ARRAY-BASED COMPARATIVE GENOMIC HYBRIDIZATION
ANALYSIS IN CHILDREN WITH DEVELOPMENTAL
DELAY/INTELLECTUAL DISABILITY
Türkyılmaz A, Geckinli BB, Tekin E, Ates EA, Yarali O, Cebi AH, Arman A
*Corresponding Author: Ayberk Türkyılmaz, M.D., Assistant Professor, Department of Medical Genetics,
Karadeniz Technical University Faculty of Medicine, Farabi Street, 61080 Ortahisar, Trabzon,
Turkey. Tel: +90-505-812-03-34. Fax: +90-462-377-51-06. E-mail: ayberkturkyilmaz@gmail.com
page: 15
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DISCUSSION
Array-based comparative genomic hybridization is
recommended as the first-tier test in unexplained DD/
ID cases as it can detect submicroscopic deletions and
duplications below 5.0 Mb that cannot be detected by conventional
karyotype analysis [11]. The widespread use of
aCGH technology in recent years has resulted in increased
diagnostic rates for DD/ID cases and identification of new
microdeletion/microduplication syndromes.
The diagnosis rates vary between 5.1-35.0% in the
literature [14,15]. The variability in diagnosis rates may
be related to differences in criteria for patient selection,
resolution of the aCGH platform used, and classification of
detected CNVs. With the use of aCGH as a first-tier test in
DD/ID cases, the frequency of VUS variants also increases
in addition to the increase in diagnosis rates, making it difficult
to demonstrate the genotype-phenotype correlation.
CNVs associated with recurrent/well-defined syndromes,
inherited CNVs from parents with a similar phenotype,
and CNVs containing defined morbid genes in the OMIM
database were identified as pathogenic, whereas polymorphic
CNVs frequently seen in population databases were
considered benign [16]. However, clinical interpretations
of unique non recurrent CNVs are not always easy. The low
number of these CNV cases in the literature, the unclear
dosage sensitivity status of the genes, and the difference
in penetrance, make interpretation difficult. In this study,
pathogenic CNVs were detected in 19 cases according to
the ACMG criteria, of which eight were cases of recurrent
microdeletion/microduplication syndrome: 22q11.21
deletion (DiGeorge) syndrome in one, 5p deletion (Cri-Du-
Chat) syndrome in one, 4p16.3 deletion (Wolf-Hirschhorn)
syndrome in one, Xp11.23-p11.22 duplication syndrome in
one, 3q26 microduplication syndrome and 3p deletion syndrome
in one, 15q13.3 deletion syndrome in one, 15q13.3
duplication syndrome in one, and 15q11-q13 duplication
syndrome in one. Additionally, rare pathogenic CNVs
were detected in 11 cases: 2q31.1 q31.3 deletion in one,
10p15.3p15.1 deletion in one, 19p13.3 duplication in one,
14q32.2q32.33 duplication in one, 16p13.11 deletion in
one, 16q12.1q23.3 duplication in one, Xp22.2p21.3 duplication
in one, 6q21q22.31 deletion in one, 8p23.3p23.1
deletion and 9p24.3p23 duplication in one, 8q24.21q24.3
deletion in one, and 17q21.32q 21.33 duplication in one.
All five CNVs that were considered likely pathogenic
have been previously reported in at least one case with
DD/ID in the literature and contain morbid genes. The
CNVs detected in all four cases in the VUS, no subclassification
group were previously reported as VUS in cases
diagnosed with DD/ID in the DECIPHER database. Cases
of frequent CNVs in the general population were grouped
as benign. According to the two-hit model proposed by
Girirajan et al. [17] for DD/ID cases, large CNVs that
are observed more frequently in patients compared to the
general population, were defined as “susceptibility loci.” In
these cases, it has been reported that there may be rare single
nucleotide variations (SNVs) and small CNVs, which
can be detected by whole-exome sequencing (WES) and
whole-genome sequencing (WGS), that are responsible for
the phenotype but cannot be detected due to the resolution of microarray platform [17]. Therefore, it is believed that
investigating cases of VUS CNVs with next-generation
sequencing methods, such as WES and WGS, will increase
the diagnostic rates.
