CLINICAL REPORT

Molecular Cytogenetic Characterization of the FirstReported Case of Inv Dup Del 20p Compatible With aU-Type Exchange ModelSandrine Leclercq,1* Kim Maincent,2 Francoise Baverel,1 Dominique Le Tessier,1 Franck Letourneur,3

Aziza Lebbar,1 and Jean-Michel Dupont1

1AP-HP; Universit�e Paris-Descartes, Facult�e de m�edecine Unit�e de Cytog�en�etique, Groupe Hospitalier Cochin—Saint Vincent de Paul,

Paris, France2AP-HP; Service de Neurop�ediatrie, Groupe Hospitalier Armand Trousseau, Paris, France3Institut Cochin; Plateforme S�equencage et Transcriptome; Groupe hospitalier Cochin-Saint Vincent de Paul, Paris, France

Received 16 May 2008; Accepted 18 September 2008

Inverted duplications with terminal deletions have been re-

ported for an increasing number of chromosome ends. The best

characterized and most frequent rearrangement reported in-

volves the short arm of chromosome 8. It derives from non-allelic

homologous recombination (NAHR) between two inverted LCRs

(low copy repeats) of the olfactory receptor (OR) gene cluster

during maternal meiosis. We report here on the cytogenetic

characterization of the first inversion duplication deletion in-

volving the short arm of chromosome 20 (inv dup del 20p) in an

18-month-old boy presenting with clinical signs consistent with

20p trisomy syndrome. This abnormality was suspected on

karyotyping, but high-resolution molecular cytogenetic inves-

tigations were required to define the breakpoints of the rear-

rangement and to obtain insight into the mechanism underlying

its formation. The duplicated region was estimated to be 18.16

Mb in size, extending from 20p13 to 20p11.22, and the size of the

terminal deletion was estimated at 2.02 Mb in the 20p13 region.

No single copy region was detected between the deleted and

duplicated segments. As neither LCR nor inversion was identi-

fied in the 20p13 region, the inv dup del (20p) chromosome

abnormality probably did not arise by NAHR. The most likely

mechanism involves a break in the 20p13 region, leading to

chromosome instability and reparation by U-type exchange or

end-to-end fusion. � 2009 Wiley-Liss, Inc.

Key words: inverted duplication, trisomy 20p, NAHR, U-type

exchange

INTRODUCTION

Inverted duplications associated with terminal deletion (inv dup

del) are complex rearrangements reported for an increasing num-

ber of chromosome ends [1p: Ballif et al., 2003; Tonk et al., 2005; 1q:

Mewar et al., 1994; De Brasi et al., 2001; 2p: Aviram-Goldring et al.,

2000; Thangavelu et al., 2004; Gruchy et al., 2007; 2q: Bonaglia

et al., 2000; 3p: Jenderny et al., 1998; Kennedy et al., 2000; 4p: Cotter

et al., 2001; Kondoh et al., 2003; Beaujard et al., 2005; 4q: Van

Buggenhout et al., 2004; 5p: Sreekantaiah et al., 1999; 7q: Stetten

et al., 1997; 9p: Teebi et al., 1993; 10q: Hoo et al., 1995; 11p: Fisher

et al., 2002; 14q: Chen et al., 2005; 15q: Genesio et al., 2004; 18p:

Morrissette et al., 2005; 18q: Courtens et al., 1998; 21q: Pangalos

et al., 1992; Xp: Milunsky et al., 1999; Dupont et al., 2007]. These

rearrangements are more frequent than first thought based on

banding techniques, as several cases were initially interpreted as

terminal duplications [Bonaglia et al., 2000; De Brasi et al., 2001;

Beaujard et al., 2005] or terminal deletions [Ballif et al., 2003]. With

the advent of molecular techniques, these rearrangements can now

be detected with greater sensitivity and have recently been shown to

be associated with ring chromosome formation [Knijnenburg et al.,

2007; Rossi et al., 2008].

The best characterized and most frequently reported rearrange-

ment involves the short arm of chromosome 8 (inv dup del 8p). Its

estimated prevalence is 1/10,000 to 1/30,000 live births [Weleber

et al., 1976; Floridia et al., 1996; Giglio et al. 2001; Vermeesch et al.,

*Correspondence to:

Sandrine Leclercq, UF de Cytog�en�etique Hopital Cochin—Saint Vincent

de Paul, F-75014 Paris, France. E-mail: sandrine.leclercq@cch.aphp.fr

Published online 10 February 2009 in Wiley InterScience

(www.interscience.wiley.com)

DOI 10.1002/ajmg.a.32640

How to Cite this Article:Leclercq S, Maincent K, Baverel F, Tessier DL,

Letourneur F, Lebbar A, Dupont J-M. 2009.

Molecular cytogenetic characterization of the

first reported case of inv dup del 20p

compatible with a U-type exchange model.

Am J Med Genet Part A 149A:437–445.

