Gene Reports 25 (2021) 101386

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Gene Reports
journal homepage: www.elsevier.com/locate/genrep

Clinical and molecular cytogenetic description of a female patient with de

novo 18q inversion duplication/deletion
Rana Mahrous a, *, Mohamed S. Gabal b, Ola M. Eid a, Engy A. Ashaat c, Mona S. Aglan c,
Ahmed E. Shoman b, Amal M. Mohamed a
a
Human Cytogenetics Department, Human Genetics and Genomics Research Division, National Research Centre, Egypt
b
Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Egypt
c
Clinical Genetics Department, Human Genetics and Genomics Research Division, National Research Centre, Egypt

A R T I C L E I N F O A B S T R A C T

Keywords: The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are heterogeneous.
Array CGH Chromosomal imbalance has been recognized as the most frequent cause of ID for years. We describe the report
SNP analysis of a female patient aged 1 year and 5 months at presentation who had GDD, prenatal growth retardation, failure
Parent of origin
to thrive, microcephaly, dysmorphic facial features including: broad forehead, high anterior hair line with sparse
Partial trisomy 18q
scalp hair, wide palpebral fissures, long eye lashes, blue sclera, sparse arched eye brows, prominent and wide
Terminal deletion 18q
nasal root, hypertelorism, micrognathia and dysplastic low set ears in addition to widely spaced nipples, bilateral
clenched fists, camptodactyly, rocker bottom feet and brittle nails.. Her karyotype revealed 46,XX,add (18)(q23).
Comprehensive cytogenomic analysis was performed using multiplex ligation-dependent probe amplification
(MLPA), fluorescence in situ hybridization (FISH), and aCGH techniques to determine the parental origin and the
possible mechanism responsible for this abnormal karyotype. Both parents had normal karyotypes. MLPA and
FISH analysis for the patient revealed deletion of 18q subtelomere, and whole chromosome paint (WCP) asso­
ciated with inverted DAPI indicated that all the duplicated segments originated from chromosome 18 and there
was inversion of 18q segment. Array CGH identified 55.8-Mb duplicated segment and 614-kb deleted terminal
18q. Single nucleotide polymorphism (SNP) analysis for the patient and the parents revealed that the duplicated
and deleted 18q regions originated from paternal chromosome 18. These findings suggested that the event
occurred during paternal meiosis or early postzygotic stage. The suggested mechanism responsible for this type of
rearrangement is nonhomologous end point recombination and U-type exchange.

1. Introduction chromosome 18 duplication, partial deletions of chromosome 18,

Chromosome 18 aberrations including either duplication or deletion
are among the most common autosomal aberrations. Although partial
trisomy 18 has been reported extensively, pure form of partial trisomy
18 without the involvement of other chromosomes is uncommon. Partial
duplication of 18q exhibits a phenotype similar to that of complete tri­
somy 18, but it is generally milder with longer life spans. Compared with
including 18q deletion, 18p deletion, ring 18, and other various forms,
are less frequent. However, terminal deletions of 18q are relatively
frequent and appear to cause a variable phenotypic spectrum (Lee et al.,
2009; Nguyen-Minh et al., 2013).
Trisomy 18, also known as Edwards syndrome (ES), is the second
most common autosomal aneuploidy whose estimated incidence ranges
from 1 in 3000 to 1 in 8000 live births, with a predilection for females

Abbreviations: array CGH, array comparative genomic hybridization; CRES, critical regions for Edwards syndrome; ES, Edwards syndrome; FISH, fluorescence in
situ hybridization; GDD, global developmental delay; GTG banding, trypsin-Giemsa G-band; ID, intellectual disability; LCR, low copy repeats; MLPA, Multiplex
Ligation Dependent Probe Amplification; MMBIR, microhomology-mediated breakpoint-induced replication; NAHR, non-allelic homologous recombination; NHEJ,
non-homologous end joining; OMIM, Online Mendelian Inheritance in Man; SD, segmental duplications; SNP, single nucleotide polymorphism; WCP, whole chro­
mosome paint.
* Corresponding author at: Human Genetics and Genome Research Division, Human Cytogenetics Department, National Research Centre, 33 El Buhouth Street, El-
Dokki, Cairo 12622, Egypt.
E-mail address: rana.mahrous.rm@gmail.com (R. Mahrous).

