Short Communication
Mosaic ring chromosome 21, monosomy 21, and isodicentric ring
chromosome 21: Prenatal diagnosis, molecular cytogenetic
characterization, and association with 2-Mb deletion of 21q21.1
eq21.2
and 5-Mb deletion of 21q22.3
Chih-Ping Chen
a,b,c,d,e,f,g,*
, Yi-Hui Lin
h, Szu-Yuan Chou
h,i, Yi-Ning Su
j, Schu-Rern Chern
c,
Yu-Ting Chen
c, Dai-Dyi Town
b, Wen-Lin Chen
b, Wayseen Wang
c,ka
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, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
i
Institute of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan
j
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
k
Department of Bioengineering, Tatung University, Taipei, Taiwan Accepted 15 August 2011
Abstract
Objective: To present the perinatal findings and molecular cytogenetic characterization of prenatally detected mosaic r(21).
Materials, Methods, and Results: A 29-year-old primigravid woman underwent amniocentesis at 22 weeks’ gestation because of hyperechogenic
cardiac foci and intrauterine growth restriction. Amniocentesis revealed a karyotype of 46,XY,r(21)[15]/45,XY,e21[5]. The parental karyotypes
were normal. The woman requested repeat amniocentesis. Oligonucleotide-based array comparative genomic hybridization was applied to the
uncultured amniocytes, rapidly detecting a 2.09-Mb deletion of 21q21.1eq21.2 (21,495,262e23,580,815 bp) and a 5.03-Mb deletion of
21q22.3
eq22.3 (41,887,412e46,914,715 bp). Cytogenetic analysis revealed a karyotype of 46,XY,r(21)[8]/45,XY,e21[3]/46,XY,idic r(21)[1].
The pregnancy was terminated, and a malformed fetus was delivered with clinodactyly, short big toes, separation between the first and second
toes, prominent nasal bridge, downward slanting palpebral fissures, protuberant occiput, prominent forehead, broad anteverted nasal tip, long
philtrum, thin upper lip, small mouth, and micrognathia. The placenta had a karyotype of 46,XY,r(21)[83]/45,XY,e21[11]/46,XY,idic r(21)[6],
and the cord blood lymphocytes had a karyotype of 46,XY,r(21)[88]/45,XY,e21[9]/46,XY,idic r(21)[3]. Polymorphic DNA marker analysis
determined a maternal origin for the deletion.
Conclusion: An extra interstitial 21q deletion can be associated with mosaic r(21) in addition to a terminal 21q deletion. aCGH is useful in
determining the breakpoints and associated subtle structural abnormalities in cases of prenatally detected ring chromosome in order to facilitate
genetic counseling.
Copyright
Ó 2012, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: 21q interstitial deletion; 21q terminal deletion; mosaicism; prenatal diagnosis; ring chromosome 21
* Corresponding author. Department of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei, Taiwan. E-mail address:[email protected](C.-P. Chen).
Taiwanese Journal of Obstetrics & Gynecology 51 (2012) 71e76
www.tjog-online.com
1028-4559/$ - see front matter CopyrightÓ 2012, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.tjog.2012.01.014
Introduction
A ring chromosome 21, or r(21) exhibits breakage and
reunion at the breakpoints on the long and short arms of
chromosome 21, with possible deletions of the chromosomal
segments distal to the breakpoints
[1]
. An r(21) has been found
in children and their mothers, implying that the r(21) can be
transmitted from parents to their children
[1
e6]
. An r(21) has
also been found in a boy with a derivative chromosome 21 in
the mother
[7]
. Further, dicentric (dic) r(21) has been found in
the children of parents with an r(21), indicating that the r(21)
is susceptible to tandem duplication
[8,9]
. The r(21) can
present with a deletion/duplication of r(21) in the form of
mosaic monosomy 21 and dic r(21) [1]. The sequelae in
patients with an r(21) are variable, including spontaneous
abortions, phenotypically normal offspring with or without
r(21), phenotypically abnormal offspring with r(21), infants
with Down syndrome with dic r(21) or
þr(21), infertility in
female carriers, or azoospermia in male carriers
[10,11]
.