� 2009 Wiley-Liss, Inc. 437

2003; Shimokawa et al., 2004]. It arises through non-allelic homol-

ogous recombination (NAHR) between two LCRs (low copy

repeats) from the olfactory receptor (OR) gene cluster during

maternal meiosis, leading to the formation of an intermediate

dicentric chromosome, which breaks during anaphase. A polymor-

phic inversion between OR clusters, present in 26% of the popula-

tion and detected in all mothers of children with an inv dup del (8p),

abrogates correct pairing and causes susceptibility for this

rearrangement [Giglio et al., 2001; Sugawara et al., 2003]. In this

case, there is a region of normal copy number between the dupli-

cated and the deleted fragment.

We report here on the cytogenetic characterization of the first

inversion duplication deletion involving the short arm of chromo-

some 20 (inv dup del 20p) in an 18-month-old boy who presents

delayed developmental milestones and craniofacial dysmorphism.

Fine molecular characterization of this rearrangement provided

insight into the mechanism underlying this abnormality.

MATERIALS AND METHODS

PatientThe patient, an 18-month-old boy, is the second child of healthy

nonconsanguineous parents. His 4-year-old sister is also healthy.

The pregnancy was uneventful and birth occurred at 36 weeks of

gestation, by spontaneous vaginal delivery. At birth, the child

weighed 2.880 kg (median), measured 46 cm (�1 SD) and had a

head circumference of 35.5 cm (þ2 SD). He was referred to our

department at the age of 18 months, due to delays in achieving

developmental milestones. He held his head up at the age of

8 months and was able to sit down unassisted at the age of 15

months. On examination at this age, he was unable to stand up

without support and to turn over into the decubitus ventral

position. Active and passive tones were normal. The patient’s

growth was normal at þ1 SD (body weight 12.4 kg, length 84 cm

and head circumference 49 cm). Clinical examination revealed

craniofacial dysmorphism with plagiocephaly (without face

asymmetry) and frontal bossing, midface hypoplasia, round face

with prominent cheeks, short nose with large nostrils and high

arched palate (Fig. 1). He presented syndactyly of the second and

third toes on both feet. Moreover, MRI examination revealed slight

hypoplasia of the antehypophysis. Echocardiogram and audiogram

results were normal. Now at the age of 30 months, the child is

beginning to pronounce monosyllables, but not words. He has no

sleep or appetite disorders.

Karyotype AnalysisChromosome analyses of the patient and his parents were carried

out with standard procedures on peripheral blood lymphocytes,

using GTG, RHG, CBG banding and high-resolution techniques

after cell culture synchronization and BrdU (5 bromo-2’-

deoxyuridine) incorporation.

Fluorescence In Situ Hybridization (FISH)AnalysisFISH analysis was performed on metaphase spreads obtained by

standard protocols, using a whole-chromosome paint probe for

chromosome 20 (WCP20, QBiogen�) and subtelomeric 20p and

20q chromosome probes (Subtelomeric-specific 20pter, 20qter

Cytocell�). For identification and definition of the derived chro-

mosome 20, several BACs covering the region from 20pter to 20p11

were selected with the UCSC genome browser database (http://

genome.ucsc.edu/cgi-bin/hgGateway, March 2006) and the En-

sembl genome browser (http://www.ensembl.org/). These clones

were kindly provided by the Sanger Institute (http://

www.sanger.ac.uk/).

CGH Array AnalysisCGH array analysis was carried out with an approximately 1.0 Mb-

spaced whole-genome clone array (Cytochip�, Bluegnome, UK).

Genomic DNA was isolated from the patient with the Qiagen mini

kit (Qiagen�, Courtaboeuf, France) and 400 ng was labeled with the

Bioprime� DNA labeling system (Invitrogen, Paris, France), either

with Cy3-dCTP or Cy5-dCTP (GE Healthcare, Velizy, France), in a

dye-swap protocol, with 400 ng of reference DNA. Slides were

hybridized and washed according to the Cytochip� protocol. The

arrays were scanned with a Genepix� 4100A scanner (Axon Instru-

ments, Molecular Devices, St. Gr�egoire, France) and the images

were processed with GenePix software. Intensity ratios were deter-

mined for the hybridized DNA, using Bluefuse for Microarrays

software (Bluegnome�, Cambridge, UK). For further high-resolu-

tion analysis of the rearrangement, CGH oligo-array analysis was

performed with the NimbleGen� high-density oligo-array HG18-

WG Tiling 385K CGH v1.0 (NimbleGen Systems, Inc., Madison,

WI), tiling the full genome at a median probe spacing of 6,000 bp.

Data were analyzed with the Nimblescan� and SignalMap� soft-

ware platform.

RESULTS

Conventional Cytogenetic and FISH AnalysisInitial cytogenetic studies showed the de novo addition of new

material to the short arm of one chromosome 20 in the proband

(Fig. 2A). As confirmed with the whole-chromosome painting

FIG. 1. Photograph of the patient: frontal and lateral view. [Color

figure can be viewed in the online issue, which is available at

www.interscience.wiley.com.]

438 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

probe, this additional material originated from chromosome 20.

Subtelomeric probes for the short and long arms of chromosome 20

showed a 20pter deletion (data not shown).

