CHROMOSOMAL MICROARRAY IN CHILDREN BORN SMALL FOR GESTATIONAL AGE – SINGLE CENTER EXPERIENCE
Perović D1, Barzegar P2, Damnjanović T1, Jekić B1, Grk M1, Dušanović Pjević M1, Cvetković D3, Đuranović Uklein A1, Stojanovski N1, Rašić M1, Novaković I1, Elhayani B2, Maksimović N1
*Corresponding Author: Corresponding Author: Nela Maksimovic, PhD, University of Belgrade Faculty of Medicine, Insti-
tute of Human Genetics, Visegradska 26a, 11000 Belgrade, Serbia, Tel: +381113607052;
Email: nela.maksimovic@med.bg.ac.rs
page: 13
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DISCUSSION
The purpose of our study was to enhance the under-
standing of SGA in the context of chromosomal abnormali-
ties, encompassing advancements in diagnostic method-
ologies with a specific focus on SGA infants. The nature
of growth disturbances is highly heterogeneous making it
crucial to comprehend the complex relationship between
fetal growth restrictions and genetic abnormalities. Ac-
curate diagnostic testing is vital, as a genetic diagnosis
significantly influences prognosis.
The majority of our patients presented with complex
forms of SGA with a lot of comorbidities, which may ex-
plain the high detection rate of positive findings: 36.4%.
The detection rate is significantly higher than the 16%
found in other cases tested in our laboratory. These dif-
ferent cases involved individuals with DD/ID, congenital
anomalies, autism, and epilepsy, but without intrauterine
growth restriction. It highlights the importance of SGA
as a key predictive phenotype in the diagnostic yield of
molecular karyotyping. Chen et al. reported a chromo-
somal structural copy number variation (csCNV) detection
rate of 33.3% in cases of FGR associated with structural
anomalies, which aligns closely with our findings [15].
In contrast, FGR cases without structural malformations,
which correspond to small for gestational age (SGA) in-
fants without additional complications, have a lower in-
cidence of genetic abnormalities. Wu et al. conducted an
analysis of 488 fetuses diagnosed with FGR but without
structural malformations. They found that the diagnostic
yield for classic and molecular karyotypes was 3.9% [16].
Additionally, one meta-analysis indicated a 4% increased
yield of chromosomal microarray analysis (CMA) com-
pared to classic karyotyping in non-malformed growth-
restricted fetuses. Furthermore, the incremental yield of
CMA in cases of FGR associated with fetal malformations
was 10% [17].
In our patient group, we most frequently observed
Williams syndrome (P5, P6, P7), caused by a microdeletion
on chromosome 7q11.23. This syndrome is characterized
by a unique combination of clinical features, including distinctive facial characteristics, cardiovascular anomalies,
intellectual disability, and a remarkably sociable person-
ality [18]. The association between Williams syndrome
and intrauterine or postnatal growth failure has been well
documented, highlighting its importance among different
types of fetal growth restrictions. At least 82% of fetuses
with typical 7q11.23 deletion have intrauterine growth
retardation [19]. Our study supports these findings, em-
phasizing that this deletion should be considered during
prenatal assessments of FGR and in cases of SGA birth.
Our study unveiled several other genetic syndromes
previously associated with FGR and SGA. In a two-year-
old girl (P1) born small for gestational age, with micro-
cephaly, failure to thrive, and facial dysmorphism, we detected a clinically significant microdeletion of 1.2 Mb in
1q21.1-q21.2 region, as well as 5p14.1-p13.3 microdele-
tion of 3.1 Mb, classified as a variant of unknown signifi-
cance (VUS). A microdeletion detected on chromosome 1
is the recurrent deletion of distal region 1q21.1 located be-
tween breakpoints BP3-BP4 and includes the GJA5 gene.
Liu et al. summarized prenatal phenotypes characteristic
for 1q21.1 microdeletions and observed IUGR in 26.7% of
the cases [20]. This microdeletion has low penetrance and
variable expressivity. In many cases, it is inherited from
healthy parents. The second CNV, a deletion in the region
5p14.1-p13.3, encompasses ten genes, none of which are
protein-coding. To our knowledge, there are no reports on
the phenotype of patients with similar deletions.
One well-known syndrome associated with prenatal
and postnatal growth failure is Drayer syndrome (MIM
#612626), caused by a deletion in the 15q26-qter region.
