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Gene 527 (2013) 405409

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Short Communication

Chromosome 22q11.2 deletion syndrome: prenatal diagnosis, array

comparative genomic hybridization characterization using uncultured
amniocytes and literature review
Chih-Ping Chen a,b,c,d,e,f,g,, Jian-Pei Huang a,h, Yi-Yung Chen a, Schu-Rern Chern b, Peih-Shan Wu i,
Jun-Wei Su a,j, Yu-Ting Chen b, Wen-Lin Chen a, Wayseen Wang b,k

Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan

Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
Department of Biotechnology, Asia University, Taichung, Taiwan
School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan
Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
Mackay Medicine, Nursing and Management College, Taipei, Taiwan
Gene Biodesign Co. Ltd, Taipei, Taiwan
Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
Department of Bioengineering, Tatung University, Taipei, Taiwan

a r t i c l e

i n f o

Article history:
Accepted 4 June 2013
Available online 17 June 2013
22q11.2 deletion syndrome
Conotruncal heart malformations
Prenatal diagnosis

a b s t r a c t
We present prenatal diagnosis of de novo 22q11.2 microdeletion syndrome using uncultured amniocytes in
a pregnancy with conotruncal heart malformations in the fetus. We discuss the genotypephenotype correlation and the consequence of haploinsufciency of TBX1, COMT, UFD1L, GNB1L and MED15 in the deleted
region. We review the literature of chromosomal loci and genes responsible for conotruncal heart
malformations and tetralogy of Fallot.
2013 Elsevier B.V. All rights reserved.

1. Introduction
Chromosome 22q11.2 deletion syndrome occurs in 1:4000
1:8000 live births (Scambler, 2000). Chromosome 22q11.2 deletion
syndrome, including DGS (OMIM 188400) and VCFS (OMIM
192430), is caused by a 1.53.0-Mb hemizygous deletion of
22q11.2 and is associated with a highly variable phenotype caused
mainly by haploinsufciency of the TBX1 gene (OMIM 602054)

Abbreviations: aCGH, array comparative genomic hybridization; OMIM, Online

Mendelian Inheritance in Man; DGS, DiGeorge syndrome; VCFS, velocardiofacial syndrome; del, deletion; MLPA, multiplex ligation-dependent probe amplication; VSD,
ventricular septal defect; FISH, uorescence in situ hybridization; DORV, double-outlet
right ventricle; TOF, tetralogy of Fallot; CTHM, conotruncal heart malformations; ASD,
atrial septal defect; AVSD, atrioventricular septal defect.
Corresponding author at: Department of Obstetrics and Gynecology, Mackay Memorial
Hospital, 92, Section 2, Chung-Shan North Road, Taipei, Taiwan. Tel.: +886 2 25433535;
fax: +886 2 25433642, +886 2 25232448.
E-mail address: (C.-P. Chen).
0378-1119/$ see front matter 2013 Elsevier B.V. All rights reserved.

which is located at 22q11.21 (McDonald-McGinn et al., 2013;

Molesky, 2011; Yu et al., 2012). DGS is characterized by outow
tract defects of the heart, thymic hypoplasia, parathyroid hypoplasia,
hypocalcemia and T-cell immunodeciency (Scambler et al., 1991).
VCFS is characterized by velopharyngeal insufciency with cleft palate, speech disorders, cardiac defects, microcephaly, short stature,
typical facial appearance, auricular anomalies, learning problems,
cognitive difculties, and intellectual disabilities (Driscoll et al.,
1992; Shprintzen et al., 1981).
With the advent of ultrasound and molecular genetic technology,
prenatal diagnosis of 22q11.2 deletion syndrome is possible by the
use of FISH, MLPA, aCGH and next generation sequencing (Chen
and Chien, 2008; Chen et al., 2004, 2009, 2013a; Chen et al., 2006;
Jensen et al., 2012; Liu et al., 2010; Mademont-Soler et al., 2012,
2013; Vialard et al., 2009). Recently, aCGH has been used prospectively on uncultured amniocytes to detect aneuploidy (Chen et al.,
2011, 2012a, 2012b, 2013b, 2013c). Here, we present our experience
of prenatal diagnosis and aCGH characterization of 22q11.2
microdeletion syndrome using uncultured amniocytes in a fetus
with conotruncal heart malformations.


