PRENATAL DIAGNOSISPrenat Diagn 2008; 28: 764–766.Published online 17 June 2008 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.2030

RESEARCH LETTER

Prenatal diagnosis of monosomy 18p involving a jumpingtranslocation

Sandra Edwards* and Jonathan J. WatersNorth-East London Regional Cytogenetics Laboratory, Great Ormond St Hospital NHS Trust, London WC1N 3BG, UK

KEY WORDS: jumping translocation; monosomy 18p syndrome; QF-PCR; general cytogenetics; fetal ultrasound;fetal imaging; prenatal cytogenetics; fetal & placental pathology

Jumping translocations are rare, de novo, chromosomerearrangements that usually involve chromosome imbal-ance. They are characterised by a donor chromosome(with a common breakpoint) and multiple recipient chro-mosomes (Jewett et al., 1998; Stankiewicz et al., 2003).Jumping translocations may be associated with clin-ically recognisable syndromes, (e.g. Prader Willi orDown syndrome) or with other phenotypic abnormali-ties. They have been reported in spontaneous abortions(Levy et al., 2000) and are commonly observed in cancerpatients (Zahed et al., 2004). There is a single previousreport of a jumping translocation, detected at prenataldiagnosis in a second-trimester foetus with tetralogy ofFallot and other malformations, which involved recipientchromosomes 5, 8 and 22 with a common breakpoint onthe donor chromosome at 22q11.21 (Aslan et al., 2005).This report describes a jumping translocation ascertainedat prenatal diagnosis referred for an increased risk ofDown syndrome where karyotypic investigation wasperformed at first trimester chorionic villus sampling(CVS), followed by second-trimester amniocentesis andpostnatal follow-up at 7 months of age.

A 37-year-old female underwent transabdominal CVSat 14 weeks’ gestation due to a Down syndrome risk of1 : 90. The foetus showed a raised nuchal translucency(NT) of 2.5 mm at 12 weeks. There was no previousobstetric history of note. Chorionic villus tissue was dis-sected and cleaned prior to further processing. Two sep-arate fronds of identified villi were used for two separaterapid quantitative fluorescent polymerase chain reaction(QF-PCR) aneuploidy tests (Mann et al., 2004). The QF-PCR result on the chorion villus sample was reported asconsistent with a normal complement for chromosomes13, 18 and 21. For chromosome 18, three informativemarkers were identified—D18S386 (18q22.1), D18S390(18q22.3) and D18S891 (18q11.2). A single distal short-arm marker D18S391, located at 18p11.31, showed asingle peak and was scored as uninformative. Karyotyp-ing was performed using standard cytogenetics tech-niques. Fluorescence in situ hybridisation (FISH) was

*Correspondence to: Sandra Edwards, NE London Regional Cyto-genetics Laboratory; Institute of Neurology, Queen Square, Lon-don WC1N 3BG, UK. E-mail: EdwarS3@gosh.nhs.uk

performed with the sub-telomeric probes D18S1244 andD18S1390 (Kreatech, formerly Qbiogene, Amsterdam,The Netherlands) using standard techniques. G-bandanalysis of cultured cells gave an abnormal result withtwo different abnormal cell lines. The karyotype wasreported as 46,XY,i(18)(q10)[11]/46,XY,der(18)(qter →p11::s)[5]. In addition, single cell abnormalities involv-ing the same breakpoint region were seen in furtherthree cells, identified as 45,XY,der(15;18) (q10;q10);46,XY,add(18)(p11.1) and 46,XY,del(18)(p11.1)(Figure 1 and Table 1). All available material was exam-ined and further characterisation of the cell lines iden-tified was not possible. Parental karyotypes were nor-mal. A follow-up amniocentesis sample was received at16 weeks’ gestation. QF-PCR rapid trisomy test resultswere again consistent with disomy 13, 18 and 21 andshowed that the genotype of the amniotic fluid wasidentical to that of the chorionic villus sample for allpolymorphic markers tested. A recognised limitation ofthe QF-PCR technique is that it is not possible to distin-guish between a homozygous and a hemizygous alleliccontribution to a single peak such as was observed at thelocus recognised by the distal 18p marker at 18p11.31.All the karyotypes observed were predicted to be hem-izygous for this marker.

Follow-up karyotypic analysis of the amniotic fluidcell cultures identified a single abnormal cell line withno evidence of mosaicism in 40 cells examined fromtwo independent cultures. The karyotype was reportedas 46,XY,del(18)(p11.1)[40]de novo, [Figure 1(b) andTable 1]. This interpretation was confirmed by FISH,which showed the presence of a single 18 short-arm sub-telomeric probe signal in all five metaphasesexamined [Figure 1(c)]. A detailed ultrasound scan wasuninformative. After counselling, the patient elected tocontinue with the pregnancy.

