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Short Communication
Inv dup del(9p): Prenatal diagnosis and molecular cytogenetic
characterization by fluorescence in situ hybridization
and array comparative genomic hybridization
Chih-Ping Chen
a,b,c,d,e,f,*
, Yi-Ning Su
g, Schu-Rern Chern
b, Chin-Yuan Hsu
a, Fuu-Jen Tsai
d,h,
Pei-Chen Wu
a, Chen-Chi Lee
a, Yu-Ting Chen
b, Meng-Shan Lee
a, Wayseen Wang
b,iaDepartment of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan b
Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
c
Department of Biotechnology, Asia University, Taichung, Taiwan
d
School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
e
Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan
f
Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
g
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
h
Department of Medical Research and Medical Genetics, China Medical University Hospital, Taichung, Taiwan
i
Department of Bioengineering, Tatung University, Taipei, Taiwan Accepted 11 November 2010
Abstract
Objective: To present molecular cytogenetic characterization of prenatally detected inverted duplication and deletion of 9p, or inv dup del(9p).
Materials, Methods, and Results: A 35-year-old primigravid woman underwent amniocentesis at 16 weeks of gestation because of advanced
maternal age. Amniocentesis revealed a derivative chromosome 9, or der(9) with additional material at the end of the short arm of one chromosome
9. Parental karyotypes were normal. Level II ultrasound showed ventriculomegaly and normal male external genitalia. Repeated amniocentesis was
performed at 20 weeks of gestation. Array comparative genomic hybridization revealed a 0.70-Mb deletion at 9p24.3 and an 18.36-Mb duplication
from 9p24.3 to 9p22.1. The distal 9p deletion encompassed the genes of DOCK8, ANKRD15, FOXD4, DMRT1, and DMRT3. Fluorescence in situ
hybridization analysis using bacterial artificial chromosome clone probes specific for 9p confirmed that the der(9) was derived from the inv dup del
(9p). The karyotype of the fetus was 46,XY,inv dup del(9)(:p22.1/p24.3::p24.3/qter)dn or 46,XY,der(9) del(9)(p24.3) inv dup(9)(p22.1p24.3)
dn. Polymorphic DNA marker analysis determined a maternal origin of the inv dup del(9p). A 512-g male fetus was subsequently terminated at 22
weeks of gestation with facial dysmorphism. The fetus had normal male external genitalia without sex reversal.
Conclusion: Fluorescence in situ hybridization and array comparative genomic hybridization are useful to determine the nature of a prenatally
detected aberrant chromosome derived from the inv dup del. Male fetuses with inv dup del(9p) and haploinsufficiency of DMRT1 and DMRT3
may present normal male external genitalia without sex reversal.
Copyright
Ó 2011, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: 9p; Array comparative genomic hybridization; Deletion; FISH; Inverted duplication; inv dup del(9p)
Introduction
An inverted duplication with a terminal deletion (inv dup
del) is a rare complex chromosomal rearrangement that
involves an inverted duplication of a part of a chromosome in
association with a deletion distal to the site of duplication. The
* Corresponding author. Department of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei, Taiwan.
E-mail address:cpc_mmh@yahoo.com(C.-P. Chen).
Available online at www.sciencedirect.com
Taiwanese Journal of Obstetrics & Gynecology 50 (2011) 67e73
www.tjog-online.com
1028-4559/$ - see front matter CopyrightÓ 2011, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.tjog.2011.01.038
inv dup del has been reported in several chromosomes, such as
1p
[1,2]
, 1q
[3,4]
, 2p
[5,6]
, 2q
[7
e10]
, 3p
[11,12]
, 4p
[13
e15]
,
4q
[16]
, 5p
[17,18]
, 6p
[19]
, 7q
[20,21]
, 8p
[22
e29]
, 9p
[30
e35]
, 10p and 10q
[20]
, 11p
[36]
, 14q
[37,38]
, 15q
[39]
,
20p
[40]
, 21q
[41]
, and Xp
[42,43]
.
Proposed mechanisms of the inv dup del include the
U-type exchange model in which an intrachromosomal
recombination and an end-to-end fusion occur in two
homol-ogous chromosomes resulting in a dicentric chromosome; and
following division, the dicentric chromosome can break and
result in a recombinant chromosome with an inverted
dupli-cation and a loss of chromosomal material distal to the site of
recombination
[44]
; the nonallelic homologous recombination
model mediated by an unequal crossover between inverted
low-copy repeats
[24]
; and the premeiotic nonhomologous
end joining model in which a terminal deleted chromosome is
generated in the germline and passes through at least one
breakage-fusion-bridge cycle leading to a sister chromatid
fusion by an nonhomologous end joining and the production of
gametes with terminal deletions and interrupted inverted
duplications
[1]
.