Analysis of the rearrangement was refined by selecting two BACs

in the 20p13 and 20p12 regions (RP4-686C3, 20p13, bp position:

2.440.424–2.601.595; RP11-829A12, 20p12.2, bp position:

10.523.017–10.706.907). Both were found to be duplicated in an

inverted position (Fig. 2B).

BAC array-CGH analysis was performed to map further the

deleted and duplicated regions. The duplication corresponded to a

17.6–20.3 Mb fragment from BAC clones RP4-686C3 to RP5-

1096J16, whereas the deletion corresponded to a 1.2–2.5 Mb

fragment from BAC clones RP5-852M4 to RP11-314N13.

Additional high-resolution CGH oligo array analysis was carried

out to extend previous findings and to search for a single-copy

segment between the two duplicated regions. The size of the

duplicated region was estimated to be 18.16 Mb in size, extending

from 20p13 to 20p11.22, and the size of the terminal deletion was

estimated to be 2.02 Mb in size in the 20p13 region (Fig. 2C). No

single copy region was detected with an average resolution of 6 kb.

FIG. 2. A: Partial karyotype, showing the normal and derivative chromosome 20 with two different chromosome banding techniques. B: Di Amino Phenyl

Indol (DAPI) staining image and FISH analysis with BACs RP4-686C3, 20p13 (red) and RP11-829A12 (green) 20p12.2 showing inverted duplicated

signals on der(20). C: Oligo-array log 2 ratio plot of whole chromosome 20 and high magnification view of 20p13 region centered on the breakpoint

between the deleted and duplicated segments. Log 2 ratios obtained for the most proximal deleted oligomer (red arrow) and the most distal

duplicated oligomer (green arrow) are shown: absence of normal copy number region between the deleted and duplicated regions. [Color figure can be

viewed in the online issue, which is available at www.interscience.wiley.com.]

LECLERCQ ET AL. 439

DISCUSSION

RearrangementWe report here on the first case of inv dup del (20p) in a boy with

delayed developmental milestones and dysmorphism. High-reso-

lution oligonucleotide CGH array analysis revealed an 18.16 Mb

duplication of 20p11.22p13 and a 2.02 Mb telomeric deletion of

20p13.

Inverted duplications associated with terminal deletions have

now been observed for various chromosomal ends and, in a few

cases, inv dup del rearrangements are cryptic [Ballif et al., 2003;

Dupont et al., 2007; Knijnenburg et al., 2007].

Several mechanisms have been proposed to explain the origin of

inv dup del. The best known case involves the short arm of

chromosome 8. Inv dup del (8p) arise through non-allelic homol-

ogous recombination, during maternal meiosis, between two mis-

aligned olfactory receptor gene clusters situated 6 Mb apart at 8p23

[Giglio et al., 2001]. This meiotic recombination event is promoted

by the presence of a polymorphic inversion between these OR

clusters. This inversion is detected in 26–27% of the population and

in all mothers of children with an inv dup del (8p) [Giglio et al.,

2001; Sugawara et al., 2003]. The dicentric chromosome interme-

diate is the first product of the abnormal meiotic recombination. It

contains two duplicated regions separated by a single copy region

flanked by the two homologous OR gene clusters. From the distal to

the proximal 8p region, the inv dup del (8p) comprises three

segments: one deleted, one present as a single copy and one inverted

and duplicated.

We investigated whether the 8p model could be extended to our

case, by searching for these two major factors (LCR regions and

polymorphic inversion) potentially favoring unequal recombina-

tion in the 20p region.

Theoretically, as the deleted and duplicated segment breakpoints

are located almost 2.0 Mb from telomere 20p, any LCR involved

should be present in this specific region. However, in silico analysis

(http://projects.tcag.ca/variation/) identified no LCRs in this area.

Inversion polymorphism has been demonstrated for various

chromosomal regions through statistical methods based on unusu-

al linkage patterns in high-density SNP analysis [Bansal et al., 2007].

However, no case of microinversion has ever been described in the

20p13 region.

Neither the 1 Mb BAC array nor the high-density oligoarray gave

conclusive results concerning the identification of a possible frag-

ment with a normal copy number between the deleted and dupli-

cated regions. These results suggest that the inv dup del (20p) was

formed through a mechanism different from that described for inv

dup del (8p).

FIG. 3. Suggested mechanism leading to the inv dup del 20p in our patient [from Ballif et al., 2003]. a: double-strand break at 2.0 Mb from the telomere

in the 20p13 region (premeiotic state). b: Terminal deletion 20p13. c: NHEJ repair by sister chromatid fusion. d: Formation of a dicentric chromosome

and breakage within the 20p11.2 band during anaphase. e: inv dup del(20p). [Color figure can be viewed in the online issue, which is available at

www.interscience.wiley.com.]

440 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

The second proposed mechanism involves a U-type exchange,

leading to end-to-end fusion and the formation of a symmetric

dicentric chromosome [Weleber et al., 1976; Mitchell et al., 1994;

Hoo et al., 1995; Kondoh et al., 2003; Van Buggenhout et al., 2004].