The infant was delivered normally at 37 weeks’ ges-tation. At age 1 month, a left inguinal hernia wasrepaired and a left orchidopexy performed. At 7 monthsof age, a blood sample was received. The resultswere consistent with a deletion of the entire shortarm of chromosome 18 with the following kary-otype: 46,XY,del(18)(p11.1)[30]de novo (Table 1). Atage 9 months, he was able to sit up unsupported butwas reluctant to weight-bear. He was described as not

Copyright 2008 John Wiley & Sons, Ltd. Received: 16 November 2007Revised: 14 April 2008

Accepted: 21 April 2008Published online: 17 June 2008

PRENATAL DIAGNOSIS OF MONOSOMY 18p 765

(a)

(b) (c)

18 der(15;18)(q10;q10) i(18)(q10) der(18)(qter-p11.1::s)

add(18p) del(18p)

18 del(18p)

Figure 1—(a) partial karyotype of abnormalities from the CVS,(b) partial karyotype showing the del(18)(p11.1) from the amnioticfluid sample (c) partial metaphase showing inverted DAPI image ofdeleted FISH probe 18p telomere (green, D18S1244) and the presenceof the control probe 18q telomere (red, D18S1390) from the amnioticfluid sample

particularly dysmorphic, but did have mild ptosis, slightwobbly nystagmus with a divergent squint, small epi-canthic folds, and a longish philtrum in the upper lip.His ears were mildly protruding, and he had slightlyunusual palmer creases, bridged on the right. His socialengagement was also poor.

Stankiewicz et al. (2003) reported that the majority ofjumping translocation breakpoints of recipient chromo-somes occur within telomeric and sub-telomeric regions,including nucleolar organiser regions (NORs) and fordonor chromosomes within centromeric and pericen-tromeric regions. Such rearrangements may be intrinsi-cally unstable due to the juxtaposition of shared repeti-tive sequences, leading to further rearrangements, whichmay in turn be more or less stable (Sawyer et al., 1998).Gross et al. (1996) and Jewett et al. (1998) reviewedprevious cases of non-acrocentric jumping transloca-tions and showed that chromosome 18 was preferentiallyinvolved. This is consistent with this report, where in

Table 1—Summary of cell lines identified from CVS, amnio-centesis and postnatal samples

Sample Cell lineNumberof cells

Numberof cultures

CVS i(18)(q10) 11 2der(18)(qter->p11.1::s) 5 1

der(15;18)(q10;q10) 1 1add(18)(p11.1) 1 1del(18)(p11.1) 1 1

Amnioticfluid

del(18)(p11.1) 41 2

Peripheralblood

del(18)(p11.1) 30 1

all the five cell lines observed, the common breakpointwas within the pericentromeric region on the donorchromosome 18. The likely NOR involvement on therecipient chromosome 15 was shown by the presenceof the derivative chromosomes der(18)(15;18) (q10q10)and der(18)(qter-p11::s). The deleted 18p cell line maythen represent the initial abnormality, with subsequentmitotic instability and exchange involving this chromo-some, giving rise to the other cell lines observed.

Huang et al. (2004) stated that jumping translocationsoccur post-zygotically, giving rise initially to a mosaickaryotype. The practical significance of this suggestion,in a prenatal context at CVS, would prompt the need toensure that a normal cell line was not present althoughclearly follow-up testing would always be advisable. Itwas noted that the final karyotype, identified in boththe amniotic fluid and peripheral blood samples as46,XY,del(18)(p11.1), was present in only a single cellat CVS albeit with limited metaphase availability.

Monosomy 18p is one of the most common autosomaldeletion syndromes. The majority of del(18p) arisede novo; however, approximately 16% originate froman unbalanced translocation between the long arms ofchromosome 18 and acrocentric chromosomes (Schinzel,2001). Clinical manifestations are variable and includemental retardation, growth retardation, and abnormalitiesof limbs, genitals, brain, eyes and heart. Dysmorphologyat birth is not striking, consistent with the findings in ourpatient, but is reported to become more prominent withage and includes round face, dysplastic ears, wide mouthand dental anomalies.

This case is the first example of a jumping transloca-tion detected at first trimester CVS and adds to the smallnumber of constitutional cases in the literature.

ACKNOWLEDGEMENTS

Dr Kathy Mann and colleagues at The CytogeneticsCentre, Guys Hospital Foundation Trust, London, forperforming the QF-PCR analyses on these samples. MrNeville Wathen, Consultant Obstetrician, and Dr RaviPrakash, Consultant Paediatrician, Homerton UniversityHospital NHS Trust, London, for providing patientsamples and Dr Louise Wilson, Consultant ClinicalGeneticist, Great Ormond St Hospital NHS Trust, forthe clinical description of the proband in this report.

REFERENCES

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Gross SJ, Tharapel AT, Phillips OP, Shulman LP, Pivnick EK,Park VM. 1996. A jumping Robertsonian translocation: a molecularand cytogenetic study. Hum Genet 98: 291–296.

Huang B, Martin CL, Sandlin CJ, Wang S, Ledbetter DH. 2004.Mitotic and meiotic instability of a telomere association involvingthe Y chromosome. Am J Med Genet 129A: 120–123.

Jewett T, Marnane D, Stewart W, et al. 1998. Jumping translocationwith partial duplications and triplications of chromosomes 7 and15. Clin Genet 53: 415–420.

Copyright 2008 John Wiley & Sons, Ltd. Prenat Diagn 2008; 28: 764–766.DOI: 10.1002/pd

766 S. EDWARDS AND J. J. WATERS

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Copyright 2008 John Wiley & Sons, Ltd. Prenat Diagn 2008; 28: 764–766.DOI: 10.1002/pd