C.-P. Chen et al. / Gene 527 (2013) 405409

2. Methods and detection

4. Discussion

2.1. Array-CGH

The present case had a 3.08-Mb deletion at 22q11.2 encompassing

the genes of TBX1, COMT, UFD1L, GNB1L and MED15, and manifested
craniofacial dysmorphism and conotruncal heart malformations.
Patients with 22q11.2 deletion syndrome are associated with a high
rate (74%) of congenital heart detects, especially conotruncal malformations, TOF, interrupted aortic arch, VSD and truncus arteriosus; and
a high rate (69%) of palatal malformations (McDonald-McGinn et al.,
2013). TBX1 is required for inner ear morphogenesis and is expressed
in otocyst development in the otic epithelium and in the periotic mesenchyme (Vitelli et al., 2003). In transgenic mice, Tbx1 deciency causes
cardiovascular defects, abnormal formation and growth of the pharyngeal arch arteries, and abnormal growth and septation of the outow
tract of the heart, interventricular septation and conal alignment
(Vitelli et al., 2002). Mutation or haploinsufciency of TBX1 has been associated with DGS, VCFS, CTHM (OMIM 217095) and TOF (OMIM
187500). TBX1 functions through wnt11r to regulate heart looping and
differentiation (Choudhry and Trede, 2013). In the patients with
22q11.2 deletion syndrome, TBX1 genotype correlates with cardiovascular phenotype (Guo et al., 2011). TBX1 regulates oral epithelial adhesion
and palatal development (Funato et al., 2012]. In the patients with
22q11.2 deletion syndrome, TBX1 genotype correlates with overt cleft
palate phenotype (Herman et al., 2012).
Patients with 22q11.2 deletion syndrome are associated with a high
rate (25%) of schizophrenia (Bassett et al., 2011; McDonald-McGinn et
al., 2013). van Beveren et al. (2012) identied decreased expression of
the genes GNB1L, COMT, UFD1L and MED15 in patients with 22q11.2
deletion syndrome. COMT (OMIM 116790) encodes catechol-Omethyltransferase which plays an important role in dopamine metabolism (Gogos et al., 1998). COMT is a strong candidate gene for schizophrenia susceptibility (OMIM 181500) (Ira et al., 2013; Lee et al.,
2005; Palmatier et al., 2004; Shifman et al., 2002; van Beveren et al.,
2012). GNB1L (OMIM 610778) encodes a G-protein -subunit-like polypeptide. There is strong evidence that the GNB1L is associated with
schizophrenia (Ishiguro et al., 2010; Li et al., 2011; van Beveren et al.,
2012; Williams et al., 2008). GNB1L is also associated with autism
(Chen et al., 2012c) and bipolar disorder (Li et al., 2011). UFD1L
(OMIM 601754) encodes ubiquitin degradation 1-like protein that
plays a role in degradation of ubiquitin fusion protein (Pizutti et al.,
1997). UFD1L polymorphism is associated with schizophrenia (Ota et
al., 2010; van Beveren et al., 2012; Xie et al., 2008). MED15 (OMIM
607372) or PCQAP encodes a component of the metazoan mediator
complex and plays a role in TGFB/Activin/Nodal/Smad2/3 signal transduction (Kato et al., 2002). MED15 polymorphism is associated with
schizophrenia (De Luca et al., 2003; Sandhu et al., 2004; van Beveren
et al., 2012). Other possible candidate genes of schizophrenia associated
with 22q11.2 deletion syndrome include ZDHHC8 (OMIM 608784),
PRODH (OMIM 606810), RTN4R (OMIM 605566), DGCR6 (OMIM
601279), DGCR6L (OMIM 609459) and ARVCF (OMIM 602269).
Prenatal diagnosis of cardiac defects should raise suspicion of aneuploidy and 22q11.2 microdeletion. In a study of 1510 cases with prenatally detected structural heart defects, Moore et al. (2004) found that
41.3% (624 cases) had chromosome abnormalities including trisomy 18
[36.9% (n = 230)], trisomy 21 [27.9% (n = 174)], trisomy 13 [15.4%
(n = 96)], trisomy 14 [0.6% (n = 4)], trisomy 16 [0.3% (n = 2)], trisomy 22 [0.3% (n = 2)], trisomy 9 [0.2% (n = 1)], 45,X [4% (n = 25)],
47,XXY [0.2% (n = 1)], triploidy [4.3% (n = 27)], balanced translocation
[5.1% (n = 32)], balanced inversion [0.6% (n = 4)], unbalanced derivative chromosome [3.2% (n = 20)] and deletion [1% (n = 6)], and 58.7%
(886 cases) had apparently normal karyotypes of which 3.1% (17 cases)
had 22q11.2 microdeletion conrmed by FISH. In a study of 169 pregnancies with prenatal FISH screening for 22q11.2 deletion because of
congenital heart defects, most being conotruncal (n = 147), extracardiac
ultrasound ndings (n = 7), positive family history (n = 10) and
unknown causes (n = 5), Bretelle et al. (2010) found that 4.7% (8/169)

