Arnold, Norbert

Bens, Susanne

Caliebe, Almuth

Grote, Werner

Heidemann, Simone

von Kaisenberg, Constantin S

Weimer, Jörg

Molecular Cytogenetics

English

PubMed

Jörg Weimer

Simone Heidemann

Constantin S von Kaisenberg

Werner Grote

Norbert Arnold

Susanne Bens

Almuth Caliebe

Crossref

Isolated trisomy 7q21.2-31.31 resulting from a complex familial rearrangement involving chromosomes 7, 9 and 10

Springer - Publisher Connector

CASE REPORT Open Access
Isolated trisomy 7q21.2-31.31 resulting from a
complex familial rearrangement involving
chromosomes 7, 9 and 10
Jörg Weimer1*†, Simone Heidemann2†, Constantin S von Kaisenberg1,3, Werner Grote2, Norbert Arnold1,
Susanne Bens2 and Almuth Caliebe2
Abstract
Background: Genotype-phenotype correlations for chromosomal imbalances are often limited by overlapping
effects of partial trisomy and monosomy resulting from unbalanced translocations and by poor resolution of
banding analysis for breakpoint designation. Here we report the clinical features of isolated partial trisomy 7q21.2
to 7q31.31 without overlapping phenotypic effects of partial monosomy in an 8 years old girl. The breakpoints of
the unbalanced rearranged chromosome 7 could be defined precisely by array-CGH and a further imbalance could
be excluded. The breakpoints of the balanced rearranged chromosomes 9 and 10 were identified by
microdissection of fluorescence labelled derivative chromosomes 9 and 10.
Results: The proband’s mother showed a complex balanced translocation t(9;10)(p13;q23) with insertion of 7q21.2-
31.31 at the translocation breakpoint at 9p13. The daughter inherited the rearranged chromosomes 9 and 10 but
the normal chromosome 7 from her mother, resulting in partial trisomy 7q21.2 to 7q31.31. The phenotype of the
patient consisted of marked developmental retardation, facial dysmorphism, short stature, strabism, and
hyperextensible metacarpophalangeal joints.
Discussion: For better understanding of genotype-phenotype correlation a new classification of 7q duplications
which will be based on findings of molecular karyotyping is needed. Therefore, the description of well-defined
patients is valuable. This case shows that FISH-microdissection is of great benefit for precise breakpoint designation
in balanced rearrangements.
Keywords: chromosome microdissection, array-CGH, developmental delay, hypotonia, speech-delay, short stature,
epicanthus, partial trisomy 7q21.2-7q31.31
Background
Phenotypic reports of chromosomal imbalances are an
important source for genetic counselling especially in
prenatal diagnosis. Chromosomal imbalances arise de
novo or as the result of a familial rearrangement. The
most common familial rearrangements are transloca-
tions. In case of an unbalanced segregation in an off-
spring the resulting imbalances consist of a combination
of partial trisomy and partial monosomy. In most of the
cases it is impossible to exactly relate the phenotypic
consequences of an unbalanced translocation to either
the underlying partial trisomy or the partial monosomy.
Therefore many case reports are of limited value for
genetic counselling because the phenotypic effects of
trisomy and monosomy overlap [1]. Another difficulty
in the description of phenotypic consequences of a cer-
tain chromosomal imbalance is the breakpoint designa-
tion. The precise description of the breakpoint is
important for the genotype-phenotype correlation. In
solely cytogenetically investigated patients, breakpoint
designation remains doubtful due to the limited resolu-
tion of chromosome banding techniques. In recent years
comparative genomic hybridisation (CGH) such as
* Correspondence: jweimer@email.uni-kiel.de
† Contributed equally
1Department of Obstetrics and Gynaecology, Christian-Albrechts-University of
Kiel, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-
Str.3, Haus 24, Kiel, Germany
Full list of author information is available at the end of the article
Weimer et al. Molecular Cytogenetics 2011, 4:28
http://www.molecularcytogenetics.org/content/4/1/28
© 2011 Weimer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
array-CGH has overcome many of the limitations of
classical chromosomal banding analysis and can estimate