The breakage of this dicentric chromosome during anaphase,

followed by and telomere-healing/capture leads to the formation

of an inv dup del chromosome. Ballif et al. described this mecha-

nism in 2003 in their detailed breakpoint analysis of three patients

with an 1p36 deletion. In two cases, a duplicated region followed the

deleted region. As the breakpoints were similar to those seen in

tumor cell lines, Ballif suggested that breakage-fusion-bridge (BFB)

cycles may play an important role in terminal deletion associated

with inverted duplication. The initial event would thus be a DNA

double-strand break in the 1p subtelomeric region, leading to

chromosome instability. The deleted chromosome is then repaired

by sister chromatid fusion (non-homologous end joining: NHEJ),

generating an intermediate dicentric chromosome. As DNA

repair by NHEJ is repressed during meiosis to favor repair by

homologous recombination, this mechanism probably occurs be-

fore the initiation of meiosis. As the formation of the inv dup del

(20p) chromosome does not seem to be due to NAHR between LCR

regions, the mechanism involved may be NEJH, as described by

Ballif (Fig. 3).

Genotype–Phenotype CorrelationWe report here the first case of inv dup del involving the short arm of

chromosome 20. Molecular cytogenetic analysis showed the patient

to be trisomic for the 20p13–p11.2 segment and monosomic for the

terminal 20p13 region.

Trisomy for the short arm of chromosome 20 is a rare chromo-

somal abnormality. Thirty-nine cases have been reported, all but

two cases [Zumel et al., 1989; Molina-Gomes et al., 2006] diagnosed

postnatally. Most partial trisomies result from reciprocal

translocation [Taylor et al., 1976; Marcus et al., 1979; Funderburk

et al., 1983; Lurie et al., 1985; Vamos et al., 1985; Zumel et al., 1989;

Grammatico et al., 1992; LeChien et al., 1994; Belin et al., 1999;

Oppenheimer et al., 2000; Wieczorek et al., 2003; Thomas et al.,

2004; T€umer et al., 2005; Brenk et al., 2007]. In a few cases, trisomy

20p results from parental inversion [Lucas et al., 1985; Bown et al.,

1986; Molina-Gomes et al., 2006; Chaabouni et al., 2007] or the

formation of isochromosomes [Sidwell et al., 2000]. The

genotype–phenotype correlation is therefore not very clear, because

these trisomies of 20p are heterogeneous and are frequently associ-

ated with segmental aneuploidies of other chromosomes. Only a

few cases may be considered to correspond to pure partial trisomy

20p [Sidwell et al., 2000].

A recognizable phenotype has emerged from these postnatal

observations. Grammatico et al. [1992] reported eight typical

features associated with trisomy of 20p (frequency 67–96%):

mental retardation, psychomotor acquisition delay, normal

growth, round face with prominent cheeks, dental abnormalities,

vertebral abnormalities, poor motor coordination and poor speech.

Oppenheimer added new phenotypic elements to this list in 2000,

mostly relating to dysmorphic features, with a frequency of

34–54%. The developmental phenotype and dysmorphic features

of our patient are consistent with these clinical features of trisomy

20p (Table I). As vertebral abnormalities are a key feature of this

condition, an X-ray was included in subsequent follow-up of the

patient. Finally, plagiocephaly was observed in this patient. This

feature was reported in two previous clinical descriptions of trisomy

20p [Lucas et al., 1985; Bown et al., 1986].

The patient described here also presented a 2 Mb terminal

deletion of the 20p13 region. Delineation of the monosomy

TABLE I. Main Traits Reported in Previous Studies [Grammatico et al., 1992; Oppenheimer et al., 2000] and in Our Case of Trisomy

20p Syndrome

Main phenotypic traits of trisomy 20p syndrome Our case Reported frequency [Oppenheimer et al., 2000]Typical signs

(1) Psychomotor retardation þ 96%(2) Mental retardation n.e. n.r.(3) Poor motor coordination þ 95%(4) Poor speech þ/� 95%(5) Normal growth þ n.r.(6) Vertebral abnormalities n.e. 77%(7) Dental abnormalities � 81%(8) Round face with prominent cheeks þ 82%

Other frequent findings(1) Mongoloid slanting of palpebral fissures � 67%(2) Coarse hair þ 74%(3) Short nose with large nostrils þ 55%(4) Hypertelorism � 54%(5) Strabismus � 40%(6) Congenital heart defect � 39%(7) Epicanthic folds þ 35%(8) Clinodactyly and other abnormalities of finger and toes þ 21–34%

n.r., not reported; n.e., not evaluated.

LECLERCQ ET AL. 441

TAB

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442 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

20p13-pter phenotype remains difficult because pure 20p terminal

deletions are rare events. Most of the described 20p deletions

concern a more proximal region (20p11p12) associated with

Alagille–Watson syndrome (AWS). The JAG1 gene, mutations in

which cause AWS, was mapped to the 20p12 subband [Li et al.,

1997] and was not part of the region deleted in our patient,

consistent with his phenotype as he presented no features of AWS.