Whole-genome aCGH on uncultured amniocytes derived from

10 mL of amniotic uid was performed using NimbleGen ISCA Plus Cytogenetic Array (Roche NimbleGen, Madison, WI, USA). The NimbleGen
ISCA Plus Cytogenetic Array has 630,000 probes and a median resolution
of 1520 kb across the entire genome according to the manufacturer's
instruction. Parental bloods were also collected, and the samples were
subjected to aCGH analysis using the same array kit.
2.2. Conventional cytogenetic analysis
Routine cytogenetic analysis by G-banding techniques at the 550
bands of resolution was performed. About 16 mL of amniotic uid
was collected, and the sample was subjected to in situ amniocyte culture according to the standard cytogenetic protocol.
2.3. FISH
Metaphase FISH analysis on cultured amniocytes was performed
using Vysis DiGeorge region probe [Vysis, LSI TUPLE 1 (red spectrum)/
LSI ARSA (green spectrum, FITC)] (Abbott Laboratories, Abbott Park,
2.4. Clinical description
A 29-year-old, primigravid woman was referred for counseling at
23 weeks of gestation because of abnormal ultrasound ndings of
congenital heart defects and transposition of great arteries in the
fetus. Her husband was 30 years old. The woman and her husband
were normal and non-consanguineous, and there was no familial history of congenital malformations. Level II ultrasound revealed a singleton fetus with microcephaly, VSD, a large overriding vessel with
pulmonary artery branching, persistent truncus arteriosus and
DORV (Fig. S1). Amniocentesis was performed at 23 weeks of gestation. Whole-genome aCGH analysis on uncultured amniocytes
detected a 3.08-Mb deletion at 22q11.21 (Fig. 1). The parents did
not have such a deletion. Cytogenetic analysis of cultured amniocytes
revealed a normal male karyotype. FISH analysis conrmed an interstitial 22q11.21 deletion (Fig. 2). The pregnancy was terminated at
24 weeks of gestation, and a malformed fetus was delivered with facial dysmorphism of narrow palpebral ssures, prominent nasal root,
bulbous nasal tip, hypoplastic alae nasi, a small mouth, micrognathia
and small overfolded ears (Fig. S2).
3. Results
Whole-genome aCGH analysis on uncultured amniocytes detected a
3.08-Mb deletion at 22q11.21, or arr [hg 19] 22q11.21 (18,656,529
21,732,904) 1 (Fig. 1). The result was obtained within one week of
examination. The deleted region encompasses 127 genes and including
43 OMIM genes of USP18, DGCR6, PRODH, DGCR2, DGCR14, TSSK2, GSC2,
and GGT2. Whole-genome aCGH analysis on parental bloods revealed
no genomic imbalance. Conventional cytogenetic analysis of cultured
amniocytes revealed a karyotype of 46,XY. Metaphase FISH analysis
on cultured amniocytes showed the presence of only one red signal of
Vysis LSI TUPLE 1 at 22q11.2, and the presence of two green FITC signals
of Vysis LSI ARSA, indicating a deletion of DiGeorge syndrome TUPLE 1
locus at 22q11.2 in the fetus (Fig. 2). The karyotype after FISH analysis
was 46,XY.ish del(22)(q11.21)(TUPLE 1-).

