Short Communication
Prenatal diagnosis of partial trisomy 3q (3q27.3qter) and partial monosomy
14q (14q31.3qter) of paternal origin associated with fetal hypotonia,
arthrogryposis, scoliosis and hyperextensible joints
Chih-Ping Chen a,b,c,d,e,f,g*, Yao-Lung Chang h, Schu-Rern Chern c, Peih-Shan Wu i, Jun-Wei Su b,j,
Wen-Lin Chen b, Li-Feng Chen b and Wayseen Wang c,k
a
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
b
Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan
c
Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
d
Department of Biotechnology, Asia University, Taichung, Taiwan
e
School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
f
Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan
g
Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei,
Taiwan
h
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Lin-Kou Medical Center,
Chang Gung University, Tao-Yuan, Taiwan
i
Gene Biodesign Co. Ltd, Taipei, Taiwan
j
Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
k
Department of Bioengineering, Tatung University, Taipei, Taiwan
* Correspondence to: Chih-Ping Chen, MD
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: cpc_mmh@yahoo.com
Highlights
 We present concomitant dup(3)(q27.3qter) and del(14)(q31.3qter).
 Clinical manifestations include upd(14)mat-like phenotype such as arthrogryposis, scoliosis and
hyperextensible joints.
 We discuss the genotype-phenotype correlation.
Abstract
We present rapid aneuploidy diagnosis of partial trisomy 3q (3q27.3qter) and partial monosomy
14q (14q31.3qter) of paternal origin by aCGH using uncultured amniocytes in a fetus with
hypotonia, scoliosis, arthrogryposis, hyperextensible joints, facial dysmorphism, ventricular septal
defect, pulmonary stenosis, clenched hands, clubfoot, scalp edema and right hydronephrosis. We
discuss the genotype-phenotype correlation of 3q duplication syndrome and terminal 14q deletion
syndrome. We demonstrate that fetuses with a paternal-origin deletion of 14q involving the
14q32.2 imprinted region may prenatally present the upd(14)mat-like phentoype such as
hypotonia, scoliosis, arthrogryposis and hyperextensible joints.
Keywords:
deletion of 14q, DLK1, duplication of 3q, MEG3, MEG8, maternal uniparental
disomy 14, RTL1, RTL1as,
Abbreviations
dup: duplication; del: deletion; pat: paternal; mat: maternal; UPD: uniparental disomy;
aCGH: array comparative genomic hybridization; FISH: fluorescence in situ hybridization;
QF-PCR: quantitative fluorescent polymerase chain reaction; t: translocation; der: derivative;
MLPA: multiplex ligation-dependent probe amplification
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1. Introduction
Rapid aneuploidy diagnosis using uncultured amniocytes by molecular cytogenetic techniques
such as aCGH, FISH, QF-PCR, and/or MLPA for rapid prenatal diagnosis of chromosomal
abnormalities without the need of cell cultures have been well described (Chen et al., 2009, 2010,
2011a, 2012). The phenotype of UPD 14 is characterized by short stature, growth retardation,
muscular hypotonia, joint laxity, truncal obesity, small hands, hyperextensible joints, scoliosis and
mild dysmorphic features of the face (Kotzot, 2004, 2008). The phenotype of paternal UPD 14 is
characterized by intrauterine growth restriction, polyhydramnios, severe psychomotor retardation,
mild contractures of the fingers, cardiomyopathy and a specific configuration of the thoracal ribs
with a coat-hanger sign (Kotzot, 2008).
Here, we present our experience of rapid aneuploidy
diagnosis of partial trisomy 3q (3q27.3qter) and partial monosomy 14q (14q31.3qter) of
paternal origin using uncultured amniocytes in a pregnancy associated with the maternal UPD 14like [upd(14)mat-like] phenotype such as fetal hypotonia, scoliosis, arthrogryposis and
hyperextensible joints.
2. Methods and detection
2.1. Array-CGH
Whole-genome aCGH on uncultured amniocytes derived from 10 mL amniotic fluid 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 15-20 kb across the entire genome according to the manufacturer’s instruction.
2.2. Conventional cytogenetic analysis
Routine cytogenetic analysis by G-banding techniques at the 550 bands of resolution was
performed. 16 mL amniotic fluid was collected, and the sample was subjected to in situ amniocyte
culture according to the standard cytogenetic protocol. 5 mL parental blood was collected from
each parent, and the samples were subjected to lymphocyte culture according to the standard blood
cytogenetic protocol. Placental and umbilical cord tissues were collected, and the samples were
subjected to tissue culture according to the standard solid tissue cytogenetic protocol.
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2.3. Chromosomal anomaly
aCGH demonstrated an 11.31-Mb duplication at 3q27.3-q29 or arr 3q27.3q29 (186,586,582197,897,268)3 and a 19.56-Mb deletion at 14q31.3-q32.33 or arr 14q31.3q32.33 (87,793,949107,349,540)1 (NCBI Build 37) (Fig. 1).