https://doi.org/10.1016/j.genrep.2021.101386
Received 19 January 2021; Received in revised form 10 September 2021; Accepted 30 September 2021
Available online 6 October 2021
2452-0144/© 2021 Elsevier Inc. All rights reserved.
R. Mahrous et al.
(Imataka et al., 2016). Although ES is generally associated with dupli­
cation of the entire chromosome 18, there have been reports of some
individuals with partial chromosome 18 trisomy. The severity of this
syndrome ranges from a relatively mild phenotype with no internal
organ malformations to the classic features of ES in these patients
(Quiroga et al., 2011).
Deletions of the long arm of chromosome 18 (18q-) was first
described by de Grouchy et al. (1964). Patients with 18q deletion syn­
drome exhibit a broad phenotypic variation, with short stature, intel­
lectual disability (ID), distinctive facial dysmorphisms, cleft lip/palate,
delayed myelination, foot deformities, and congenital aural atresia
being the most prominent features (Feenstra et al., 2007; van Trier et al.,
2013). Partial deletions of chromosome 18 have an overall incidence of
approximately 1 in 40,000 live births in humans (Feenstra et al., 2007).
The size of terminal deletions has been reported to vary between in­
dividuals from 0.5 to 30 Mb (Heard et al., 2009).
The primary mechanism responsible for the recurrent rearrange­
ments is the nonallelic homologous recombination (NAHR) that origi­
nates due to low copy repeats (LCRs) and segmental duplications (SD).
However, non recurrent imbalance primarily originates due to non ho­
mologous end joining (NHEJ) (Sibbons et al., 2012).
Most often, a duplication proximal to a terminal deletion is inverted
(Heard et al., 2009; Hulick et al., 2009; Lee et al., 2009; Rowe et al.,
2009; Córdova-Fletes et al., 2014).
The detection of chromosomal aberrations was improved by the use
of array CGH, which has become a first-tier test for patients with ID or
multiple congenital anomalies.
We aimed to determine the parental origin of the chromosomal ab­
normality and the possible mechanism responsible for this abnormal
karyotype.
Herein, we report the clinical, cytogenetic, and molecular cytoge­
netic data of a female patient with de novo 18q inversion duplication/
deletion. To the best of our knowledge, our patient is the seventh case to
be reported with dup/del 18q. Trio SNP analysis indicated that the
rearrangement was paternally originated. And as the breakpoints were
not within the regions of segmental duplication (SD), we suggested that
the rearrangement is a postzygotic event most probably due to a
nonhomologous end point recombination or the U-type exchange
mechanism.
2. Material and methods
A female child was referred to the Clinical Genetics Clinic, Center of
Excellence for Human Genetics, National Research Centre, due to failure
to thrive and global developmental delay (GDD).
A written informed consent was provided by the parents according to
the guidelines and approval of the Medical Research Ethics Committee
of the National Research Centre.
The patient was subjected to the following:
• Comprehensive clinical examination.
• Anthropometric measurements (at the time of clinical evaluation)
with regard to weight, length, and head circumference.
• Conventional cytogenetic analysis was performed on peripheral
blood lymphocytes using the GTG banding technique at the 550 band
level using standard protocols. At least 25 metaphases karyotyped
for the patient and parents.
• Multiplex ligation-dependent probe amplification (MLPA) assay was
performed for the patient using the SALSA MLPA probemix P070-B2
Human Telomere-5, according to the manufacturer's instruction
(MRC-Holland, Netherlands). DNA denaturation and overnight hy­
bridization of the MLPA probemix were performed, followed by
probe ligation and amplification on the next day. The amplified
products were separated using Genetic Analyzer ABI 3500 (USA).
Results were interpreted using the Coffalyser.Net software (MRC-
Holland). Ratios <0.75 were considered as deletion, those between
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Gene Reports 25 (2021) 101386
0.75 and 1.30 were considered as normal, and ratios >1.30 were
considered as duplication.
• Fluorescence in situ hybridization (FISH) was conducted to confirm
the MLPA results. We used mix 11 and 12 from the ToTelVysion
probe (Abbott Molecular, USA). These mixes had probes for chro­
mosome 11 p and q subtelomeres with 18p subtelomere and chro­
mosome 12 p and q subtelomeres with 18q subtelomere,
respectively; we also used whole chromosome paint (WCP)18
(Cytocell Cambridge UK).
• Array comparative genomic hybridization (aCGH) was performed for
the patient and her parents. The Affymetrix CytoScan HD microchip
was used, which includes 2.67 million probes for 750,000 SNPs and
1.9 million CNVs, 36,000 RefSeq genes, 12,000 OMIM genes, and all-
important cytogenetic regions.
• Cytoscan HD method: After DNA digestion, ligation, amplification,