However, this gene maps to the duplicated region. Alagille syn-

drome has been reported in one family with 20p duplication [Moog

et al., 1996] and was caused by disruption, by the duplication

breakpoints, of the gene usually deleted in Alagille patients. The few

reported cases of pure terminal deletions in the 20p13 region were

identified through subtelomere screening studies in patients pre-

senting idiopathic mental retardation and developmental delay

[Baker et al., 2002; Adeyinka et al., 2005; Ravnan et al., 2006] or

patients presenting a non-supernumerary ring chromosome 20

with isolated loss of the 20p13 region [Zou et al., 2006]. To our

knowledge, no interstitial deletion overlapping our deleted region

has ever been reported. The genotype–phenotype correlation of

monosomy 20pter is presented in Table II. Most subjects presenting

a terminal 20p deletion display developmental retardation (8 of 12

cases). In our case, it is difficult to determine whether this feature is

related to the loss of the 20p subtelomeric region or interstitial

trisomy of 20p. Three familial cases of deletion 20pter have been

reported [Baker et al., 2002; Adeyinka et al., 2005; Ravnan et al.,

2006]. Clinical findings reported for two of these cases suggested

that the phenotypic consequences of this chromosomal imbalance

were variable. In one case, the phenotype of the transmitting mother

was much milder (isolated hearing loss; Table II) than that of the

child, whereas, in the second case, the transmitting mother and the

affected child had much more similar phenotypes. It is therefore

difficult to evaluate the phenotypic repercussions of monosomy

20pter.

In silico analysis of the deleted region of 20p13 revealed that

several genes known to be selectively expressed in the brain,

including those encoding NRSN2, syntaphilin and SIRP, had been

deleted. NRSN2 is a small membrane protein present in various

neurons [Nakanishi et al., 2006], whereas syntaphilin is a presyn-

aptic membrane protein that regulates synaptic vesicle exocytosis

and endocytosis [Lao et al., 2000; Das et al., 2003]. The p84 or SIRP

protein is a neural adhesion molecule that may play an important

role in synaptogenesis [Eckert et al., 1997]. These genes have not

previously been implicated in any disease, but their absence could

be involved in the developmental retardation observed in our

patient.

In conclusion, we describe here the first patient presenting a de

novo inv dup del (20p) with clinical manifestation mostly consis-

tent with partial trisomy 20p. This abnormality was suspected on

karyotyping, but high-resolution molecular cytogenetic investiga-

tions made it possible to define the breakpoints of the rearrange-

ment and to establish the most likely mechanism.

ACKNOWLEDGMENTS

We thank the parents of our patient for supporting this

publication.

REFERENCES

Adeyinka A, Adams SA, Lorentz CP, Van Dyke DL, Jalal SM. 2005.Subtelomere deletions and translocations are frequently familial. Am JMed Genet Part A 135A:28–35.

Aviram-Goldring A, Fritz B, Bartsch C, Steuber E, Daniely M, Lev D, ChakiR, Barkai G, Frydman M, Rehder H. 2000. Molecular cytogenetic studiesin three patients with partial trisomy 2p, including CGH from paraffin-embedded tissue. Am J Med Genet 91:74–82.

Baker E, Hinton L, Callen DF, Altree M, Dobbie A, Eyre HJ, Sutherland GR,Thompson E, Thompson P, Woollatt E, Haan E. 2002. Study of 250children with idiopathic mental retardation reveals nine cryptic anddiverse subtelomeric chromosome anomalies. Am J Med Genet107:285–293.

Ballif BC, Yu W, Shaw CA, Kashork CD, Shaffer LG. 2003. Monosomy 1p36breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cyclesare involved in generating terminal deletions. Hum Mol Genet 12:2153–2165.

Bansal V, Bashir A, Bafna V. 2007. Evidence for large inversion poly-morphisms in the human genome from HapMap data. Genome Res17:219–230.

Beaujard MP, Jouannic JM, Bessieres B, Borie C, Martin-Luis I, Fallet-Bianco C, Portnoi MF. 2005. Prenatal detection of a de novo terminalinverted duplication 4p in a fetus with the Wolf-Hirschhorn syndromephenotype. Prenat Diagn 25:451–455.

Belin V, Farhat M, Monset-Couchard M. 1999. Intracytoplasmic sperminjection pregnancy with trisomy 20p and monosomy 22q in a newbornresulting from a balanced paternal translocation. Biol Neonate 75:398–401.

Bonaglia MC, Giorda R, Poggi G, Raggi ME, Rossi E, Baroncini A, Giglio S,Borgatti R, Zuffardi O. 2000. Inverted duplications are recurrent rear-rangements always associated with a distal deletion: Description of a newcase involving 2q. Eur J Hum Genet 8:597–603.

Bown N, Cross I, Davison EV, Burn J. 1986. Partial trisomy 20p resultingfrom a recombination of a familial pericentric inversion. Hum Genet74:417–419.

Brenk CH, Prott EC, Trost D, Hoischen A, Walldorf C, Radlwimmer B,Wieczorek D, Propping P, Gillessen-Kaesbach G, Weber RG, Engels H.2007. Towards mapping phenotypical traits in 18p-syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybrid-isation. Eur J Hum Genet 15:35–44.

Chaabouni M, Turleau C, Karboul L, Jemaa LB, Maazoul F, Attie-Bitach T,Romana S, Chaabouni H. 2007. De novo trisomy 20p of paternal origin.Am J Med Genet Part A 143A:1100–1103.