2.4. Method of confirmation
The mother had a karyotype of 46,XX. The father had a karyotype of 46,XY,t(3;14)(q27.3;q31.3)
(Fig. 2). The cultured amniocytes, and cord and placental tissues had a karyotype of 46,XY,
der(14)t(3;14)(q27.3;q31.3)pat (Fig. 3). Polymorphic DNA marker analysis using parental blood and
fetal tissues confirmed a paternal origin of the distal 14q deletion.
3. Clinical description
A 30-year-old, gravida 2, para 1, woman was referred to the hospital for genetic counseling at 20
weeks of gestation because of multiple fetal abnormalities detected by prenatal ultrasound. Her
husband was 32 years old. She had a 1-year-old healthy daughter, and there was no family history
of congenital malformations. The pregnancy was uneventful until 20 weeks of gestation when
fetal hypotonia, ventricular septal defect, pulmonary stenosis, scoliosis, arthrogryposis with
clenched hands and clubfoot, scalp edema and right hydronephrosis were noted.
The fetal
biometry was equivalent to 20 weeks. Amniocentesis was performed. The aCGH investigation on
uncultured amniocytes manifested an 11.31-Mb duplication at 3q27.3-q29 and a 19.56-Mb
deletion at 14q31.3-q32.33. An unbalanced reciprocal translocation was suspected. Analysis of
the parental blood revealed a karyotype of 46,XX in the mother and a karyotype of
46,XY,t(3;14)(q27.3;q31.3) in the father. Cytogenetic analysis of cultured amniocytes revealed a
karyotype of 46,XY,der(14)t(3;14)(q27.3;q31.3)pat. The pregnancy was subsequently terminated,
and a 326-g malformed fetus was delivered with hypertelorism, down-slanting palpebral fissures,
epicanthic folds, a broad nose with the bulbous nasal tip, long philtrum, micrognathia, large lowset ears, cryptorchidism, arthrogryposis with clenched hands and clubfoot, malposition of the toes
and hyperextension of bilateral knee joints. Postnatal X-ray showed arthrogryposis, scoliosis and
extension deformities of the knee joints.
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4. Discussion
Unbalanced reciprocal translocations detected at amniocentesis are frequently associated with
abnormal ultrasound findings in the fetus, and prenatal diagnosis of an unbalanced translocation
may incidentally detect a balanced translocation in the family (Chen et al., 2011b). The present
case prenatally manifested congenital heart defects, skin edema, hypotonia, scoliosis, joint
deformities and hydronephrosis. The fetus had an unbalanced reciprocal translocation inherited
from a paternal balanced translocation. However, the father was not aware of his translocation
status before prenatal genetic testing. Our case has demonstrated the usefulness of aCGH on
uncultured amniocytes for rapid aneuploidy diagnosis of chromosome aberration in case of fetal
abnormalities. We suggest that prenatal diagnosis of fetal structural abnormalities should include
detailed cytogenetic or molecular cytogenetic investigations of the fetus as well as the parents if
chromosome aberration is detected in the fetus.
The present case is associated with partial trisomy 3q (3q27.3qter). The 3q duplication
syndrome is a well-defined entity that resembles the Cornelia de Lange syndrome and includes
developmental delay, low anterior hairline, prominent eyelashes, depressed nasal bridge,
anteverted nostrils, long philtrum, micrognathia, short limbs, genital hypoplasia, hypertelorism,
up-slanting palpebral fissures, epicanthic folds and a broad nose (Grossmann et al., 2009; Chen et
al., 2011c; Dundar et al., 2011; Jung et al., 2012). Major malformations may occasionally occur in
the cases with partial trisomy 3q such as omphalocele, cystic hygroma, holoprosencephaly, spina
bifida, lumbosacral meningocele, Dandy-Walker malformation, cerebellar hypoplasia and agenesis
of the corpus callosum (Chen et al., 2011c). The critical genomic region for most of the clinical
features of the 3q duplication syndrome has been narrowed down to 3q26.33q29 (Faas et al.,
2002; Battaglia et al., 2006). Most reported cases with partial trisomy 3q are associated with a
large 3q duplication and a second chromosomal imbalance. The phenotypic findings, therefore,
are various. Essentially pure trisomy 3q (3q27qter) is very rare. Grossmann et al. (2009) first
reported a 4-year and 8-month-old girl with a 15.3-Mb duplication of 3q273qter, developmental
delay and dysmorphic features of hypertelorism, down-slanting palpebral fissures, epicanthic folds,
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wide nasal bridge, bulbous nasal tip, prominent philtrum, down-turned corners of the mouth and
brachydactyly.
The facial dysmorphisms in our case are very similar to those reported by
Grossmann et al. (2009).
