Citation: De novo 8p21.3→ p23.3 Duplication With t(4;8)(q35;p21.3) Translocation Associated With Mental Retardation, Autism Spectrum Disorder, and Congenital Heart Defects: Case Report With Literature Review

Abstract

Duplications of chromosome 8p lead to rare genetic conditions characterized by variable phenotypes. 8p21 and 8p23 duplications were associated with mental retardation but only 8p23 duplication was associated with heart defects. 8p22→ p21.3 duplications were associated with an autism spectrum disorder in several cases. We present a rare case with a de novo duplication of the entire 8p21.3→ p23.3 region, documented by karyotype, FISH, and array CGH, with t(4;8)(q35;p21.3) translocation in a 7 years-old girl. She was referred for genetic counseling at the age of 20 months due to mild dysmorphic facial features, psychomotor retardation, and a noncyanotic heart defect. Another examination carried out at the age of 5 years, enabled the diagnosis of autism spectrum disorder and attention deficit hyperactivity disorder. Upon re-examination after two years she was diagnosed with autism spectrum disorder, attention deficit hyperactivity disorder, liminal intellect with cognitive disharmony, delay in psychomotor acquisitions, developmental language delay, an instrumental disorder, and motor coordination disorder. Cytogenetic analysis using GTG technique revealed the following karyotype: 46,XX,der(4),t(4;8)(q35;p21.3). The translocation of the duplicated 8pter region to the telomeric region 4q was confirmed by FISH analysis (DJ580L5 probe). Array CGH showed: arr[GRCh37]8p23.3p21.3(125733_22400607)×3. It identified a terminal duplication, a 22.3 Mb copy number gain of chromosome 8p23.3-p21.3, between 125,733 and 22,400,607. In this case, there is a de novo duplication of a large chromosomal segment, which was translocated to chromosome 4q. Our report provides additional data regarding neuropsychiatric features in chromosome 8p duplication. The phenotypic consequences in our patient allow clinical-cytogenetic correlations and may also reveal candidate genes for the phenotypic features.

Full text

CASE REPORT
published: 08 July 2020
doi: 10.3389/fped.2020.00375
Frontiers in Pediatrics | www.frontiersin.org 1July 2020 | Volume 8 | Article 375
Edited by:
Enrico Baruffini,
University of Parma, Italy
Reviewed by:
Xiu Xu,
Fudan University, China
Amal Mahmoud Mohamed,
National Research Centre
(Egypt), Egypt
*Correspondence:
Ioana Mozos
ioana_mozos@yahoo.com
†These authors share first authorship
Specialty section:
This article was submitted to
Genetic Disorders,
a section of the journal
Frontiers in Pediatrics
Received: 14 March 2020
Accepted: 03 June 2020
Published: 08 July 2020
Citation:
Gug C, Stoicanescu D, Mozos I,
Nussbaum L, Cevei M, Stambouli D,
Pavel AG and Doros G (2020) De
novo 8p21.3→p23.3 Duplication
With t(4;8)(q35;p21.3) Translocation
Associated With Mental Retardation,
Autism Spectrum Disorder, and
Congenital Heart Defects: Case
Report With Literature Review.
Front. Pediatr. 8:375.
doi: 10.3389/fped.2020.00375
De novo 8p21.3→p23.3 Duplication
With t(4;8)(q35;p21.3) Translocation
Associated With Mental Retardation,
Autism Spectrum Disorder, and
Congenital Heart Defects: Case
Report With Literature Review
Cristina Gug 1†, Dorina Stoicanescu 1† , Ioana Mozos 2,3
*, Laura Nussbaum 4, Mariana Cevei 5,
Danae Stambouli 6, Anca Gabriela Pavel 6and Gabriela Doros 7
1Department of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania,
2Department of Functional Sciences, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania, 3Center for
Translational Research and Systems Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania,
4Department of Neurosciences, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania, 5Department of
Psychoneuro Sciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania,
6Department of Molecular Genetics and Cytogenetics, Cytogenomic Medical Laboratory, Bucharest, Romania, 7Department
of Pediatrics, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
Duplications of chromosome 8p lead to rare genetic conditions characterized by variable
phenotypes. 8p21 and 8p23 duplications were associated with mental retardation but
only 8p23 duplication was associated with heart defects. 8p22→p21.3 duplications
were associated with an autism spectrum disorder in several cases. We present a rare
case with a de novo duplication of the entire 8p21.3→p23.3 region, documented
by karyotype, FISH, and array CGH, with t(4;8)(q35;p21.3) translocation in a 7
years-old girl. She was referred for genetic counseling at the age of 20 months
due to mild dysmorphic facial features, psychomotor retardation, and a noncyanotic
heart defect. Another examination carried out at the age of 5 years, enabled the
diagnosis of autism spectrum disorder and attention deficit hyperactivity disorder. Upon
re-examination after two years she was diagnosed with autism spectrum disorder,
attention deficit hyperactivity disorder, liminal intellect with cognitive disharmony, delay
in psychomotor acquisitions, developmental language delay, an instrumental disorder,
and motor coordination disorder. Cytogenetic analysis using GTG technique revealed the
following karyotype: 46,XX,der(4),t(4;8)(q35;p21.3). The translocation of the duplicated
8pter region to the telomeric region 4q was confirmed by FISH analysis (DJ580L5 probe).
Array CGH showed: arr[GRCh37]8p23.3p21.3(125733_22400607)×3. It identified a
terminal duplication, a 22.3 Mb copy number gain of chromosome 8p23.3–p21.3,
between 125,733 and 22,400,607. In this case, there is a de novo duplication of a large
chromosomal segment, which was translocated to chromosome 4q. Our report provides
additional data regarding neuropsychiatric features in chromosome 8p duplication. The
phenotypic consequences in our patient allow clinical-cytogenetic correlations and may
also reveal candidate genes for the phenotypic features.
Keywords: 8p(21.3–p23.3) duplication, translocation(4;8), de novo, array CGH, FISH, mental retardation, autism
spectrum disorder, congenital heart defects