the breakpoints with an accuracy of some kb. However,
breakpoint designation by CGH and Array-CGH is
restricted to unbalanced rearrangements. In case of
balanced rearrangements or combinations of balanced
and unbalanced rearrangements as in the present case
further molecular cytogenetic techniques have to be
combined with array CGH such as microdissection and
Fluorescence-in-situ-hybridisation (FISH).
Case report
The female patient is the first child of healthy non con-
sanguineous parents. The father is German, the mother
is from Pakistan. The family history was unremarkable.
The girl was born spontaneously after an uneventful
pregnancy at 39 weeks + 0 days with a length of 48 cm
(- 1.3 SD), a weight of 2260 g (- 3.2 SD) and a head cir-
cumference of 34 cm (- 0.4 SD). The APGAR scores
were 8/9/10 and the umbilical cord pH was 7.2. Due to
muscular hypotonia nasogastral feeding had to be
initiated. At the age of four months she was admitted to
hospital due to repeated vomiting. At that time develop-
mental delay was noted. At the age of five months fron-
tal bossing, relative macrocephaly and strabismus were
observed. With 5 3/12 years she started walking. During
the last presentation at the age of 7 8/12 years she only
spoke single words while, according to her parents, her
receptive language skills were considerably better. There
were no behaviour problems. At that time she was not
continent yet. Her general health was good. Length was
112.5 cm (- 2.6 SD) and head circumference 51.5 cm (-
0.4 SD). The inner canthal distance was 3.3 cm (+ 2.0
SD). She had bilateral epicanthus and slightly down-
slanting palpebral fissures. The previously noted strabis-
mus had improved. The metacarpophalangeal joints of
the fingers were hyperextensible. Due to recurrent ear
infections she had received ventilation tubes twice. Gen-
eralised hypertrichosis was observed (Figure 1).
Methods and Results
Chromosome analysis in the girl was performed on per-
ipheral blood lymophocytes according to standard tech-
niques and revealed derivative chromosomes 9 and 10.
Chromosome analysis of the parents revealed a normal
male karyotype in the father and a balanced rearrange-
ment t(9;10)(p13;q23)ins(9;7)(p13;q21.3q31.3) in 20
metaphases analysed (karyotype described according to
ISCN 2009) in the mother. This unmasked the deriva-
tive chromosomes of the daughter as the result of a
malsegregation of the complex maternal translocation
(Figure 2): the girl inherited the derivative chromosomes
9 and 10 but a normal chromosome 7 from the mother
resulting in isolated partial trisomy 7q21.3 to 7q31.3.
To estimate the chromosomal breakpoints of the deri-
vative chromosome 7 and to exclude further imbalances
we performed array-CGH from the patient’s lympho-
cytes using the Human Genome CGH Microarray 244A
platform (overall resolution 0,15 Mb, Agilent Technolo-
gies, Santa Clara, USA) according to the manufacturer’s
instructions. The array was scanned with the G2565CA
Microarray Scanner System (Agilent Technologies,
Figure 1 The girl at the age of 7 8/12 years. Note strabism, epicanthus, down-slanting palpebral fissures and slight hypertelorism.
Weimer et al. Molecular Cytogenetics 2011, 4:28
http://www.molecularcytogenetics.org/content/4/1/28
Page 2 of 6
Santa Clara, USA) at a resolution of 5 μm/pixel. Signal
intensities from the generated images were measured
and evaluated with the Feature Extraction v10.7.3.1 and
the Agilent Genomic Workbench Standard Edition 6.5
software packages (Agilent Technologies). By this analy-
sis we detected a 28.82-28.83 Mb duplication of 7q21.2
to 7q31.31 (Figure 3) with the most telomeric duplicated
probe starting at chr7:91,941,487 bp and the most cen-
tromeric duplicated probe ending at 120,764,345 bp (arr
7q21q31.31(91,932,809x2,91,941,487-120,764,345x3,
120,770,258x2) (mapped according to GRCh37, hg 19)
resulting in a revision of the breakpoint at 7q21.3 into
7q21.2 and in more detailed definition of the breakpoint
at 7q31.3 into 7q31.31. Further chromosomal imbal-
ances were not detected. A list of benign copy number
polymorphisms can be obtained upon request.
To estimate the chromosomal breakpoints of the deri-