Prenatal diagnosis of the inv dup del(9p) has not been
previously described. Here, we report prenatal diagnosis,
molecular cytogenetic analysis, and perinatal findings of
a male fetus with inv dup del(9p).
Materials, methods, and results
A 35-year-old primigravid woman underwent
amniocen-tesis at 16 weeks of gestation because of advanced maternal
age. Cytogenetic analysis then revealed a derivative
chromo-some 9, or der(9), with additional material at the end of the
short arm of one chromosome 9. The parental karyotypes were
normal. The woman requested repeated amniocentesis at 20
weeks of gestation, which revealed an inv dup del(9p) (
Fig. 1
).
Using uncultured amniocytes, bacterial artificial chromosome
(BAC)-based
array
comparative
genomic
hybridization
(aCGH) (CMDX BAC-based aCGH CA3000 chips) (CMDX,
Irvine, CA, USA) demonstrated a 9p deletion encompassing
about 0.37 Mb from clone RP11-1112G24 to RP11-130C19
and a 9p duplication encompassing about 17.87 Mb from
clone RP11-690N7 to RP11-322J7. The result of BAC-aCGH
was arr cgh 9p24.3p24.3 (RP11-1112G24
/RP11-130C19)
1, 9p24.3p22.1 (RP11-690N7
/RP11-322J7)3 (
Fig. 2
).
Fig. 1. (A) A karyotype 46,XY,inv dup del(9)(:p22.1/p24.3::p24.3/qter) or 46,XY,der(9)del(9)(p24.3) inv dup(9)(p22.1p24.3) in the fetus; (B) Partial G-banded karyotype of the fetus showing one normal chromosome 9 and one derivative chromosome 9, or der(9), with inv dup del(9p). The arrows indicate the breakpoints. inv dup del¼ inverted duplication with a terminal deletion.
Fig. 2. BAC based-aCGH shows a deletion of terminal 9p [arr cgh 9p24.3p24.3 (RP11-1112G24/RP11-130C19)1] and a duplication of distal 9p [arr 9p24.3p22.1 (RP11-690N7/RP11-322J7)3]. aCGH ¼ array comparative genomic hybridization; BAC¼ bacterial artificial chromosome.
For fluorescence in situ hybridization determination of the
inv dup del in the der(9), the BAC clone probe mapping the
genomic region of the distal chromosome 9p, and the
telo-meric region of 9p were used. The BAC clone probes
RP11-32F11 (3,104,722
e3,267,008) (spectrum green) at 9p24.2 and
RP11-340N12 (17,136,369
e17,298,494) (spectrum red) at
9p22.2 were used to determine the inverted duplication. The
BAC clone probe RP11-31F19 (537,217
e682,143) (spectrum
green) at 9p24.3 and the Telomere 9q probe (TelVysion 9q;
Vysis, Downers, Grove, IL, USA) (spectrum red) (control)
were used to determine the terminal 9p deletion. Fluorescence
in situ hybridization analysis showed an inverted duplication
of distal 9p with an inverted duplication orientation of
red-green-green-red (
Fig. 3
) and a terminal deletion with absence
of a green signal on der(9) (
Fig. 4
). The karyotype of the fetus
was 46,XY,inv dup del(9)(:p22.1
/p24.3::p24.3/qter)dn or
46,XY,der(9) del(9)(p24.3) inv dup(9)(p22.1p24.3)dn.
Level II ultrasound showed ventriculomegaly and normal
male external genitalia at 21 weeks of gestation. The parents
opted to terminate the pregnancy at 22 weeks of gestation. A
518-g male fetus was delivered with dysmorphism of
hyper-telorism, a prominent nose, and low-set ears (
Fig. 5
). The male
external genitalia were normal (
Fig. 6
). Cytogenetic analysis
of the cord blood confirmed the prenatal diagnosis. Using fetal
blood, oligonucleotide-based (oligo) aCGH (SurePrint G3
Human CGH Microarray kit 60K; Agilent Technologies, Santa
Clara, CA, USA) demonstrated a 0.70-Mb deletion at 9p24.3
(271,057
e974,003) (NCBI build 36 March 2006) and an
18.36-Mb duplication from 9p24.3 to 9p22.1 (1,036,210
e
19,396,808) (
Fig. 7
). The result of oligo-aCGH was arr cgh
9p24.3p24.3 (271,057
e974,003)1, 9p24.3p22.1 (1,036,210e
19,396,808)
3. Microsatellite analysis using the fetal and
parental DNA demonstrated that the deletion and duplication
of 9p were maternal in origin. In the duplicated segment of 9p,
all the informative microsatellites were homozygous
indi-cating an intrachromosomal event.