C.-P. Chen et al. / Gene 527 (2013) 405409

had 22q11.2 microdeletion. In a study of 276 pregnancies with abnormal

cardiac ultrasound ndings, Mademont-Soler et al. (2013) found that
15.9% (44/276) had chromosome abnormalities. In their study, of 78 fetuses with normal karyotypes and prenatal FISH screening for 22q11.2
deletion, 6.4% (5/78) had 22q11.2 deletion syndrome, and of 51 fetuses
with normal karyotypes and negative or no 22q11.2 deletion syndrome
study, one case (2%) had 6q21q22.31 deletion following chromosomal
microarray-based analysis. Mademont-Soler et al. (2013) suggested that
chromosomal microarray-based analysis is a good alternative to
karyotyping in pregnancies with prenatally detected cardiac defects.
Various chromosomal loci and genes have been responsible for CTHM
and TOF in addition to TBX1 such as CFC1 (2q21.1; OMIM 605194),
NKX2-5 (5q35.1; OMIM 600584), NKX2-6 (8q21.2; OMIM 611770),


ZFPM2 (8q23.1; OMIM 603693), GATA6 (18q11.2; OMIM 601656),

GDF1 (19p13.11; OMIM 602880) and JAG1 (20p12.2; OMIM 601920).
Goldmuntz et al. (2002) reported CFC1 mutations in patients with transposition of the great arteries and DORV. Mutations of NKX2-5 have been
associated with congenital heart defects of CTHM, TOF, ASD, VSD and hypoplastic heart syndrome (Chen et al., 2010; Goldmuntz et al., 2001;
Gutierrez-Roelens et al., 2006; McElhinney et al., 2003; Peng et al.,
2010; Rauch et al., 2010; Schott et al., 1998; Stallmeyer et al., 2010;
Wang et al., 2011). Heathcote et al. (2005) reported mutation of
NKX2-6 in a family with persistent truncus arteriosus. Mutations of
ZFPM2 have been associated with DORV and TOF (De Luca et al., 2011;
Tan et al., 2012). Mutations of GATA6 have been associated with persistent truncus arteriosus, TOF, ASD, VSD and AVSD (Kodo et al., 2009; Lin

Fig. 1. Whole-genome array comparative genomic hybridization analysis on uncultured amniocytes shows a 3.08-Mb deletion at 22q11.21 or arr [hg 19] 22q11.21 (18,656,529
21,732,904) 1]. (A) Chromosomal view and (B) zoom in view.


C.-P. Chen et al. / Gene 527 (2013) 405409

Fig. 2. Fluorescence in situ hybridization analysis using Vysis LSI DiGeorge/velocardiofacial syndrome region ARSA dual color DNA probes with a DiGeorge critical region probe at
22q11.2 (LSI DiGeorge/velocardiofacial syndrome; red spectrum) and a 22q13.3 telomeric probe (LSI ARSA; green spectrum, FITC) (Abbott Laboratories, Abbott Park, IL, USA) shows
a normal chromosome 22 (one red signal and one green signal) and a del(22) chromosome (only one green signal) in a metaphase amniocyte. The interphase amniocytes show one
red signal and two green signals.

et al., 2010; Maitra et al., 2010). Karkera et al. (2007) reported

loss-of-function mutations in GDF1 associated with DORV, TOF and
transposition of the great arteries. Eldadah et al. (2001) and Lu et al.
(2003) reported TOF caused by mutations in JAG1.
Although FISH and MLPA have become standard procedures for
rapid diagnosis of 22q11.2 deletion syndrome, routine aCGH analysis using uncultured amniocytes has the advantage of detecting
uncharacterized chromosomal deletions or genomic imbalance
with haploinsufciency of the genes responsible for CTHM and TOF
as well as rening the 22q11.2 deletion breakpoints. We suggest
that aCGH on uncultured amniocytes at amniocentesis is a useful adjunct to conventional karyotyping, MLPA and FISH for genetic analysis of prenatally detected congenital heart defects.
Supplementary data to this article can be found online at http://
Conict of interest
The authors declare no conict of interest.
This work was supported by research grants NSC-99-2628-B195-001-MY3 and NSC-101-2314-B-195-011-MY3 from the National
Science Council and MMH-E-102-04 from Mackay Memorial Hospital,
Taipei, Taiwan.
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