vative chromosomes 9 and 10 these chromosomes as
Figure 2 Partial karyograms after GTG-banding. A mother: 46,XX,t(9;10)(p13;q23)ins(9;7)(p13; q21.2-31.31) and B daughter: der(9)(10qter®
10q23::7q21.2® 7q31.31::9p13® 9qter), der(10)(10pter® 10q23::9p13® 9pter) (according to ISCN 2009). The derivative chromosomes are
marked by arrows.
Figure 3 Results of array CGH analysis using the Human Genome CGH Microarray 244A platform (Agilent Technologies, Santa Clara,
USA), showing the internal boundaries of the duplication in 7q21q31.31 (91,941,487-120,764,345) and its exact size (28,822,858 Mb).
The last normal oligonucleotide is 91,932,809 Mb and the first normal oligonucleotide is 120,770,258 Mb. The position of the array targets was
mapped to the UCSC genome browser release February 2009 (GRCh37/hg19).
Weimer et al. Molecular Cytogenetics 2011, 4:28
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Page 3 of 6
well as the derivative chromosome 7 were microdis-
sected from chromosome preparations of the mother
and rehybridised to normal human chromosomes [2]. In
brief, to detect the chromosomal breakpoints spreads of
the derivative metaphases of the mother were hybridised
with three self made whole chromosome painting probes
(wcp): the wcp probe for chromosome 7 was labelled
with DEAC (Diethylaminocoumarin-5-dUTP; NEN Life
Science Prod. Inc.; Boston, MA, U.S.A.), the wcp probe
for chromosome 10 was labelled with R110-dUTP (Per-
kin Elmer; Waltham, MA, U.S.A.), and the wcp probe
for chromosome 9 was labelled with Spectrum Orange-
dUTP (Vysis Inc.; Downers Grove, Il, U.S.A.). Subse-
quently, the fluorescence labelled derivative chromo-
somes were isolated by a glass needle, amplified by
DOP-PCR, labelled with three different fluorochromes
and re-hybridised to normal human chromosomes. The
microdissected chromosome 7 was labelled with R110-
dUTP, the microdissected chromosome 10 was labelled
with Spectrum Orange-dUTP and the microdissected
chromosome 9 was labelled with Texas Red-12-dUTP.
For better discrimination between the labelling of the
wcp probes and the subsequent labelling of the micro-
dissected chromosomes the rehybridised chromosomes
were displayed in different colours (R110-dUTP in ice
blue, Spectrum orange-dUTP in purple and Texas red-
dUTP in yellow; Figure 4). The breakpoints of the deri-
vative chromosomes could be identified by tracing back
the labelled chromosomal segments to the ideograms of
chromosomes 7, 9 and 10 (Figure 4).
Because of the complex maternal rearrangement
amniocentesis was performed in a subsequent pregnancy
revealing a balanced complex translocation in a male
fetus. The boy was born at term with normal
Figure 4 FISH-microdissection of rearranged maternal chromosomes. The origin of chromosomes was identified by whole chromosome
painting probes (WCP): chromosome 7 (ice blue), chromosome 10 (purple) and chromosome 9 (yellow) are displayed and measured by the
fluorescence and FISH Imaging System ISIS 3 (Metasystems, Altlußheim, Germany). The rearranged chromosomes of the balanced rearrangement
are marked with circles. On the left side normal chromosomes are displayed hybridized with the labelled DNA from the microdissected
chromosomes (reverse painting). Statistical analysis of the measured chromosome paintings was done using Microcal™ OriginR 6.0 (Microcal,
Northampton,MA). On the very left side ideograms of the reverse painted derivative chromosomes are displayed to allow breakpoint
designation.
Weimer et al. Molecular Cytogenetics 2011, 4:28
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Page 4 of 6
measurements (length 56 cm (+2 SD), weight 3020 g
(-1.7 SD)). His motor development was normal. He
started walking at the age of 11 months. At the age of 5
10/12 years length was 121 cm (0.74 SD). He attended
preschool timely.
Discussion
There are many publications on partial trisomies in 7q.
In most cases the duplication resulted from a familial
translocation involving the long arm of chromosome 7
and another chromosome leading to partial trisomy/
monosomy 7 and partial trisomy/monosomy of the
translocation partner, respectively [3-9]. About 19
patients with isolated trisomy 7 involving various
regions of 7q have been described [10,11]. The pheno-