Discussion
We have reported an inverted duplication of the distal
portion of the short arm of chromosome 9 (9p22.1
/p24.3)
and a deletion of the distal portion (9p24.3
/pter) in a male
fetus who manifested ventriculomegaly on prenatal ultrasound
and facial dysmorphism at birth. The inv dup del(9p) was
maternal in origin and intrachromosomal. The homozygosity
throughout the duplicated segment implicates a possible
U-type exchange mechanism, although other mechanisms
cannot be completely excluded. To date, at least six cases with
9p duplication/deletion have previously been reported, and all
were females. Teebi et al
[30]
first reported a 20-month-old
female with an inverted duplication of proximal 9p and
a deletion of distal 9p, or inv dup del(9)(:p13
/p22::p22/
qter), prenatal intrauterine growth restriction, psychomotor
developmental delay, a small umbilical hernia, and
craniofa-cial dysmorphisms, including a narrow forehead with metopic
ridging, a small anterior fontanelle, a small nose, midface
hypoplasia, mild upward slant of palpebral fissures, mild
epicanthic folds, thin and long eyebrows with mild synophrys,
thin lips, and a short neck. The girl had an inverted duplication
of proximal 9p (9p13
/p22) and a deletion of distal 9p
(p22
/pter). In this case, during pregnancy, intrauterine
Fig. 3. FISH using BAC RP11-340N12 (red) at 9p22.2 and RP11-32F11 (green) at 9p24.2. The der(9) shows four signals in the order of red-green-green-red indicating an inverted duplication of 9p. BAC¼ bacterial artificial chromosome; FISH¼ fluorescence in situ hybridization.
Fig. 4. FISH using BAC RP11-31F19 (green) at 9p24.3 and the Telomere 9q probe (TelVysion 9q) (red) shows absence of a green signal on der(9) indi-cating a terminal deletion of 9p. BAC¼ bacterial artificial chromosome; FISH¼ fluorescence in situ hybridization.
growth restriction was noted but a chromosome analysis
of amniocytes was reportedly normal. Krepischi-Santos and
Vianna-Morgante
[31]
reported a 16-year-2-month-old female
with terminal deletion and an inverted duplication involving at
least 9p23-p25.1. The duplication was paternal in origin. The
girl manifested microcephaly, frontal bossing, a low-set frontal
hairline, facial hirsutism, hypertelorism, deep-set and
down-slanting eyes, epicanthus, a broad-based nose with a bulbous
tip, a short and well-defined philtrum, downturned corners of
the mouth, retrognathia, low-set large and protruding ears,
hypoplastic nails, and bilateral single transverse creases. Her
menstrual cycles were normal. Chabchoub et al
[32]
reported
a 10-year-old female with mosaicism for inv dup del(9p)
and a karyotype of 46,XX,del(9)(p22.1)/46,XX,der(9)t(5;9)
(p13.3;p22.1), del(9)(p22.1),dup(9) (p13.3
/p22.1::p22.1/
qter). The girl manifested psychomotor developmental delay,
mild synophrys, hypoplastic alae nasi, long and smooth
phil-trum, a thin upper lip, small and dysmorphic ears,
campto-dactyly of the fifth fingers, upslanting palpebral fissures,
prominent metopic suture, depressed and broad nasal root,
plagiocephaly, a hypoplastic ectopic right kidney, and
ves-iculoureteral reflux. The inv dup del(9p) was paternal in
origin. Swinkels et al
[33]
in 2008 reported a 2-year-old
female (Case 7) with a deletion of 9p (p22.3
/pter) and an inv
dup(9)(p22.1p22.3).
The
girl
manifested
developmental
speech and motor delay, hypotonia, short stature,
trig-onocephaly, upward slant short palpebral fissures, epicanthal
folds, low-set posteriorly angulated ears, a short flat nose with
anteverted nostrils, a flat philtrum, a thin upper lip, a high/
narrow palate, broad internipple distance, tapering fingers,
hyperconvex nails, and cardiac defects. Hulick et al
[34]
reported a 4-month-old female with a deletion of 9p
(p24.2
/pter) and an inv dup(9)(p21.3p24.2). The girl
man-ifested hypotonia, growth and developmental delay, cleft
palate, absent uvula, clinodactyly, large palpebral fissures,
hypertelorism, a bulbous nose, abnormal ears, and dystrophic
nails. Mosca et al
[35]
reported a 12-year-old female with
22q11.2 microdeletion and inv dup del(9p) consisting of
a deletion region spanning 0.4
e0.6 Mb and a duplication
region spanning 1.6
e11.8 Mb. The girl manifested mental
retardation and asymmetric polymicrogyria predominantly
affecting the right occipital lobe.