Patient P11 exhibited a 5.6 Mb deletion in this region
(15q26.2-q26.3) and presented with developmental de-
lay, mild facial dysmorphia, short stature, and skeletal
dysplasia. Microcephaly, congenital heart disease, epi-
lepsy, diaphragmatic hernia, renal anomalies, neonatal
lymphedema, and aplasia cutis congenita could be ad-
ditional characteristics of this syndrome [21]. Haploin-
sufficiency of the insulin-like growth factor-1 receptor
(IGF1R) gene, located in this region, has been previously
associated with the growth pathway and linked to impaired
prenatal and postnatal growth [22]. More proximally on
chromosome 15 is a region frequently linked to benign but
also pathogenic CNVs, 15q11.2, which contains imprinted
genes. Deletion of paternal copy of SNRPN and the NDN
genes in this region cause Prader-Willi syndrome (PWS;
MIM #176270). P13, from our cohort, is a 12-year-old
girl with DD/ID, obesity, brachydactyly, and a 6 Mb dele-
tion characteristic of PWS. Her obstetric history includes
intrauterine growth restriction beginning in the third tri-
mester. During her first year of life, she experienced failure
to thrive but subsequently became overweight, which is
typical for individuals with PWS. This syndrome is rarely
diagnosed prenatally due to the lack of well-defined fetal
phenotypes, which would warrant prenatal molecular ge-
netic testing [23]. In the study by Dudley et al. focusing on
prenatal, perinatal, and postnatal complications in PWS,
it was observed that 29.4% (10 out of 34) of patients with
PWS caused by uniparental disomy (UPD) and 42.3%
(22 out of 52) of PWS patients resulting from deletion
were classified as small for their gestational age [24]. The
reasons for SGA in these PWS cases remain unexplained.
We identified other recurrent syndromes linked to
fetal and postnatal growth restriction. This includes a 3.8
Mb microdeletion in the 17p13.3-p13.2 region, causing
Miller-Dieker syndrome, and a 425 kb microdeletion in
the 17q21.31 region, associated with Koolen-de Vries syn-
drome. Haploinsufficiency of the PAFAH1B1 and YWHAE
genes in Miller-Dieker syndrome is believed to cause in-
tractable seizures, severe developmental delays, lissenceph-
aly, facial dysmorphisms, intrauterine growth restriction,
and involvement of other organ systems. Growth restric-
tion often persists during the postnatal period [25]. In our
sample, this syndrome was diagnosed in a one-month-old
infant with FGR identified from the 20th week of gestation,
along with facial dysmorphia and abnormal neuroimag-
ing findings observed after birth (P14). In the case of an
11-month-old boy (P15) born SGA, with DD, microceph-
aly, congenital hypothyroidism, and surgically corrected
colon perforation postnatally, diagnosis of Koolen-de Vries
syndrome was established by CMA. This condition is mul-
tisystemic and characterized by DD/ID, epilepsy, distinct
facial features, and congenital malformations affecting mul-
tiple organ systems. Research conducted by Koolen et al.
on a cohort of 45 children with this syndrome revealed that
26% of cases experienced intrauterine growth retardation,
30.4% presented with low birth weight, and 41.7% also had
proportionate short stature postnatally [26].
A rare and interesting example of microduplication
of the 19p13.2-p13.12 region associated with impaired
growth was detected in a 12-year-old girl born SGA (P16),
later followed by short stature treated with growth hormone
therapy. She also had microcephaly, atrial septal defect,
mild ID with learning difficulties, and autistic features. Pre-
viously, in Trimouille et al., ten patients with 19p13 dupli-
cations were reported. Common clinical features included
short stature, small head circumference, delayed bone age,
and ID (mild to severe). Unfortunately, birth parameters
were unknown for six patients, and only one had a birth
weight below the 10th percentile. The research indicates
that the phenotype linked to 19p13 duplication may, in
some respects, be regarded as the reciprocal phenotype
of Malan syndrome (MIM # 614753, previously known
as Sotos syndrome-2), which is caused by heterozygous
mutations, including deletions of the NFIX gene [27, 28].
This syndrome is characterized by DD/ID, overgrowth,
macrocephaly, prominent forehead, high anterior hairline,
up-slanted palpebral fissures, and prominent chin. The
observed phenotype in all patients with 19p13 microdu-
plications that include NFIX indicates that the phenotypes
associated with both 19p13 microdeletions and microdu-
plications may result from the contrasting effects of NFIX
haploinsufficiency and overexpression.