Chen CP, Chern SR, Lin SP, Lin CC, Li YC, Wang TH, Lee CC, Pan CW,Hsieh LJ, Wang W. 2005. A paternally derived inverted duplication ofdistal 14q with a terminal 14q deletion. Am J Med Genet Part A139A:146–150.

Cotter PD, Kaffe S, Li L, Gershin IF, Hirschhorn K. 2001. Loss ofsubtelomeric sequence associated with a terminal inversion duplicationof the short arm of chromosome 4. Am J Med Genet 102:76–80.

Courtens W, Grossman D, Van Roy N, Messiaen L, Vamos E, Toppet V,Haumont D, Streydio C, Jauch A, Vermeesch JR, Speleman F. 1998.Noonan-like phenotype in monozygotic twins with a duplication-defi-ciency of the long arm of chromosome 18 resulting from a maternalparacentric inversion. Hum Genet 103:497–505.

Das S, Boczan J, Gerwin C, Zald PB, Sheng ZH. 2003. Regional anddevelopmental regulation of syntaphilin expression in the brain: Acandidate molecular element of synaptic functional differentiation. BrainRes Mol Brain Res 116:38–49.

LECLERCQ ET AL. 443

De Brasi D, Rossi E, Giglio S, D’Agostino A, Titomanlio L, Farina V, AndriaG, Sebastio G. 2001. Inv dup del (1)(pter–>q44::q44–>q42:) with theclassical phenotype of trisomy 1q42-qter. Am J Med Genet 104:127–130.

Dupont C, Lebbar A, Teinturier C, Baverel F, Viot G, Le Tessier D, Le BozecJ, Cuisset L, Dupont JM. 2007. First reported case of intrachromosomalcryptic inv dup del Xp in a boy with developmental retardation. Am J MedGenet Part A 143A:1236–1243.

Eckert C, Olinsky S, Cummins J, Stephan D, Narayanan V. 1997. Mappingof the human P84 gene to the subtelomeric region of chromosome 20p.Somat Cell Mol Genet 23:297–301.

Fisher AM, Thomas NS, Cockwell A, Stecko O, Kerr B, Temple IK, ClaytonP. 2002. Duplications of chromosome 11p15 of maternal origin result in aphenotype that includes growth retardation. Hum Genet 111:290–296.

Floridia G, Piantanida M, Minelli A, Dellavecchia C, Bonaglia C, Rossi E,Gimelli G, Croci G, Franchi F, Gilgenkrantz S, Grammatico P, Dalpra L,Wood S, Danesino C, Zuffardi O. 1996. The same molecular mechanismat the maternal meiosis I produces mono- and dicentric 8p duplications.Am J Hum Genet 58:785–796.

Fryns JP, Kleczkowska A, Decock P, Massa G, van den Berghe H. 1992.46,XX/46,XX,del(20)(pter! p12.2) mosaicism limited to fibroblastsassociated with MCA/MR and severe growth deficit. Ann Genet35:234–236.

Funderburk SJ, Sparkes RS, Sparkes MC. 1983. Trisomy 20p due to apaternal reciprocal translocation. Ann Genet 26:94–97.

Genesio R, De Brasi D, Conti A, Borghese A, Di Micco P, Di Costanzo P,Paladini D, Ungaro P, Nitsch L. 2004. Inverted duplication of 15q withterminal deletion in a multiple malformed newborn with intrauterinegrowth failure and lethal phenotype. Am J Med Genet Part A128A:422–428.

Giglio S, Broman KW, Matsumoto N, Calvari V, Gimelli G, Neumann T,Ohashi H, Voullaire L, Larizza D, Giorda R, Weber JL, Ledbetter DH,Zuffardi O. 2001. Olfactory receptor-gene clusters, genomic-inversionpolymorphisms, and common chromosome rearrangements. Am J HumGenet 68:874–883.

Grammatico P, Cupilari F, Di Rosa C, Falcolini M, Del Porto G. 1992. 20 pduplication as a result of parental translocation: Familial case report and acontribution to the clinical delineation of the syndrome. Clin Genet41:285–289.

Gruchy N, Jacquemont ML, Lyonnet S, Labrune P, El Kamel I, Siffroi JP,Portnoi MF. 2007. Recurrent inverted duplication of 2p with terminaldeletion in a patient with the classical phenotype of trisomy 2p23-pter.Am J Med Genet Part A 143A:2417–2422.

Hoo JJ, Chao M, Szego K, Rauer M, Echiverri SC, Harris C. 1995. Four newcases of inverted terminal duplication: A modified hypothesis of mecha-nism of origin. Am J Med Genet 58:299–304.

Jenderny J, Poetsch M, Hoeltzenbein M, Friedrich U, Jauch A. 1998.Detection of a concomitant distal deletion in an inverted duplicationof chromosome 3. Is there an overall mechanism for the origin of suchduplications/deficiencies? Eur J Hum Genet 6:439–444.