Prenatal diagnosis of r(21) is very rare, and to date, only
three cases have been reported
[6,12,13]
. Stetten et al
[12]
first
reported the prenatal diagnosis of 46,XY,r(21)/45,XY,
e21 with
mosaicism for majority of the r(21) in a fetus with a normal
outcome. In that case, amniocentesis was performed because of
the risk of sickle cell anemia. Melnyk et al
[6]
reported the
prenatal diagnosis of 46,XX,r(21) (77%)/45,XX,
e21 (23%) in
a fetus with a normal outcome. In that case, amniocentesis was
performed because of the carrier status of r(21) in the normal
mother. Papoulidis et al
[13]
recently reported the prenatal
diagnosis
of
46,XY,r(21)[34]/45,XY,
e21[4]/46,XY[14] in
a fetus with a normal outcome. In that case, amniocentesis was
performed because of maternal anxiety. Here, we report the
perinatal findings and molecular cytogenetic characterization of
an additional case with mosaic r(21).
Materials, methods, and results
A 29-year-old primigravid woman underwent
amniocen-tesis at a community obstetric clinic because of
hyper-echogenic cardiac foci and intrauterine growth restriction. Her
husband was also 29 years of age. Amniocentesis at 22 weeks’
gestation revealed a male fetus with mosaicism for ring
chromosome 21 [r(21)] and monosomy 21, or 46,XY,r(21)
[15]/45,XY,
e21[5]. The parental karyotypes were normal.
Prenatal ultrasound findings at 24 weeks’ gestation were
unremarkable except for IUGR, dolichocephaly, protuberant
occiput, prominent forehead, prominent nasal bridge, and
micrognathia (
Fig. 1
). The fetal biometry was equivalent to 22
weeks’ gestation. The woman requested repeat amniocentesis.
Oligonucleotide-based array comparative genomic
hybrid-ization (aCGH) using CytoChip Oligo Array (BlueGnome,
Cambridge, UK) was applied to the uncultured amniocytes.
aCGH rapidly detected a gene dosage decrease at 21q21.1
e
q21.2 and 21q22.3 in the uncultured amniocytes. There
were a 2.09-Mb deletion of 21q21.1
eq21.2 (21,495,262e
23,580,815 bp) and a 5.03-Mb deletion of 21q22.3
eq22.3
(41,887,412
e46,914,715 bp) (
Fig. 2
) [UCSC genome browser
on March 2006 (NCBI build 36/hg18) assembly]. Conventional
cytogenetic analysis revealed a karyotype of 46,XY,r(21)[8]/
45,XY,
e21[3]/46,XY,idic r(21)[1] (
Figs. 3
e5
).
The parents elected to terminate the pregnancy, and a
mal-formed 750-g fetus was delivered with clinodactyly, short big
toes, separation between the first and second toes, prominent
nasal bridge, downward slanting palpebral fissures,
protu-berant occiput, prominent forehead, broad anteverted nasal tip,
long philtrum, thin upper lip, small mouth, and micrognathia
(
Fig. 6
). Conventional cytogenetic analyses of the cord blood
and placenta were carried out. The placenta had a karyotype
of 46,XY,r(21)[83]/45,XY,
e21[11]/46,XY,idic r(21)[6]. The
cord blood lymphocytes had a karyotype of 46,XY,r(21)[88]/
45,XY,
e21[9]/46,XY,idic r(21)[3]. Polymorphic DNA marker
analysis determined a maternal origin of the deletion (
Fig. 7
and
Table 1
).
Discussion
We previously demonstrated the utility of aCGH in the
molecular cytogenetic characterization of mosaic r(18)
[14]
. In
this report, we also demonstrate the use of aCGH to determine
the breakpoints and the interstitial microdeletion of a small
ring chromosome in a case in which the ring chromosome
comprises the majority of the mosaicism. The present case was
initially found to have high-level mosaicism for r(21) and
low-level mosaicism for r(21) deletion/duplication. aCGH further
identified a 2.09-Mb interstitial deletion of 21q21.1
eq21.2
and a 5.03-Mb terminal deletion of 21q22.3.