type varies according to the region which is duplicated
and the size of the duplication. In an attempt to corre-
late the karyotype with the phenotype, patients with par-
tial trisomy 7 have been divided into groups. Novales
and co-workers suggested three groups [3]. Patients
with a duplication 7q21 or q22 to 7q31 belong to group
1. The phenotype includes facial dysmorphism (frontal
bossing, narrow palpebral fissures, epicanthus, and
hypertelorism), strabism, hypotonia, and developmental
delay. Group 2 includes patients with duplication 7q31
to 7qter. The phenotype is characterised by low birth
weight, large fontanel, facial dysmorphism (narrow pal-
pebral fissures, hypertelorism, small nose, low-set and
malformed ears, microretrognathia), cleft palate, devel-
opmental delay, skeletal anomalies, and a reduced life
expectancy. Group 3 is defined by a duplication of 7q32
to 7qter. These patients show low birth weight, facial
dysmorphism (low-set ears, small nose, and hypotonia),
kyphoscoliosis, skeletal anomalies, hypotonia and devel-
opmental delay. Courtens et al. described group 4 with
a duplication involving 7q21 or q22 to 7qter [12]. One
has to bear in mind that the clinical descriptions are
mainly based on patients assessed by chromosome
banding analyses.
The patient described herein has isolated partial tris-
omy 7q21.2 to 7q31.31 without additional chromosomal
imbalances as confirmed by array-CGH. She therefore
fits best into group 1 and displays the typical symptoms,
namely low birth weight, global developmental delay
with marked hypotonia in infancy, marked delay in
speech development, mild short stature, normal head
circumference, strabism and mild unspecific facial dys-
morphism. Our patient can be best compared to the
patients described by Humphreys et al. and Romain et
al. [13,14]. Low birth weight was also a symptom in the
patients described by Grace et al. and Berger et al.
[15,16]. In contrast to other descriptions the palpebral
fissures were of normal size.
Conclusion
To enable a future new classification of duplications in
7q which will be based on findings of molecular karyo-
typing the description of well-defined patients is valu-
able. Furthermore, this case shows that FISH-
microdissection is of great benefit for breakpoint desig-
nation in cases of balanced and/or complex
rearrangements.
Consent
Written informed consent was obtained from the par-
ents of the patient for publication of this case report
and all images.
Acknowledgements
We thank Professor Dr. med. Reiner Siebert, Institute of Human Genetics,
Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein,
Campus Kiel, for the ongoing support of this study.
Author details
1Department of Obstetrics and Gynaecology, Christian-Albrechts-University of
Kiel, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-
Str.3, Haus 24, Kiel, Germany. 2Institute of Human Genetics, Christian-
Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Campus
Kiel, Arnold-Heller-Str.3, Haus 10, Kiel, Germany. 3Department of Obstetrics,
Gynaecology and Reproductive Medicine, Hannover Medical School,
Hannover, Germany.
Authors’ contributions
JW, SH and AC wrote the manuscript. JW carried out the FISH-MD and
molecular cytogenetic analysis. CSvK did high resolution prenatal analysis of
the patient. SB performed the array-CGH. AC performed cytogenetic
analyses, clinical genetic investigation and genetic counselling. WG and NA
coordinated the investigations.
All the authors have read and approved the manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 23 November 2011 Accepted: 5 December 2011
Published: 5 December 2011
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Cite this article as: Weimer et al.: Isolated trisomy 7q21.2-31.31 resulting
from a complex familial rearrangement involving chromosomes 7, 9
and 10. Molecular Cytogenetics 2011 4:28.
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Weimer et al. Molecular Cytogenetics 2011, 4:28
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Isolated trisomy 7q21.2-31.31 resulting from a complex familial rearrangement involving chromosomes 7, 9 and 10

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