purification, fragmentation, labeling, and injection into the micro­
chips, the microchips were hybridized for 16 h in Hybridization Oven
645 (Affymetrix Santa Clara USA). These steps were followed by
washing and staining in fluidics station 450 (Affymetrix Santa Clara
USA). The microchips were scanned using Gene Chip Scanner 3000
(Affymetrix Santa Clara USA). Data analysis was conducted using the
Chromosome Analysis Suite software (ChAS 3.1) (Affymetrix Santa
Clara USA).
3. Results
3.1. Clinical report
A female child aged 1 year and 5 months was referred to the Clinical
Genetics Clinic, Center of Excellence for Human Genetics, National
Research Centre, due to failure to thrive and GDD. She was the first child
of healthy nonconsanguineous parents. The pregnancy history was un­
remarkable apart from reporting intrauterine growth retardation (IUGR)
by ultrasound follow up. The parents had a history of previous abortion
at 4 months of gestation of unknown cause. The patient has a normal
younger brother. At birth, the proband's weight was 2 kg and she suf­
fered from respiratory distress, cyanotic spells, poor activity, and weak
cry.
Clinical examination showed that she had delayed motor and mental
development. Irritability and continuous crying were noted. Anthropo­
metric measurements at the time of referral disclosed growth retarda­
tion in all parameters as follows: weight was 5.7 kg (− 4.0 SD), length
was 69 cm (− 3.7 SD), and head circumference was 40 cm (− 4.3 SD).
Facial examination revealed dysmorphic features including broad
forehead, high anterior hair line with sparse scalp hair, wide palpebral
fissures, long eyelashes, blue sclera, sparse arched eye brows, prominent
and wide nasal root, hypertelorism, long grooved philtrum, thin upper
lip, micrognathia and dysplastic low set ears. She also had short webbed
neck, wide-spaced nipples, short sternum, bilateral clenched fists with
camptodactyly of fingers, rocker bottom feet, and brittle nails. Skin
manifestations in the form of dry skin, scattered small hypopigmented
areas on the chest, abdomen, and back, and localized hemangioma on
the abdomen were noted (Fig. 1). Hypertonia with brisk reflexes was
detected at neurological examination. Brain MRI showed thin corpus
callosum. EEG showed generalized epileptogenic activity. Echocardi­
ography, abdominal ultrasound and fundus examination revealed
normal findings.
3.2. Cytogenetics report
Patient karyotype was 46,XX,add (18)(q23) (Fig. 2). Father and
mother karyotypes were normal, 46,XY and 46,XX respectively. This
indicates de novo chromosomal abnormality in our patient.
MLPA assay performed for the patient showed subtelomeric deletion
at 18q23 (Fig. 3) but did not reveal the origin of the added material
denoting that the added material came from an interstitial chromosomal
R. Mahrous et al.
Fig. 1. Dysmorphic features in the form of broad forehead, high anterior hair
line with sparse scalp hair, wide palpebral fissure, long eye lashes, blue sclera,
sparse arched eye brows, prominent and wide nasal root, hypertelorism, long
grooved philtrum, large simple ears, and short webbed neck.
Fig. 2. Conventional GTG banded karyotype: 46,XX,add (18)(q).
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Gene Reports 25 (2021) 101386
segment.
FISH confirmed the 18q subtelomeric deletion, WCP 18 delineate
that the added segment originate from chromosome 18 and the inverted
DAPI pattern clarified the inversion duplication of 18q (Fig. 4a, b and c).
Array CGH was performed for the patient and both parents showed a
56 Mb heterozygous duplication at 18q11.2q23 and 613 kb heterozy­
gous deletion at 18q23 (Fig. 5).
The array CGH results were defined according to ISCN 2016 as
follows:
Father: arr[GRCh38](1-22)x2,(X,Y)x1.
Mother: arr[GRCh38](1-22,X)x2.
Patient: 46,XX,add(18)(q23).arr[GRCh38]18q12.2q23
(23625943_79639731)x3,18q23(79643021_80256240)x1 dn.
Deleted region included four OMIM genes, viz., CTDP1 (604927),
KCNG2 (605696), TXNL4A (611595), and PARD6G (608976). The
duplicated region includes 158 entries with 61 phenotypes.
https://www.omim.org/search?index=geneMap&start=1&sor
t=chromosome_number+asc%2C+chromosome_sort+asc&search
=18q12-2q23&limit=10.
SNP genotype analysis of the patient and her parents indicated that
the duplicated and deleted segments originated from the father.
4. Discussion
The patient exhibited a 56-Mb heterozygous duplication at
18q11.2q23 and a 0.613-Mb heterozygous deletion at 18q23 with a
breakpoint within 3788-bp distance between them. A total of 17 cases
have been reported in the literature with rearrangements involving a
18q proximal duplication and a terminal deletion within the same arm.
R. Mahrous et al.
Fig. 3. A ratio chart of MLPA results using SALSA MLPA probemix P070-B2 Human Telomere-5. The chart shows the subtelomeric deletion at 18q23. The deletion is
denoted by the red spot below the deletion cut-off line (red) in the ratio chart.
However, 11 cases were excluded by considering them as “segmental