The 2-Mb 21q21.1
eq21.2 interstitial deletion in this case
encompasses the genes NCAM2, C21orf74, and ZNF299P, and
has NCAM2 haploinsufficiency. Neural cell adhesion molecule
2 (NCAM2; OMIM 602040) belongs to the NCAM family,
which is highly expressed in the nervous system and
partici-pates in mediating cell adhesion, neurite outgrowth, cell
migration, differentiation and survival, and the formation and
plasticity of synapses
[15,16]
. Molloy et al
[17]
suggested that
NCAM2 may be a candidate gene for autism.
Haldeman-Englert et al
[18]
reported an autistic male with a de novo
Fig. 1. Prenatal ultrasound at 24 weeks’ gestation shows a protuberant occiput, prominent forehead, prominent nasal bridge, and micrognathia.
8.8-Mb deletion of 21q21.1
eq21.3 encompassing the NCAM2
gene and suggested that NCAM2 is a candidate gene for autism
and other neurobehavioral disorders.
The 5-Mb 21q22.3 terminal deletion in this case
encom-passes 94 genes including TRPM2, C21orf29, PCNT, DIP2A,
S100B, PRMT2, COL18A1, COL6A1, COL6A2, and LSS.
Specchio et al
[19]
reported a patient with the karyotype
of 46,XY,r(21)(p13q22.3)/45,XY,
e21 and the phenotype of
generalized epilepsy, intellectual disability, and dysmorphic
features. In the mouse model, deficiencies in the region
corre-sponding to human 21q22.3 cause cognitive deficits
[20]
.
McQuillin et al
[21]
reported that TRPM2 and C21orf29
(TSPEAR) are candidate genes for bipolar disorder. The
posi-tional candidate approach has shown an association between
Fig. 3. A karyotype of 46,XY,r(21).
Fig. 2. Oligonucleotide-based array comparative genomic hybridization shows a 2.09-Mb deletion of 21q21.1eq21.2 (21,495,262e23,580, bp) and a 5.03-Mb deletion of 21q22.3eq22.3 (41,887,412e46,914, bp) (NCBI build 36/hg18).
bipolar disorder and TRPM2
[22]
. TRPM2 (OMIM 603749)
encodes a transient receptor potential cation channel subfamily
M member 2 protein, which is a calcium channel receptor and is
associated with oxidative stress-induced cell death and
inflam-matory processes. C21orf29 or TSPEAR (OMIM 612920) is an
epilepsy gene that encodes chromosome 21 open reading frame
29 peptide with epilepsy-associated repeats.
Poelmans et al
[23]
reported that PCNT, DIP2A, S100B, and
PRMT2 are candidate genes for dyslexia. PCNT (OMIM
605925) encodes pericentrin, which is important for cell-cycle
progression and for the normal functioning of centrosomes
and cytoskeleton. DIP2A (OMIM 607711) encodes Drosophila
homologue of disco-interacting protein 2A protein, which is
involved in the AMPA glutamate receptor recycling pathway
and is important in the regulation of synaptic plasticity. S100B
(OMIM 176990) encodes S100 calcium-binding protein, which
is a calcium-binding peptide produced mainly by astrocytes and
exerts paracrine and autocrine effects on neurons and glial cells.
PRMT2 (OMIM 601961) encodes protein arginine
N-methyl-transferase 2 and is involved in mRNA metabolism.
Rope et al
[24]
reported a dilated ascending aorta in a child
with ring chromosome 21 and suggested that haploinsufficiency
of the collagen genes COL6A1 (OMIM 120220), COL6A2
(OMIM 120240), and COL18A1 (OMIM 120328) might be
responsible for the phenotype. The LSS gene (OMIM 600909)
encodes lanosterol synthase, which is required for cholesterol
modification of the Sonic hedgehog protein and was considered
to be an excellent candidate gene for HPE1 (OMIM 236100).
However, in a mutational analysis of the LSS gene in patients
with holoprosencephaly (HPE), Roessler et al
[25]
could not
find evidence that LSS gene was responsible for HPE1.
Partial deletions of 21q are rare, and the patients display
variable phenotypes according to the size and position of the
deletion
[26
e29]
. Lindstrand et al
[28]
suggested that the
Fig. 4. A karyotype of 45,XY,e21.
Fig. 5. A karyotype of 46,XY,idic r(21).