The present case was associated with partial trisomy 9p
and ventriculomegaly. Gene dosage effect on chromosome 9p
is responsible for normal development of the central nervous
system. Partial trisomy 9p has been reported to be associated
with abnormal neural migration, subcortical band heterotopia,
Fig. 5. The craniofacial appearance of the fetus at birth.
Fig. 6. The male external genitalia of the fetus at birth.
Dandy-Walker malformation, ventriculomegaly, corpus
cal-losum hypogenesis or agenesis, and polymicrogyria
[35,45
e49]
.
The present case was also associated with a distal 9p
deletion encompassing the genes of DOCK8, ANKRD15,
FOXD4, DMRT1, and DMRT3. Genetic aberrations in DOCK8,
ANKRD15, and FOXD4 may result in neurological and
psychiatric disorders. DOCK8 [Online Mendelian Inheritance
in Man (OMIM) 611432] is a gene associated with autosomal
dominant mental retardation 2
[50]
. Heterozygous disruption
of the DOCK8 gene by deletion or by translocation breakpoints
has been reported to cause mental retardation and
develop-mental disability. ANKRD15 (OMIM 607704) is a maternally
imprinted gene that is expressed only from the paternal allele
[51]
. Deletion of the ANKRD15 gene causes
parent-of-origin-dependent inheritance of familial cerebral palsy that occurs
only in individuals inheriting the deletion from the father
[51]
.
FOXD4 (OMIM 601092) encodes forkhead box D4 protein,
which is a transcription factor. FOXD4 is expressed in the
heart, skeletal muscles, and brain
[52]
. Mutations in the human
FOXD4 gene can cause a complex phenotype consisting of
dilated cardiomyopathy, obsessive-compulsive disorders, and
suicidality
[53]
.
Distal 9p deletion can be associated with 46,XY gonadal
dysgenesis and sex reversal
[54
e56]
. There are three DMRT
genes, namely DMRT1, DMRT2, and DMRT3 genes, all at
9p24.3. DMRT1 and DMRT2 are well-known sex-determining
genes
[54,56]
, but the role of DMRT3 on sex determination is
not clear at the present time. DMRT1 (OMIM 602424)
encodes doublesex- and MAB3-related transcription factor 1,
which is a male-specific transcriptional regulator involved in
sex determination and differentiation
[57,58]
. DMRT2 (OMIM
604935) encodes DMRT2 protein, which is also associated
with gonadal dysgenesis and XY sex reversal
[54,59]
. In the
present case, only DMRT1 and DMRT3 were deleted, and
DMRT2 was intact. Our fetus showed normal male external
genitalia without sex reversal. Although DMRT1 gene is
involved in sex development, incomplete penetrance with
differences in the phenotype of abnormal male sex
develop-ment still exists
[60]
. Patients with a 9p24 deletion have been
reported to manifest normal male external genitalia and/or
mild gonadal abnormalities
[33,61
e63]
. Barbaro et al
[60]
suggested that a more complicated mechanism should be
hypothesized to explain the variable penetrance. In addition to
DMRT, other sex-determining genes, such as SF1, DAX1,
WT1, WNT4, and SOX9 are associated with male gonadal
development. Investigations of the interaction among those
sex-determining genes and the gene dosage threshold effect
are required for further elucidation of the complicated
mech-anism of the variable penetrance.
Acknowledgments
This work was supported by research grants
NSC-96-2314-B-195-008-MY3 and NSC-97-2314-B-195-006-MY3 from the
National Science Council and MMH-E-99004 from Mackay
Memorial Hospital, Taipei, Taiwan.
Fig. 7. Oligonucleotide-based aCGH shows a 0.70-Mb deletion at terminal 9p [arr cgh 9p24.3p24.3 (271,057e974,003)1] and an 18.36-Mb duplication of 9p22.1/p24.3 [arr cgh 9p24.3p22.1 (1,036,210e19,396,808)3]. aCGH ¼ array comparative genomic hybridization.
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![Fig. 7. Oligonucleotide-based aCGH shows a 0.70-Mb deletion at terminal 9p [arr cgh 9p24.3p24.3 (271,057 e974,003)1] and an 18.36-Mb duplication of 9p22.1 /p24.3 [arr cgh 9p24.3p22.1 (1,036,210e19,396,808)3]](https://thumb-ap.123doks.com/thumbv2/9libinfo/8969149.278931/6.892.134.781.134.581/fig-oligonucleotide-based-acgh-shows-deletion-terminal-duplication.webp)