duplications” (SD) (Chia et al., 1992; Courtens et al., 1998; Heard et al.,
2009; Lee et al., 2009; Rowe et al., 2009; Nguyen-Minh et al., 2013;
Córdova-Fletes et al., 2014).
The microdeletion and microduplication syndromes caused by losses
or gains within regions of low copy repeats (LCR), which is also known
as segmental duplication (SD), are recurrent and mediated through
nonallelic homologous recombination (NAHR). This rearrangement has
an equal maternal and paternal origin and occurs primarily in meiosis
(Thomas et al., 2006a). The interchromosomal event occurs in meiosis,
whereas the intrachromosomal event occurs in both meiosis and mitosis
(Sibbons et al., 2012).
To the best of our knowledge, our patient is the seventh case to be
reported with dup/del 18q rearrangements. Table 1 shows a comparison
between the current case and the six others reported in the literature.
Our patient showed the largest duplication area sized approximately 56
MB and the smallest deleted area sized approximately 0.6 Mb compared
to previously reported patients listed in (Table 1).
Our patients showed trisomy 18q clinical manifestations that may be
overlapped by 18q deletion phenotype. The monozygotic twins reported
by Courtens et al. (1998) carried deletion (18q22.3–qter) and duplica­
tion (18q12.1–q21.1). The mother carried a paracentric inversion of the
long arm of chromosome 18, inv(18)(q21.1q22.3). Their patients
showed overlapping phenotypes of both T18 and 18q− syndromes.
Unlike our patient, the authors suggested that the deletion of distal 18q
has a major contribution to the observed phenotype in their patients. Lee
et al. (2009) studied a fetus with 46,XY,der(18)del(18) (q22)dup(18)
(q22q11.2)dn. Pregnancy was terminated upon the result. The abortus
weighed 735 g, and showed no gross abnormalities (including those that
may be seen in trisomy 18 such as clenched fists and rocker-bottom feet)
by external inspection. Their patient was not assessed in detail for
deletion features. Rowe et al. (2009) reported a patient with 46,XX, inv?
dup del(18q)., they didn't asses their patient for feature of both syn­
dromes. Nguyen-Minh et al. (2013) reported a patient with combined
deletion 18q22.2 and duplication/triplication 18q22.1 with phenotypic
features of isolated 18q deletion syndrome and absence of phenotypic
features characteristic of Edwards syndrome. They suggested that a
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Gene Reports 25 (2021) 101386
distal or terminal duplication of chromosome 18q is not sufficient for the
appearance of the Edwards syndrome phenotype but that a combined
duplication of a specific proximal and distal region of 18q is necessary to
induce this phenotype. These regions may comply with a combination of
18q11 and 18q22-qter or combination of 18q12.1–q21.2 and 18q22.3-
qter. Córdova-Fletes et al. (2014) reported a patient with de novo
dup/del of 18q with mixed phenotypes. Their patient showed large,
duplicated region sized 34 Mb and deletion region sized 8841 Mb which
may explain the presence of phenotypic features of both syndromes in
their patient. Our patient showed a large, duplicated area sized 56 Mb
with a small deletion area sized 0.6 Mb. This may explain the presence of
T18 phenotype in our patient that may be overlapped with 18q deletion
syndrome phenotype. The variability of phenotypes reported may be
due to the differences in the sizes of the duplicated/deleted regions and
the involved critical regions.
Edwards et al. (1960) and Smith et al. (1960) were the first to
describe the clinical characteristics of trisomy 18, a condition commonly
known as ES. Due to the low rate of survival and massive genetic ab­
errations, there has been limited research on the molecular significance
of trisomy 18 or the possible therapeutic methods (Albizua et al., 2020).
The 18q11.2-qter region has been proposed as the critical region for
the trisomy 18 phenotype (Cereda and Carey, 2012). The presence of
two additional critical regions for ES (CRES) was suggested including a
proximal critical region within 18q12.1–18q21.2 and a distal critical
region within 18q22.3–qter. Meanwhile, two patients were reported by
the same authors with trisomy 18q11.2 to qter lacking the complete
phenotype of trisomy 18; those patients had better survival and growth.
It was assumed that the expression of the complete phenotype could be
attributed to the 18q11.1 region or genes on the short arm of chromo­
some 18 (Boghosian-Sell et al., 1994; Cereda and Carey, 2012). Simi­
larly, our patient exhibited duplication of the long arm of chromosome
18, including region 18q11.2 to 18q23 that encompasses the two sug­
gested CRES.
Epilepsy is commonly described in patients with trisomy 18. It has
been attributed to structural malformations in only a few cases (del
Gaudio et al., 2014). 18q22.1-q22.2 region was suggested to be the CRES
for seizures in trisomy 18 (Lustosa-Mendes et al., 2017). Epilepsy in
