A de novo microdeletion 2p24.3-25.1 identified in a girl with global development delay

Abstract

Citation: Ivanov HY, Stoyanova VK,. Vazharova R, Linev A, Ivanov I, Ivanov S et al. A de novo microdeletion 2p24.3-25.1 identified in a girl with global development delay. Abstract Interstitial microdeletions of the distal 2p are very rare. A small number of cases have been reported in the literature, involving regions 2p23-p25, 2p23-p24 and 2p24-p25. The most common symptoms involve: intrauterine growth retardation, developmental delay, mental retardation, microcephaly, craniofacial anomalies, musculoskeletal abnormalities, congenital heart defect and hearing impairment. Herein we report on a Caucasian girl, born after in vitro fertilization with discrete facial dysmorphism, growth failure, borderline neurodevelopment and congenital heart defect. A de novo pericentric inversion of chromosome 2 was identified by routine karyotyping. An interstitial microdeletion of 2p24.3p25.1 was found by array karyotyping and following FISH analysis revealed that the deletion affects the inverted chromosome 2. This case illustrates the utility of high resolution methods to identify submicroscopic quantitative changes in structurally rearranged chromosomes. The precise determination of the genetic content of small quantitative changes in the genome provides important information for genetic counseling, enabling to predict the course of disease and the planning of adequate therapy and prophylaxis in affected families.

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BioDiscovery
BioDiscovery | www.biodiscoveryjournal.co.uk October 2015 | Issue 18 | 1
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SHORT COMMUNICATION
A de novo microdeletion 2p24.3-25.1 identied in a girl
with global development delay
Hristo Y. Ivanov1#, Vili K. Stoyanova1,2*#, Radoslava Vazharova3,4#, Aleksandar Linev2, Ivan
Ivanov1,2, Samuil Ivanov4, Lubomir Balabanski4, Draga Toncheva4,5
1Medical University - Plovdiv, Department of Pediatrics and Medical Genetics, Plovdiv, Bulgaria
2University Hospital „St. George „- Plovdiv, Bulgaria
3Soa University „St. Kliment Ohridski“, Faculty of Medicine, Department of Biology, Medical Genetics and Microbiology, Soa, Bulgaria
4Gynecology and Assisted Reproduction Hospital «Dr. Malinov»; Soa, Bulgaria
5Medical University - Soa, Department of Medical Genetics, Bulgaria
Citation: Ivanov HY, Stoyanova VK,. Vazharova R, Linev A, Ivanov I, Ivanov S et al. A de novo microdeletion 2p24.3-25.1 identied in a
girl with global development delay. Biodiscovery 2015; 18: 1; DOI: 10.7750/BioDiscovery.2015.18.1
Copyright: © 2015 Ivanov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, provided the original authors and source are credited.
Received: 26 August 2015; Accepted: 08 October 2015; Available online/Published: 10 October 2015
Keywords: microdeletion 2p24.3-25.1, global development delay
*Corresponding Author: Vili K. Stoyanova, e-mail: vi1sto@abv.bg
Conict of Interests: No potential conict of interest was disclosed by any of the authors.
#These authors contributed equally to this work.
Abstract
Interstitial microdeletions of the distal 2p are very rare. A small number of cases have been reported in the literature,
involving regions 2p23-p25, 2p23-p24 and 2p24-p25. The most common symptoms involve: intrauterine growth
retardation, developmental delay, mental retardation, microcephaly, craniofacial anomalies, musculoskeletal
abnormalities, congenital heart defect and hearing impairment. Herein we report on a Caucasian girl, born
after in vitro fertilization with discrete facial dysmorphism, growth failure, borderline neurodevelopment and
congenital heart defect. A de novo pericentric inversion of chromosome 2 was identied by routine karyotyping.
An interstitial microdeletion of 2p24.3p25.1 was found by array karyotyping and following FISH analysis
revealed that the deletion affects the inverted chromosome 2. This case illustrates the utility of high resolution
methods to identify submicroscopic quantitative changes in structurally rearranged chromosomes. The precise
determination of the genetic content of small quantitative changes in the genome provides important information
for genetic counseling, enabling to predict the course of disease and the planning of adequate therapy and
prophylaxis in affected families.
Introduction
Constitutional interstitial deletions of the distal short
arm of chromosome 2 are very rare. A small number
of cases have been described in the medical literature,
involving regions 2p23-p25, 2p23-p24 and 2p24-p25
[1]. The most common symptoms involve: intrauterine
growth retardation; developmental delay; mental
retardation; microcephaly, craniofacial anomalies; facial
dysmorphism (hypotelorism/hypertelorism, epicantal
folds, narrow, short palpebral ssures, large, low-set
ears), musculoskeletal abnormalities; congenital heart
defect, seizures and hearing impairment.
We report on a girl with discrete facial dysmorphism,
global development delay and congenital heart defect. A
de novo pericentric inversion of chromosome 2 was found
by routine karyotyping and an interstitial microdeletion
2p24.3-p25.1 was identied by array karyotyping.
Clinical Report
The proband is a Caucasian girl who came to our genetic
clinic because of dysmorphism, growth failure and
suspected neurodevelopmental delay. She was born at
37th gestational week of a twin pregnancy after in vitro