ITSN1 gene is involved in severe mental retardation, and that
genes KCNE1, DSCR1, CLIC6, and RUNX1 are associated
with severe congenital heart defects in patients with a 21q
deletion. Our patient did not have haploinsufficiency of such
genes and did not manifest congenital heart defects.
An HPE1 (OMIM 236100) critical region has been
sug-gested on chromosome 21q22.3
[30]
. HPE has been reported
in patients with ring chromosome 21
[31,32]
or a minute
deletion of chromosome 21q22.3
[33]
. An agenesis of the
corpus callosum (ACC) critical region has also been suggested
on chromosome 21q22.2
eq22.3
[34]
. ACC has been reported
in patients with satellited 21q
[35]
and a deletion of
21q22.1
/qter
[36]
. However, the present case did not have
any central nervous system abnormality. Therefore, the
phenotype associated with the distal 21q deletion
encom-passing the critical regions of HPE and ACC can be variable.
Recently, several reports have been published describing
the atypical ring chromosome in which aCGH showed not
only the deletions at the chromosomal ends but also an extra
deletion or duplication
[37
e39]
. Glass et al
[37]
reported loss
of the 15q subtelomeric clone and a discontinuous interstitial
bacterial artificial chromosome clone on distal 15q in a patient
with r(15). Knijnenburg et al
[38]
reported inverted
duplica-tion and terminal deleduplica-tion in a patient with r(14). In a study of
33 ring chromosomes, Rossi et al
[39]
found that seven had
duplications in addition to terminal deletions. The seven
atypical duplication/deletion chromosomes include a single
case of r(13) with inv dup del 13q, r(13) with dup del 13q,
r(15) with inv dup del 15q, r(21) with dup 21q21.3q22.2 and
trp 21q22.2q22.3, r(22) with dup del 22q, and two cases of
r(18) with dup del 18 p.
To our knowledge, the case presented here is the first report
of mosaic r(21) with a terminal deletion/interstitial duplication
of 21q. Our case provides evidence for an extra interstitial
21q deletion in addition to terminal 21q deletion in the case
with mosaic r(21). It can be concluded that aCGH is useful
in determining the breakpoints and the associated subtle
Fig. 6. The craniofacial appearance of the fetus at birth.Fig. 7. Representative electrophoretograms of quantitative fluorescent poly-merase chain reaction assays at short tandem repeat markers specific for chromosome 21q using fetal and parental DNAs. With the markers D21S11 (21q21.1) and D21S2052 (21q21.3), two alleles of 234 bp: 250 bp (mater-nal:paternal) and 147 bp: 143 bp (mater(mater-nal:paternal), respectively, in the fetus, have a ratio of 1:1 (maternal:paternal), indicating a biparental inheritance in 21q21.1 and 21q21.3. With the markers D21S1409 (21q21.2) and D21S1446 (21q22.3), only one allele of 202 bp (paternal) and 222 bp (paternal), respectively, in the fetus, is present, indicating paternal inheritance in 21q21.2 and 21q22.3 and a maternal origin of the deletion in 21q21.2 and 21q22.3.
Table 1
Molecular results using polymorphic DNA markers specific for chromosome 21q.a
Markers Father Mother Proband Locationb
D21S1432 142, 142 134, 134 134, 142 16,265,317e16,265,448 D21S11 230, 250 234, 234 234, 250 19,476,130e19,476,352 D21S1409 202, 202 190, 190 202 23,270,598e23,270,778 D21S2052 131, 143 139, 147 143, 147 27,740,433e27,740,559 D21S2054 174, 174 178, 178 174, 178 29,978,408e29,978,580 D21S1446 222, 222 214, 214 222 46,862,013e46,862,233 a
Alleles (base pair sizes) are listed below each individual; b Location according to NCBI build 36/hg18.
structural abnormalities in case of prenatally detected ring
chromosome in order to facilitate the genetic counseling.
Acknowledgments
This work was supported by research grants
NSC-97-2314-B-195-006-MY3 and NSC-99-2628-B-195-001-MY3 from the
National Science Council, and MMH-E-100-04 from Mackay
Memorial Hospital, Taipei, Taiwan.
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