R. Mahrous et al.
Fig. 4. a. ToTelVysion probemix 12 with chromosome 12p subtelomere (green
arrow) two copies, 12 q subtelomere (red arrow) two copies and chromosome
18q subtelomere (orange arrow) only one copy. b. Whole chromosome paint
(green) showing the normal and duplicated chromosome 18. The duplicated
region was derived from chromosome 18. c. diagram showing the normal and
inversion/duplication chromosome 18 is shown. In the inverted DAPI photo­
graph, the duplicated 18q23 bands are adjacent in the middle, whereas the
duplicated 18q12.1q12.3 are separated by the two segments of 18q23.
5
Gene Reports 25 (2021) 101386
partial trisomy 18 (18p/18q) appears to be a common clinical and
electroencephalographic (EEG) pattern, characterized by late-onset ep­
ilepsy with generalized and focal seizures in 18q- or only focal in 18p-
(Grosso et al., 2005; d'Orsi et al., 2013; del Gaudio et al., 2014). Our
patient demonstrated an EEG pattern of generalized epileptogenic ac­
tivity, which is the most common pattern in patients with trisomy 18.
The fact that epilepsy is of late-onset may explain the absence of seizures
due to the young age of our patient.
The detailed clinical features of trisomy 18 reviewed by Rosa et al.
(2013) are compared to those our patient (Table 2).
Most of the patients with 18q deletion syndrome have breakpoints
within 18q21. However, more distal deletions (18q23), as that detected
in our patient may also cause the classical phenotype; however, there
exists a wide phenotypic variability (De Vries et al., 2003).
Our patient had a 0.614-Mb deletion of 18q23, including four OMIM
genes: CTDP1 (604927), KCNG2 (605696), TXNL4A (611595), and
PARD6G (608976). PARD6G and KCNG2 genes have unknown conse­
quences with no reported associated phenotypes. Meanwhile, the
TXNL4A gene causes Burn–McKeown syndrome (BMKS) (OMIM #
608572), which is known to be inherited in an autosomal recessive
pattern. Patients with 18q- can exhibit features of BMKS if their
remaining allele carries a specific genetic variant, which is an extremely
rare event (Goos et al., 2017; Cody et al., 2018). Similarly, the CTDP1
gene which causes congenital cataracts, facial dysmorphism, and neu­
ropathy is inherited in an autosomal recessive pattern. This may explain
the absence of the distinctive features caused by either gene in our
patient.
The literature reports a wide variation in the deletion size of terminal
18q, ranging from 0.5- to 30.076-Mb hemizygous terminal deletion of
DNA (Heard et al., 2009), and it has been reported that a patient with the
0.5-Mb terminal deletion had no phenotypic picture aberrations (South
et al., 2008). Meanwhile, the smallest terminal deletion reported with
any clinical consequences was a 3.78-Mb deletion (Heard et al., 2009).
In our present case, we report a 0.6-Mb deletion that may explain the
lack of 18q del syndrome complete phenotype in our patient.
The breakpoint in our patient occurred within 3.7 kb between c-
3NTDW and c-7PQHK SNP marker interval between the duplicated and
deleted regions with no normal copy segment between both regions.
Normal copy regions between the deletion/duplication were reported in
two patients by Zuffardi et al. (2009). Our patient showed no normal
copy regions between the deletion/duplication segments.
De novo non-LCR rearrangements are not recurrent, and the mech­
anism of repair differs from that of NAHR, and may be NHEJ or
microhomology-mediated breakpoint-induced replication or others.
There is excess of paternal derived patients (Thomas et al., 2006b).
The chromosomal rearrangements, in the form of unbalanced
translocations, deletions, and duplications, transmitted from the same
parental origin are the result of repair of genome damage. However,
biparental transmitted chromosomal rearrangement occurs due to
mechanisms other than NAHR, e.g., breakage fusion bridge cycles, and
indicates that the event occurs postzygotic (Daniel et al., 2008; Sibbons
et al., 2012; Bonaglia et al., 2018; Wu et al., 2018).
The U-type exchange following a double-strand break, which results
in a mirror image of unstable dicentric chromosome, is the most com­
mon mechanism responsible for de novo interstitial inverted duplication
with simultaneous terminal deletion. Sometimes, the deleted duplicated
chromosome acquires new telomere by telomere capture from another
chromosome or the opposite arm of the same chromosome. There is no
recurrence risk for de novo inv dup del (Zuffardi et al., 2009; Rowe et al.,
2009; Pham et al., 2014). Meanwhile, a “direct” duplication (with no
inversion) was once reported by Córdova-Fletes et al. (2014). They
presumed the healing of the broken 18q by creation of a neotelomere
through the formation of a tandem direct duplication, and the acquisi­
tion of the new telomere was from another chromosome or from the
opposite arm of the same chromosome.
As detected by the SNP markers of Cytoscan HD and the analysis of
R. Mahrous et al. Gene Reports 25 (2021) 101386