Kennedy D, Silver MM, Winsor EJ, Toi A, Provias J, Macha M, Precht K,Ledbetter DH, Chitayat D. 2000. Inverted duplication of the distal shortarm of chromosome 3 associated with lobar holoprosencephaly andlumbosacral meningomyelocele. Am J Med Genet 91:167–170.

Knijnenburg J, van Haeringen A, Hansson KB, Lankester A, Smit MJ,Belfroid RD, Bakker E, Rosenberg C, Tanke HJ, Szuhai K. 2007. Ringchromosome formation as a novel escape mechanism in patients withinverted duplication and terminal deletion. Eur J Hum Genet15:548–555.

Kondoh Y, Toma T, Ohashi H, Harada N, Yoshiura K, Ohta T, Kishino T,Niikawa N, Matsumoto N. 2003. Inv dup del(4)(:p14 –>p16.3::p16.3 –>

qter) with manifestations of partial duplication 4p and Wolf-Hirschhornsyndrome. Am J Med Genet Part A 120A:123–126.

Lao G, Scheuss V, Gerwin CM, Su Q, Mochida S, Rettig J, Sheng ZH. 2000.Syntaphilin: A syntaxin-1 clamp that controls SNARE assembly. Neuron25:191–201.

LeChien KA, McPherson E, Estop AM. 1994. Duplication 20p identified viafluorescent in situ hybridization. Am J Med Genet 50:187–189.

Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ,Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA,Hood L, Spinner NB. 1997. Alagille syndrome is caused by mutationsin human Jagged1, which encodes a ligand for Notch1. Nat Genet16:243–251.

Lucas J, Le M�ee F, Le Marec B, Pluquailec K, Journel H, Picard F. 1985.Trisomy 20p derived from a maternal pericentric inversion and brachy-mesophalangy of the index finger. Ann Genet 28:167–171.

Lurie IW, Rumyantseva NV, Zaletajev DV, Gurevich DB, Korotkova IA.1985. Trisomy 20p: Case report and genetic review. J Genet Hum33:67–75.

Marcus ES, Fuller B, Riccardi VM. 1979. Triplication of chromosome arm20p due to inherited translocation and secondary nondisjunction. Am JMed Genet 4:47–50.

Mewar R, Harrison W, Weaver DD, Palmer C, Davee MA, Overhauser J.1994. Molecular cytogenetic determination of a deletion/duplication of1q that results in a trisomy 18 syndrome-like phenotype. Am J Med Genet52:178–183.

Milunsky J, Huang XL, Wyandt HE, Milunsky A. 1999. Schizophreniasusceptibility gene locus at Xp22.3. Clin Genet 55:455–460.

Mitchell JJ, Vekemans M, Luscombe S, Hayden M, Weber B, Richter A,Sparkes R, Kojis T, Watters G, Der Kaloustian VM. 1994. U-typeexchange in a paracentric inversion as a possible mechanism of originof an inverted tandem duplication of chromosome 8. Am J Med Genet49:384–387.

Molina-Gomes D, Nebout V, Daikha-Dahmane F, Vialard F, Ville Y, SelvaJ. 2006. Partial trisomy 20p resulting from recombination of a maternalpericentric inversion: Case report of a prenatal diagnosis by chorionicvillus sampling. Prenat Diagn 26:239–241.

Moog U, Engelen J, Albrechts J, Hoorntje T, Hendrikse F, Schrander-Stumpel C. 1996. Alagille syndrome in a family with duplication 20p11.Clin Dysmorphol 5:279–288.

Morrissette JJ, Medne L, Bentley T, Owens NL, Geiger E, Pipan M, ZackaiEH, Shaikh T, Spinner NB. 2005. A patient with mosaic partial trisomy 18resulting from dicentric chromosome breakage. Am J Med Genet Part A137A:208–212.

Nakanishi K, Ida M, Suzuki H, Kitano C, Yamamoto A, Mori N, Araki M,Taketani S. 2006. Molecular characterization of a transport vesicleprotein Neurensin-2, a homologue of Neurensin-1, expressed in neuralcells. Brain Res 1081:1–8.

Oppenheimer S, Dignan P, Soukup S. 2000. Partial trisomy 20p: Familialoccurrence. Am J Med Genet 95:316–319.

Pangalos C, Theophile D, Sinet PM, Marks A, Stamboulieh-Abazis D,Chettouh Z, Prieur M, Verellen C, Rethore MO, Lejeune J, et al. 1992. Nosignificant effect of monosomy for distal 21q22.3 on the Down syndromephenotype in ‘‘mirror’’ duplications of chromosome 21. Am J HumGenet 51:1240–1250.

Ravnan JB, Tepperberg JH, Papenhausen P, Lamb AN, Hedrick J, Eash D,Ledbetter DH, Martin CL. 2006. Subtelomere FISH analysis of 11 688cases: An evaluation of the frequency and pattern of subtelomererearrangements in individuals with developmental disabilities. J MedGenet 43:478–489.

444 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Rossi E, Riegel M, Messa J, Gimelli S, Maraschio P, Ciccone R, Stroppi M,Riva P, Perrotta C, Mattina T, Baumer A, Kucinskas V, Castellan C,Schinzel A, Zuffardi O. 2008. Duplications in addition to terminaldeletions are present in a proportion of ring chromosomes. Clues tothe mechanisms of formation. J Med Genet 45:147–154.