Of the 26 pathogenic/likely pathogenic CNVs, 13
were gains and 13 were losses. Additionally, 88.4%
(23/26) of these CNVs were alterations larger than 1.0
Mb. It has been reported in the literature that microdeletion
syndromes are more frequently observed, and microduplication
syndromes are overlooked owing to their
mild phenotype [18,19]. The more frequent detection of
micro-duplication syndromes in this study can be attributed
to the inclusion of cases with a mild phenotype. The
interpretation of pathogenicity of microduplications is
more difficult due to incomplete penetrance and unclear
triplosensitivity status of the genes it involves. Microduplications
that are not found in the general population,
larger than 1.0 Mb, de novo, and contain morbid genes,
are more likely pathogenic [20].
Some cases of pathogenic CNVs with novel clinical
and radiological findings are rarely described in the literature.
Patient 1, a 4-year-old male with DD, short stature,
microcephaly and scoliosis findings, was diagnosed with a
de novo 1554 kb duplication in the 17q21.32q21.33 region.
Two cases with duplication detected by aCGH analysis in a
similar region were reported in the literature and two cases
were reported in the DECIPHER database (DECIPHER
ID 997 and 356717) [21,22]. Developmental delay, short
stature, microcephaly, scoliosis, micrognathia, upslanting
palpebral fissures were common in all the reported cases.
In our case, proximally placed thumbs are a novel finding.
It has been reported that COL1A1, CHAD and SGCA genes
located in the duplication region may be responsible for
skeletal abnormalities, whereas the PPP1R9B gene may
be responsible for the DD phenotype [22]. In Patient 2, a
6-year-old male with ID and epilepsy findings, a 597 kb
maternal duplication in the Xq21.31q 21.32 region, was
detected. Left temporal uncal dysplasia, which was not
previously reported in this syndrome, was detected in the
brain MRI of the patient, who had clinical findings similar
to the cases reported in the literature. It has been reported
that the PCDH11X gene located in the duplication region,
may be responsible for the ID phenotype [23,24]. In Patient
4, a 6-year-old male with ID in addition to ventricular septal
defect (VSD) and dysmorphic features, epilepsy 9985 kb
de novo deletion, was detected in the 8q24.21q24.3 region.
Two cases with deletion in the same region have been reported
in the literature; additionally, it has been reported
that the KCNQ3 gene may be responsible for the epilepsy
phenotype [25]. Duplications were detected in patients 7
and 33 at 50.3 Mb in the 4q28.2q35.1 (137, 877, 879-188,
257, 773) region and 2.9 Mb in the 4q34.2q34.3 (177, 322,
096-180, 306, 130) region, respectively. Developmental
delay, microcephaly, and epilepsy phenotype of both cases
are in common with the cases reported in the literature [26].
The bifid thumb in patient 7 was a novel finding for this
syndrome. Although the epilepsy types of both cases were
different, seizures could be controlled by anti-epileptic
treatment. More dysmorphic findings were observed in patient
7 who had a larger duplication. Chromosome 15q13.3
deletion and 15q13.3 duplication syndromes were detected
in patients 11 and 27, respectively. In both cases, no significant
facial dysmorphic findings were found except for ID.
It has been reported that the OTUD7A and CHRNA7 genes
may be responsible for the phenotype in both cases [27].
Patient 24, who was previously presented in a case report,
had a de novo pure partial trisomy 16q and contributed
to the literature with its novel dysmorphic findings [28].
The widespread use of aCGH analysis in DD/ID cases
increases the diagnostic rate. However, karyotype analysis
must also be considered in each case for evaluating the
cases for balanced translocations, inversions, and low-level
mosaicisms that cannot be detected by the aCGH method.
Determination of the location, size, and involved genes of
the chromosomal abnormality using aCGH is important in
terms of genotype-phenotype correlations. Additionally,
a clear presentation of the chromosomal abnormality is
critical for prognosis, clinical follow-up, and rehabilitation
program planning. In terms of the family of the index
case, it becomes possible to present prenatal diagnosis and
pre-implantation genetic diagnosis options by screening
other family members for chromosomal anomalies and
explaining the risk of recurrence in subsequent pregnancies
to the family [29].
The first limitation of this study is the small number
of patients. The small sample size may have resulted in
the low detection rate of frequently observed microdeletion/
microduplication cases. The second limitation of the
study was that FMR1 and/or MECP2 gene analyses were
not done before the aCGH analysis in these cases. Some
guidelines recommend the analysis of these two genes
in cases of DD/ID [30]. The strengths of this study are
the detailed clinical, neurological, radiological and EEG
findings of the cases.
In conclusion, the use of aCGH analysis as a first-tier
test in DD/ID cases contributes significantly to the diagnosis
rates and enables the detection of rare microdeletion/
microduplication syndromes. The clear determination of
genetic etiology contributes to the literature in terms of
genotype-phenotype correlation.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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