Fig. 5. Partial molecular karyotype of chromosome 18 showing the copy number state; normal at 2, duplication at 3, and deletion at 1.

Table 1
Description of the six reported cases having dup/del 18q rearrangements and our patient.
Cytogenetic result Parental karyotype aCGH result Clinical features (T18/del18q)

Courtens et al. Monozygotic twins 46,XY,rec(18) Maternal 46,XX, inv NA Overlapping phenotypes of both
(1998) (pter→q21.1:: (18)(q21.1q22.3) T18 and 18q− syndromes
q22.3→q21.1→q12.1)
Rowe et al. 46,XX, inv? dup del(18q) Normal parental [hg 18]18q (48,239,284_ 54,445,616)×3, Not assessed for feature of both
(2009) karyotype (54,451,359_76,111,164)×1 syndromes
Duplication size: 7206 Mb
Deletion size 21,659 Mb
Lee et al. (2009) 46,XY,der(18),del(18)(q22),dup Normal parental NA No clinical features of T18. Not
(18)(q22q11.2)dn. karyotype assessed in detail for deletion
features
Nguyen-Minh Normal karyotype Normal parental arr[hg18]18q22.1(65,727,264_66,554,628)×3, Phenotypic traits of 18q deletion
et al. (2013) karyotype 18q22.1q22.2(66,554,687_68,093,381)×4, 18q22.2q23 syndrome without overt clinical
(68,093,837_78,010,032)×1 signs of Edwards syndrome
Duplication size 827 kb
Triplication size 1538 Mb
Deletion size 9916 Mb
Córdova-Fletes 46,XX,add(18)(q22.3) Normal parental arr[hg18]18q12.2q22.3 (32,371,790_67,274,247)×3, Phenotype visibly evokes both T18
et al. (2014) karyotype 18q22.3q23(67,274,767_76,116,029)×1 and 18q− syndromes
Duplication size 34,902 Mb
Deletion size 8841 Mb
The studied 46,XX,add (18)(q23) Normal parental arr[GRCh38]18q12.2q23(23625943_79639731) Phenotype of T18 and 18q-
patient in this karyotype x3,18q23(79643021_80256240)x1 dn syndromes
report Duplication size 56 Mb
Deletion size 613 Kb