Sauter S, von Beust G, Burfeind P, Weise A, Starke H, Liehr T, Zoll B.2003. Autistic disorder and chromosomal mosaicism 46,XY[123]/46,XY,del(20)(pter! p12.2)[10]. Am J Med Genet Part A 120A:533–536.

Shimokawa O, Kurosawa K, Ida T, Harada N, Kondoh T, Miyake N,Yoshiura K, Kishino T, Ohta T, Niikawa N, Matsumoto N. 2004.Molecular characterization of inv dup del (8p): Analysis of five cases.Am J Med Genet Part A 128A:133–137.

Sidwell RU, Pinson MP, Gibbons B, Byatt SA, Svennevik EC, Hastings RJ,Flynn DM. 2000. Pure trisomy 20p resulting from isochromosomeformation and whole arm translocation. J Med Genet 37:454–458.

Sreekantaiah C, Kronn D, Marinescu RC, Goldin B, Overhauser J. 1999.Characterization of a complex chromosomal rearrangement in a patientwith a typical catlike cry and no other clinical findings of cri-du-chatsyndrome. Am J Med Genet 86:264–268.

Stetten G, Charity LL, Kasch LM, Scott AF, Berman CL, Pressman E,Blakemore KJ. 1997. A paternally derived inverted duplication of 7q withevidence of a telomeric deletion. Am J Med Genet 68:76–81.

Sugawara H, Harada N, Ida T, Ishida T, Ledbetter DH, Yoshiura K, Ohta T,Kishino T, Niikawa N, Matsumoto N. 2003. Complex low-copy repeatsassociated with a common polymorphic inversion at human chromo-some 8p23. Genomics 82:238–244.

Taylor KM, Wolfinger HL, Brown MG, Chadwick DL, Francke U. 1976.Partial trisomy 20p derived from a t(18;20) translocation. Hum Genet34:155–162.

Teebi AS, Gibson L, McGrath J, Meyn MS, Breg WR, Yang-Feng TL. 1993.Molecular and cytogenetic characterization of 9p- abnormalities. Am JMed Genet 46:288–292.

Thangavelu M, Frolich G, Rogers D. 2004. Partial duplication 2p as the soleabnormality in two cases with anencephaly. Am J Med Genet Part A124A:170–172.

Thomas MA, Duncan AM, Bardin C, Kaloustian VM. 2004. Lissencephalywith der(17)t(17;20)(p13.3;p12.2)mat. Am J Med Genet Part A124A:292–295.

Tonk VS, Wilson GN, Yatsenko SA, Stankiewicz P, Lupski JR, Schutt RC,Northup JK, Velagaleti GV. 2005. Molecular cytogenetic characterizationof a familial der(1)del(1)(p36.33)dup(1)(p36.33p36.22) with variablephenotype. Am J Med Genet Part A 139A:136–140.

T€umer Z, Berg A, Mikkelsen M. 1995. Analysis of a whole arm translocationbetween chromosomes 18 and 20 using fluorescence in situ hybridiza-tion: Detection of a break in the centromeric alpha-satellite sequences.Hum Genet 95:299–302.

Vamos E, Pratola D, Van Regemorter N, Freund M, Flament-Durand J,Rodesch F. 1985. Prenatal diagnosis and fetal pathology of partial trisomy20P-monosomy 4P resulting from paternal translocation. Prenat Diagn5:209–214.

Van Buggenhout G, Maas NM, Fryns JP, Vermeesch JR. 2004. A dysmor-phic boy with 4qter deletion and 4q32. 3-34. 3 duplication: Clinical,cytogenetic, and molecular findings. Am J Med Genet Part A131A:186–189.

Vermeesch JR, Thoelen R, Salden I, Raes M, Matthijs G, Fryns JP. 2003.Mosaicism del (8p) inv dup/(8p) in a dysmorphic female infant: A mosaicformed by a meiotic error at the 8p OR gene, and an independent terminaldeletion event. Med Genet J 40:e93.

Weleber RG, Verma RS, Kimberling WJ, Fieger HG Jr, lubs HA. 1976.Duplication-deficiency of the short arm of chromosome 8 followingartificial insemination. Ann Genet 19:241–247.

Wieczorek D, Bartsch O, Gillessen-Kaesbach G. 2003. Distal monosomy18p/distal trisomy 20p—A recognizable facial phenotype? Am J MedGenet Part A 120A:429–433.

Zou YS, Van Dyke DL, Thorland EC, Chhabra HS, Michels VV, Keefe JG,Lega MA, Feely MA, Uphoff TS, Jalal SM. 2006. Mosaic ring 20 with nodetectable deletion by FISH analysis: Characteristic seizure disorder andliterature review. Am J Med Genet Part A 140A:1696–1706.

Zumel RM, Darnaude MT, Delicado A, Diaz de Bustamante A, de TorresML, L�opez Pajares I. 1989. Trisomy 20p from maternal translocation andanencephaly. Case report and genetic review. Ann Genet 32:247–249.

LECLERCQ ET AL. 445