Patient P3, a 1-month-old infant, has a 64 Mb duplica-
tion of the region 3q22.1-q29. The patient presented with
cleft lip, and a congenital heart anomaly. In most cases, this
condition is diagnosed only after birth. Individuals with
this syndrome may exhibit a range of defects, including abnormalities of the central nervous system, facial dysmor-
phia, congenital heart defects, urogenital tract anomalies,
intellectual disabilities, and growth disturbances [29].
Our cohort revealed some recurrent or non-recurrent
syndromes not previously linked to SGA. In the first group
it is interesting to mention a two-year-old boy (P8) with
mild DD, palatoschisis and hydronephrosis, with two recur-
rent CNVs: 22q11.2 deletion characteristic for DiGeorge
syndrome, and 7q11.23 microduplication, reciprocal to
Williams syndrome chromosomal region. In patients with
DiGeorge syndrome, FGR/SGA has been noted at a rate
close to the population incidence [30]. There is insufficient
prenatal information available regarding 7q11.23 microdu-
plication. In the study conducted by Wang et al., fetuses
diagnosed with 7q11.23 microduplication syndrome pre-
sented with several intrauterine phenotypes, including low-
lying conus medullaris, dilated ascending aorta, cleft palate,
anencephaly, hydronephrosis, and other renal anomalies
[31]. While the other characteristics of the phenotype could
be accounted for by the presence of the two different CNVs,
associated with two well-described syndromes, intrauterine
growth restriction is not typically observed in these cases.
Similarly, a one-month-old infant with SGA (P12)
exhibited a 1.6 Mb microdeletion in the 16p13.11 region.
This CNV has been previously described and reported
as a predisposition to neurodevelopmental disorders and
different congenital anomalies. Short stature has been
observed in several cases [32]. This deletion can occur
de novo; however, due to its incomplete penetrance and
variable expressivity, it is often inherited from a parent
who is either mildly affected or presents with a completely
normal phenotype. In a study by Cai et al. on the 16p13.11
microdeletion/microduplication, it was found that fetuses
with CNVs in this region typically do not exhibit any
characteristic features on intrauterine ultrasound and are
generally healthy after birth. [33]. Therefore, the SGA ob-
served in our case cannot be attributed to the detected CNV.
Additionally, our study identifies some csCNVs in
children with SGA that have not been linked to growth
restriction before, either prenatal or postnatal. A 19-month-
old boy (P2), who experienced FGR, developmental delay,
and microcephaly, exhibited a microduplication at chromo-
some 2p25.3. This microduplication includes part of the
MYT1L gene, previously associated with neurodevelop-
mental disorders. MYT1L acts as a transcriptional repressor
in neuronal progenitor cells, inhibiting Notch signaling
and promoting neuronal differentiation [34]. However,
there is no possible explanation for FGR in patients with
deletion of this gene. In the study by Coursimaults et al.,
which investigated 40 children with pathogenic variants
of MYT1L and 22 previously published patients, FGR
was not frequently observed (6-8% of the patients) [35].
Patient P4 was referred for CMA due to severe FGR,
born small for gestational age, with atrial septal defect,
renal hypoplasia, and shortened long bones. The analysis
revealed a deletion of 9.75 Mb in the region 7p15.3-p14.3,
which includes 60 protein-coding genes, 16 linked to vari-
ous human diseases. Crippa et al described a patient with
de novo deletion of 7.5 Mb in the same region. This patient
experienced both prenatal and postnatal growth restriction
and was part of a cohort exhibiting features consistent
with Silver-Russell syndrome. The authors suggested that
the growth restriction might be attributed to the insulin-
growth factor 2 mRNA binding protein 3 (IGF2BP3) gene
(OMIM*608259) deletion and confirmed its decreased
expression. This gene looks like a promising candidate for
FGR since it regulates the amounts of IGF2 transcripts by
encoding an RNA-binding factor unique to the 5′UTR of
IGF2 mRNA [36].
We had three patients with two pathogenic CNVs on
different chromosomes. In these cases, it is challenging to
determine the impact of a single region or specific gene
because the phenotype often results from the interaction
between the two variants from different genomic regions.