NA: not available.

the child and her mother and father (Trios), both the deletion and
duplication of 18q were paternally originated. The breakpoints were not
within the regions of SD, which suggests that the NAHR is not the
mechanism responsible for the rearrangement in our patient. Therefore,
the inversion duplication deletion chromosomal anomaly in our patient
was most probably developed due to a postzygotic event and a nonho­
mologous end point recombination or the U-type exchange mechanism.
Fig. 6 shows the suggested mechanism responsible for our patient's
chromosomal rearrangement.
In conclusion, although our patient exhibited some phenotypic fea­
tures that could be explained by the terminal 18q- syndrome, including
prenatal and postnatal growth retardation, microcephaly, and GDD,
these phenotypic features could be attributed to both the deleted and
duplicated areas. Facial dysmorphism with epileptogenic activity may
be more explained by the duplication. Furthermore, the cytogenetic,
FISH, and MLPA analyses together with the array-based methods are the
gold standard for detecting copy number variants in patients with GDD
with or without multiple congenital anomalies. In our patient, the
duplication/deletion segments were paternally originated, which pri­
marily indicated a postzygotic event with the U-type exchange that
caused the inversion duplication/deletion.
Statement of ethics
This study was conducted according to the guidelines of the Medical
Research Ethics Committee of the National Research Centre based on the
World Medical Association Declaration of Helsinki, and an informed
consent has been obtained from the patient's guardians.

6
R. Mahrous et al. Gene Reports 25 (2021) 101386

Table 2 Funding sources

Comparison between common features of trisomy 18 syndrome (Rosa et al.,
2013) and our patient. Science and Technology Development Fund (STDF) Grant; Project
Common features of trisomy 18 syndrome (Rosa et al., 2013) Our number 5253
patient National Research Centre, Egypt; Project number 11010163.
Growth Failure to thrive +
Central nervous system Neurodevelopmental delay + CRediT authorship contribution statement
Hypertonia +
Skull and face Prominent occipitus −
All authors have made substantial contributions to the conception of
Long or sparse eyelashes +
Blue sclera + the work, analysis, and interpretation of data, participated in revising
Micrognathia + the work, and was responsible for all aspects of the work in ensuring that
Dysplastic, low-set ears + questions related to the accuracy of the work are appropriately inves­
Microcephaly + tigated. All authors approved the final version to be published.
Thorax Widened spaced nipples +
Heart defects −
Ventricular sept defects − Declaration of competing interest
Patent ductus arteriosus −
Patent foramen ovale − Authors have no conflict of interest to declare.
Polyvalvular heart disease −
Abdomen Umbilical/inguinal hernia −
Ectopic pancreas − Acknowledgment
Meckel's diverticulum −
Urogenital − The authors acknowledge the patient and her parents for partici­
Cryptorchidism − pating in this study and late Prof. Dr. Samira Ismail, Professor of Clinical
Prominent clitoris
Genetics, Human Genetics & Genome Research Division, National
−
Renal defects −
Horseshoe kidney − Research Centre, for her great help and support. We also acknowledge
Cystic kidneys − the Science and Technology Development Fund (STDF) Grant and the
Limbs Hypoplastic nails + National Research Centre for funding this work: STDF project number
Camptodactyly of the fingers +
5253, Centre of Scientific Excellence for Human Genetics and National
Clubfoot −
Prominent calcaneous − Research Centre project number 11010163.
Dorsiflexed hallux −
Rocker-bottom foot + References
Syndactyly of the second and third toes −
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