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Microdeleon 2p24.3-25.1
fertilization with birth weight 1550 g., body length of
37 cm and head circumference of 29 cm. Her twin sister
weighed 2200 g at birth and develops normally thus far.
The pregnancy was complicated by bleeding in 6th m.l.
Intrauterine growth retardation was noted at 35 g.w.
Congenital heart defect (three apical ventricular septal
defects) was found shortly after birth. Initial physical
examination demonstrated axial musclе hypotonia.At
the time of examination the proband is 1 year and 5
months old. Her weight is 6 kg (-3.23 SD), height is 64
cm (-3.9SD) and her head circumference is 39 cm (-4.38
SD).
Dysmorphic features include: hypertelorism,
epicanthus, hirsutism of the forehead, prominent
metopic suture, depressed nasal bridge, down slanting
mouth corners, low set large and simple ears, high
arched palate, misaligned dentition, carious teeth,
short neck and low hairline at the neck. Her ngers
are short with exion contractures, clinodactyly of the
fth ngers and proximally placed thumbs and toes
(Fig. 1). Neurological examination revealed a musclе
hyperotonia of lower limbs. Her neurodevelopment was
borderline:: able from prone to supine at 6 months of
age; pronounce syllables at 1 year of age; rst word at 13
months of age; able to walk with support at 17months..
Developmental delay – DQ - 71% by Manova-Tomova.
Palm X-ray for bone age scan at chronological age 17
months revealed bone age of 1 month age. Abdominal
echography showed normal liver, spleen and kidneys.
Echocardiography detected ventricular septal defect.
The thyroid function is normal.
Cytogenetic and Molecular Analysis
Cytogenetic analysis of cultured blood lymphocytes was
performed using standard protocols. In all metaphases
a female karyotype with a large pericentric inversion
of chromosome 2 was found – 46XX,inv(2)(p24q14.3)
(Fig. 2). The inversion is apparently balanced at 400 GTG
bands resolution. The karyotypes of the parents appeared
normal at 400 bands resolution. The karyotype of the
proband’s healthy twin-sister has not been analyzed.
Because of the “chromosomal phenotype” of the
patient the presence of a submicroscopic chromosomal
imbalance was suspected.
Molecular karyotyping
To investigate the DNA of the patient for submicroscopic
deletions and duplications, the Illumina Human
CytoSNP-12 microarray, iScan system and the
KaryoStudio 1.4.3.0 software were used according to
the manufacturer’s instructions. The analysis revealed
a heterozygous interstitial microdeletion encompassing
4.46 Mb in the short arm of chromosome 2 with
breakpoints in bands 2p24.3 and 2p25.1 – arr[hg19] 2p2
5.1p24.3(8,822,787-13,462,596)x1 (Fig. 3).
In order to validate the presence of the microdeletion
and to determine if it affects the inverted chromosome
2 we performed FISH analysis using directly labelled
custom probes (RP11-327F6 for 2p25.1 labelled with
Cy3.5 (SO) and RP11-425I16 for 2q11.2 labelled with
FITC (SG)). All interphase nuclei demonstrated two
green signals but only one orange signal. In all analyzed
metaphases it was obvious that the deletion affects the
inverted chromosome 2 (Fig. 4).
Discussion
Interstitial deletions of the distal 2p are very rare as
constitutional abnormalities of the genome. There have
been several reports of deletions encompassing the distal
part of the short arm of chromosome 2 [1-7] but the
number of patients with overlapping deletions is relatively
small and a specic recognizable phenotype remains to be
elucidated. A comparison of clinical ndings in the present
case and previously reported patients with overlapping
Figure 1. Phenotype of the proband. Note the prominent metopic
suture, hypertelorism, epicanthus, hirsutism of the forehead, down
slanting mouth corners, low set large and simple ears the short
ngers with exion contractures, clinodactyly of the fth nger and
proximally placed thumb.
Figure 2. (A) Partial GTG banded karyotype of the
patient showing pericentric inversion of chromosome 2,
the rearranged chromosome is on the right. (B) Ideogram
of the inverted chromosome 2.