A newborn (P9) was found to have a 15.5 Mb deletion in
the region 7q35-q36.3. This presented with microcephaly,
SGA, and a progeroid appearance characterized by a “bird-
like face.” Fan et al. summarized the phenotypes of 17
previously reported patients with terminal deletions in the
7q35-q36.3 region, noting that 16 of these patients experi-
enced growth restriction. Additionally, multiple congenital
malformations were observed, including abnormalities in
brain and facial structures, DD/ID, limb and sacral anoma-
lies [37]. The patient in our cohort also had a 3.37 Mb
microduplication in the 16q24.1-q24.3 region, which has
previously been linked to mild-to-moderate ID, speech
delay, and slight dysmorphic features [38]. However, there
are no reports connecting this microduplication with FGR
or SGA. It appears that terminal deletion on chromosome
7q has a more significant impact on growth restriction.
A newborn patient (P10) was born small for gestational
age and presented with facial dysmorphism, cryptorchidism,
and hypospadias. Genetic analysis revealed a terminal dele-
tion of 14.7 Mb in the region 9p24.3-p22.3 and a terminal
duplication of 8.71 Mb in the region 19q13.33-q13.43. The
deleted region contains 44 protein-coding genes and 14
disease-associated. The phenotype of patients with a distal
deletion of chromosome 9 includes trigonocephaly, DD/ID,
and genitourinary malformations (MIM# 158170). The du-
plicated region on chromosome 19 contains 290 protein-cod-
ing genes, with 29 of these genes associated with diseases.
Distal duplications of chromosome 19 are linked to various
conditions, including low birth weight, short stature, crani-
ofacial dysmorphia, and psychomotor delay. Additionally, individuals may exhibit hypotonia, epilepsy, congenital heart
defects, as well as urogenital and gastrointestinal malforma-
tions [39]. In this case, the expression of both pathogenic
CNVs overlaps; however, the distal duplication of 19q may
better explain the observed features related to SGA.
Identifying these syndromes has significant clinical
implications beyond merely confirming a diagnosis. It in-
cludes early interventions to improve long-term outcomes
for individuals affected by these conditions. Key manage-
ment strategies for individuals with genetic syndromes
include cardiac and other organ systems examination and
monitoring, developmental support, and behavioral inter-
ventions. This underscores the importance of early detec-
tion and timely intervention in their care.
Most patients born SGA experience catch-up growth
until they are 2 to 4 years old; however, 10% to 15% of
them do not. Six of our patients with pathogenic CNVs
were at neonatal age when the CMA was performed. At
the same time, only five were older than two years. As a
result, we have limited information regarding the postnatal
growth of our patients. Among the five children older than
two, short stature was documented only in two: one girl
with Dryer syndrome (P11) and another with duplication
at 19p13.2-p13.12 (P16). The latter patient was already
receiving recombinant human growth hormone therapy
(rhGH). For the past twenty years, rhGH has been ap-
proved for use in children SGA and short stature aged 2 in
the USA and 4 in Europe. The response to this treatment is
not always optimal, and it depends on the underlying cause
of the SGA, which highlights the importance of genetic
testing before starting the therapy [40].
In cases with detected csCNVs but without a clear
association with SGA, it is possible that SGA may have
been caused by different external environmental factors.
The limitation of our study is that we did not have infor-
mation about possible factors present during pregnancy
that could lead to SGA. Other significant limitations are
the small number of patients that were available for our
research since this was a single-center study and the lack
of follow-up data on the growth in the case of the chil-
dren who were tested as newborns. Increasing the size of
the study group and collecting information regarding the
growth of children born small for gestational age would
be of great importance for the following research.
In conclusion, integrated genetic testing that com-
bines chromosomal microarray analysis with a thorough
assessment of phenotypes provides valuable insights into
the genetic causes of growth restriction. This method al-
lows for the identification of clinically significant copy
number CNVs and supports the development of personal-
ized management strategies tailored to the specific needs
of individuals affected by this condition.
Ethics Committee approval
The study was approved by the Ethics Committee
Faculty of Medicine, University of Belgrade (1322/VII‐4).
Conflict of interest
The authors declare no conflict of interest.
Funding
The project was funded by the Ministry of Science,
Technological Development and Innovation of the Repub-
lic of Serbia grant no 451-03-66/2024-03/200110.
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