrangements. In factthe abnormalities of growth have been reported in

been several instances of uniparental disomy in

man3' and mouse.35

We thank Professor M Fraccaro for importants? suggestions and critical reading of the manu-;titial script. This work was supported in part byragi- Associazione Studio Malformazioni, Milano.

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Types, stability, and phenotypic consequences of chromosome rearrangements leading to interstitial telomeric sequences

1 Blackburn EH. Structure and function of telomeres. Nature1991 ;350:569-73.

2 Meyne J, Baker RJ, Hobart HH, et al. Distribution of non-telomeric sites of the (TTAGGG)n telomeric sequences invertebrate chromosomes. Chromosoma 1990;99:3-10.

3 Ijdo JW, Baldini A, Ward DC, Reeders ST, Wells RA.Origin of human chromosome 2: an ancestral telomere-telomere fusion. Proc Natl Acad Sci USA 1991;88:905 1-5.

4 Wiley JE, Meyne J, Little ML, Stout JC. Interstitialhybridization sites of the (TTAGGG) telomeric se-quence on the chromosomes of some bqorth Americanhylid frogs. Cytogenet Cell Genet 1992;61:55-7.

5 Ashley T, Ward DC. A "hot spot" of recombinationcoincides with an interstitial telomeric sequence in theArmenian hamster. Cytogenet Cell Genet 1993;62:169-71.

6 Murtif Park V, Gustashaw KM, Wathen TM. The pres-ence of interstitial telomeric sequences in constitutionalchromosome abnormalities. Am Hum Genet1992;50:914-23.

7 Allshire RC, Gosden JR, Cross SH, et al. Telomeric repeatfrom T thermophila cross hybridizes with human telo-meres. Nature 1988;332:656-9.

8 Rivera H, Zuffardi 0, Gargantini L. Nonreciprocal andjumping translocations of 1 5ql --qter in Prader-Willisyndrome. Am Med Genet 1990;37:31 1-17.

9 Fraccaro M, Zuffardi 0, Buhler E. Deficiencies involvingthe paracentromeric regions of chromosome 15: Prader-Willi or a new syndrome? Klinische Genetik in der Padia-trie. I. Symposium in Kiel. Herausgegeben von M Tolks-dorf und J Spranger. Stuttgart: Georg Thieme Verlag,1978:33-8.

10 Di Lernia R, Magnani I, Doneda L, Rizzi R, Larizza L.Cytogenetic instability in a family with gastric cancerrecurrence. Cancer Genet Cytogenet 1987;27:299-310.

11 Magnani I, Larizza L, Doneda L, Weitnauer L, Rizzi R, DiLernia R. Malformation syndrome with t(2;22) in acancer family with chromosome instability. Cancer GenetCytogenet 1989;38:223-7.

12 Dallapiccola B, Mastroiacovo P, Gandini E. Clinical casereport. Centric fission of chromosome no 4 in the motherof two patients with trisomy 4p. Hum Genet 1976;31:121-5.

13 Schmid M, Feichtinger W, Jessberger A, Kohler J, LangeR. The fragile site (16)(q22). I. Induction by AT-specificDNA-ligands and population frequency. Hum Genet1986;74:67-73.

14 Sutherland GR, Parslow MI, Baker E. New classes ofcommon fragile sites induced by 5-azacytidine and bro-modeoxyuridine. Hum Genet 1985;69:233-7.

15 Austin MJF, Collins JM, Corey LA, et al. Aphidicolin-inducible common fragile-site expression: results from apopulation survey of twins. Am Jf Hum Genet 1992;50:76-83.

16 Waye JS, Mitchell AR, Willard HF. Organization andgenomic distribution of '82H' alpha satellite. DNA evid-ence for a low-copy or single-copy alphoid domain locatedon human chromosome 14. Hum Genet 1988;78:27-32.

17 Hastie ND, Allshire RC. Human telomeres: fusion andinterstitial sites. Trends Genet 1989;5:326-31.

18 Maraschio P, Peretti D, Lambiase S, et al. A new chromo-some instability disorder. Clin Genet 1986;30:353-65.

19 Sandberg AA. The chromosomes in human cancer and leuk-emia. Vol II. Amsterdam: Elsevier, 1990.

20 Pezzolo A, Gimelli G, Cohen A, et al. Presence of telomericand subtelomeric sequences at the fusion points of ringchromosomes indicates that the ring syndrome is causedby ring instability. Hum Genet 1993;92:23-7.

21 Reeve A, Norman A, Sinclair P, Hamey Y, Whittington-Smith R, Read A. A true telomeric translocation in a babywith Prader-Willi phenotype. 7 Med Genet 1992;29:205A.

22 Kuwano A, Mutirangura A, Dittrich B, et al. Moleculardissection of the Prader-Willi/Angelman syndrome re-gion (15qll-13) by YAC cloning and FISH analysis.Hum Mol Genet 1992;1:417-25.

23 Aurias A, Dutrillaux B. A possible new type of chromosomerearrangement: telomere-centromere translocation (tct)followed by double duplication. Hum Genet 1986;72:25-6.

24 Willard HF. Centromeres-primary constrictions are pri-marily complicated. Hum Mol Genet 1992;1:667-8.

25 Yu GL, Blackburn EH. Developmentally programmedhealing of chromosomes by telomerase in Tetrahymena.Cell 1991;67:823-32.

26 Muller F, Wicky C, Spicher A, Tobler H. New telomereformation after developmentally regulated chromosomalbreakage during the process of chromatin diminution inAscaris lumbricoides. Cell 1991;67:815-22.

27 Morin GB. Recognition of a chromosome truncation siteassociated with a-thalassemia by human telomerase.Nature 1991;353:454-6.

28 Lamb J, Harris PC, Wilkie AOM, Wood WG, Dauwerse G,Higgs DR. De novo truncation of chromosome 16p andhealing with (TTAGGG)n in the a-thalassemia/mentalretardation syndrome (ATR-16). Am i Hum Genet1993;52:668-76.

29 Drets ME, Therman E. Human telomeric 6; 19 transloca-tion chromosome with a tendency to break at the fusionpoint. Chromosoma 1983;88:139-44.

30 Robinson WP, Bottani A, Yagang X, et al. Molecular,cytogenetic, and clinical investigations of Prader-Willisyndrome patients. Am Jf Hum Genet 1991;49:1219-34.

31 Spence JE, Perciaccante RG, Greig GM, et al. Uniparentaldisomy as a mechanism for human genetic disease. Am JfHum Genet 1988;42:217-26.

32 Voss R, Ben-Simon E, Avital A, et al. Isodisomy of chro-mosome 7 in a patient with cystic fibrosis: could unipar-ental disomy be common in humans? Am J Hum Genet1989;45:373-80.

33 Temple K, Cockwell A, Hassold T, Pettay D, Jacobs P.Maternal uniparental disomy for chromosome 14. J MedGenet 1991;28:511-14.

34 Wang JCC, Passage MB, Yen PH, Shapiro LJ, MohandasTK. Uniparental heterodisomy for chromosome 14 in aphenotypically abnormal familial balanced 13/14 Robert-sonian translocation carrier. Am J Hum Genet1991;48:1069-74.

35 Cattanach BM. Parental origin effects in mice. J EmbryolExp Morphol 1986;97(suppl): 137-50.

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