The present case is also associated with partial monosomy 14q (14q31.3qter). The typical
clinical findings of the terminal 14q deletion syndrome include intellectual disability,
developmental delay, muscular hypotonia, postnatal growth retardation, microcephaly, congenital heart
defects, genitourinary malformations, ocular coloboma, and dysmorphisms of high and prominent
forehead, blepharophimosis, down-slanting palpebral fissures, hypertelorism, telecanthus, epicanthic
folds, broad/depressed nasal bridge, short bulbous nose, up-turned nares, low-set ears, poor ear helix
formation, broad philtrum and columella, high palate, small pointed chin, small mouth, thin upper
lip vermillion and widely spaced nipples (Engels et al., 2012). To date, at least 24 cases with a pure
14q deletion involving 14q32.3 without the ring formation have been reported and well characterized
(Hreidarsson and Stamberg, 1983; Masada et al., 1989; Yen et al., 1989; Gorski et al., 1990; Telford et
al., 1990; Wang and Allanson, 1992; Wintle et al., 1995; Ortigas et al., 1997; Meschede et al., 1998;
Rittinger, 2002; van Karnebeek et al., 2002; Merritt et al., 2005; Schlade-Bartusiak et al., 2005, 2009;
Chung et al., 2006; Maurin et al., 2006; Schneider et al., 2008; Wu et al., 2010; Engels et al., 2012;
Holder et al., 2012; Jezela-Stanek et al., 2012). However, only few of these cases are the extent of the
deletion was analyzed by molecular cytogenetic techniques. The present case manifested congenital
heart defects and genitourinary abnormalities. In a literature review of 15 cases (6 males/9 females)
with 14q32.3 terminal deletions, Engels et al. (2012) found congenital heart defects in five of 14 cases
and genitourinary abnormalities in five of six males including hypospadias, cryptorchidism and
micropenis.
The peculiar aspect of the present case is the association of a paternal origin of partial
monosomy 14q involving 14q32.2 and upd(14)mat-like phenotype such as fetal hypotonia,
scoliosis, arthrogryposis and hyperextensible joints. Human chromosome 14q32.2 region harbors
paternally expressed genes such as DLK1 and RTL1, maternally expressed genes such as MEG3
(also known as GTL2), RTL1as (RTL1 antisense) and MEG8, and the differentially methylated
5
region (DMR) of intergenic DMR (IG-DMR) and MEG3-DMR (Hosoki et al., 2008; Kagami et al.,
2008, 2010; Ogata et al., 2008). It has been shown that decreased DLK1 and RTL1 expression or
loss of paternal methylation of the DMR can play a role in the development of the upd(14)mat-like
phenotype (Kagami et al., 2008). Kagami et al. (2008) reported three patients with microdeletions
affecting the 14q32.2 imprinting region of paternal origin and the upd(14)mat-like phenotype.
Buiting et al. (2008) reported the upd(14)mat-like phenotype in four patients of whom three
patients had loss of paternal methylation and one patient had a paternally derived deletion of the
imprinted DLK1/GTL2 gene cluster. Kotzot (2004) reported hypotonia, scoliosis and hyperextensible
joints in patients with maternal uniparental heterodisomy 14 or maternal uniparental isodisomy 14 due
to autosomal recessive inherited traits, trisomy mosaicism and genomic imprinting. Zechner et al.
(2009) reported severe hypomethylation at the 14q32.2 imprinted gene region in a boy with the
upd(14)mat-like phenotype.
The present case additionally shows that hypotonia, scoliosis,
arthrogryposis and hyperextensible joints can be prenatal features in the fetuses associated with a
paternal-origin deletion of 14q involving the 14q32.2 imprinted region.
Acknowledgements
This work was supported by research grants NSC-99-2628-B-195-001-MY3 and NSC-101-2314-B-195011-MY3 from the National Science Council and MMH-E-101-04 from Mackay Memorial Hospital,
Taipei, Taiwan.
Appendix A. Supplementary data
Supplementary data to this article can be found online at GENE.
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Figure Legends
Fig. 1. The array comparative genomic hybridization (aCGH) analysis using whole-genome NimbleGen
ISCA Plus Cytogenetic array on uncultured amniocytes shows a distal 3q duplication and a distal
14q deletion on (A) whole genome view and (B) chromosome view, and (C) an 11.31-Mb
duplication at 3q27.3-q29 and a 19.56-Mb deletion at 14q31.3-q32.33.
Fig. 2. A karyotype of 46,XY,t(3;14)(q27.3;q31.3) in the father. The arrows indicate the breakpoints.
Fig. 3. A karyotype of 46,XY,der(14)t(3;14)(q27.3;q31.3) in the fetus.
The arrows indicate the
breakpoints.
Appendix A. Supplementary data
Fig. S1. Prenatal ultrasound at 20 weeks of gestation shows (A) pulmonary stenosis, (B) ventricular septal
defect, (C) right hydronephrosis and (D) scoliosis.
Fig. S2. (A) The craniofacial appearance, (B) the whole body view and (C) the clenched hand and
malposition of the toes of the fetus at birth.
Fig. S3. X-ray shows arthrogryposis, scoliosis and extension deformities of the knee joints.
9