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Microdeleon 2p24.3-25.1
Figure 4. FISH analysis of the patient showing deletion of
2p25.1 (one orange signal for the probe RP11-327F6, and two
green signals for the probe RP11-425I16) and location of the
probe RP11-425I16 (2q11.2) in the ”short” arm of the derivative
chromosome 2.
Figure 3. Deleted region of the patient is presented compared to CNVs reported in the DECIPHER database. Only 4 cases show
deletions overlapping the region observed in the present case. Deletions are visualized as red bars and duplications as blue bars,
corresponding GTG bands are shown on the top.
interstitial deletions of the distal 2p is presented in Table
1. Mental retardation / developmental delay have been
reported in all patents but with a variable degree of
severity ranging from mild to severe. Intrauterine growth
retardation / failure to thrive, anomalies of hands and feet,
microcephaly / craniofacial anomalies and congenital
heart defects have been observed in most patients sharing
deletion of 2p24p25. The phenotypic heterogeneity may be
the result of diagnostic difculties in the identication and
exact localization of 2p deleted segments in the prearray
era [3, 4, 7]. Number of patients studied by molecular
karyotyping is limited and present case contributes to a
better understanding of genotype-phenotype correlation in
carriers of subtle deletions of distal 2p.
Fifty two genes have been mapped to the region deleted
in the patient. Among these genes 3 have been already
implicated in monogenic human diseases: ADAM17
(autosomal recessive form - Inammatory skin and bowel
disease, neonatal, OMIM# 614328), KLF11 (autosomal
dominant form of Maturity-onset diabetes of the young,
type VII, OMIM# 610508), and LPIN1 (autosomal
recessive form of acute recurrent Myoglobinuria, OMIM#
268200).
The deletion probably led to disruption of the gene
KIDINS220 (kinase D-interacting substrate, 220kDa)
and to a heterozygous loss of at least 1st to 22th exon of
the gene. So far there are not any detected mutations of
this gene associated with a particular disease in humans,
but research on mouse models provides an association
between change in gene dose and abnormal development
of the heart and nervous system [8].
Some of the genes mapped to the region are predicted to

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Microdeleon 2p24.3-25.1
be dosage-sensitive. ITGB1BP1 encodes Integrin beta-1-
binding protein 1, which has been found to be involved in
cell proliferation, differentiation, adhesion and migration
in the context of the mineralization and development of
bones and blood vessels, stimulating cell proliferation in
a bronectin-dependent manner. The loss of one copy of
the gene could affect the development of bones and blood
vessels. YWHAQ encodes the protein 14-3-3-THETA and
is expressed in all tissues, with highest expression in the
CNS. So far there are not any detected mutations in the
gene associated with a particular disease, but a change in
its expression is observed in patients with amyotrophic
lateral sclerosis [9]. RRM2 encodes the small subunit (R2)
of the enzyme ribonucleotide reductase which mediates the
rate-limiting step in the synthesis of deoxyribonucleotides.
Haploinsufciency of the gene could be associated with
retention in physical development observed in the patient.
ROCK2 encodes RHO-associated coiled-coil-containing
protein kinase 2. According to studies in animal models
it has been found that loss of the gene leads to ROCK2
placental dysfunction and may cause delay in intrauterine
fetal growth and even fetal death [10]. Recently, the gene
has been identied as one of the candidate genes for
heterotaxy in humans [11]. Another gene in the region -
PDIA6, encodes the enzyme disulde isomerase, family
A, member 6, which is involved in the establishment of
left-right symmetry during embryonic development and
is important for the formation of the internal organs in the
midline (heart, liver, pancreas) [12].
Conclusion
In conclusion we can say that this case illustrates the
utility of high resolution methods in order to identify
subtle quantitative changes in genome of patients with
microscopically balanced chromosomal rearrangements.
The precise determination of the genetic content of
submicroscopic imbalances of the genome provides
important information for genetic counseling, enabling to
predict the course of disease and to plan adequate therapy
and prophylaxis in affected families. As molecular
karyotyping results become more frequently reported, a
genotype–phenotype correlation based on contents and
specic location may give clinicians further guidance
for the diagnosis and prognosis of similar chromosome
anomalies.
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