Gug et al. 8p Duplication With t(4;8)
INTRODUCTION
Significance of segmental duplications leading to abnormal
gene dosage and consequently to different disorders has been
intensively studied in recent years (1).
Duplications of the short arm of chromosome 8 are structural
chromosomal abnormalities that lead to rare genetic conditions
characterized by a variable phenotype. Depending on the size
and part of the chromosome that is duplicated, some individuals
may be apparently normal, while others may have a range of
clinical features from mild to very severe (2,3). The duplicated
material from 8p may remain on the same chromosome or, rarer,
can be translocated to a different chromosome. It seems that
the phenotypic effects are not influenced by the position of the
duplicated part (4,5). Some chromosome 8p duplications may
be familial, but an appreciable number of cases result from de
novo mutations (6–9). Although inverted duplications adjacent
to terminal deletions of chromosome 8p are the most common,
cases with direct duplications have been also described (10,11).
Known and Novel Scientific Information
•8p21→8p23 duplications were associated with mental
retardation (MR), interstitial duplication 8p23 was associated
with congenital heart defects (CHDs).
•8p23.1 duplication syndrome defined as a 3.75 Mb duplication
of most band 8p23.1 is characterized by mild to moderate
developmental delay, mental retardation (MR), mild facial
dysmorphism, and CHDs.
•Duplications in chromosome 8p21.3→p22 were previously
associated with autism spectrum disorder (ASD).
We present a de novo duplication of the entire region 8p21.3→
p23.3, documented by karyotype, FISH, and array CGH, with
translocation t(4;8)(q35;p21.3) in a 7 years-old girl with liminal
intellect with cognitive disharmony, ASD, attention deficit
hyperactivity disorder (ADHD) and cardiac defects.
•In this case, there is a de novo duplication of a large
chromosomal segment, the duplicate part being translocated
to chromosome 4q, without deletion of the 4q35.2 telomere,
which has not been reported before.
•The phenotypic consequences in our patient allow clinical-
cytogenetic correlations and may reveal candidate genes for
the phenotypic features. Our case has a large duplication of the
entire 8p21.3→p23.1 region and displays a combination of
Abbreviations: ABA, Applied Behavioral Analysis; aCGH, Array Comparative
genomic hybridization; ADHD, Attention deficit hyperactivity disorder;
ADI-R, Autism Diagnostic Interview-Revised; ADOS, Autism Diagnostic
Observation Schedule; ASD, Autism spectrum disorder; BAC, Bacterial Artificial
Chromosomes; BS, Binet-Simon Intelligence scale; CARS, Childhood Autism
Rating Scale; CHD, Congenital heart defect; DGV, Database Genomic Variation;
DSM-5, Diagnostic and Statistical Manual of Mental Disorders; GTG banding,
Giemsa Trypsin G-band; IQ, Intelligence quotient; ISCA, International Standards
for Cytogenomic Arrays; K-SADS, Kiddie Schedule for Affective Disorders and
Schizophrenia; Mb, megabase; MR, mental retardation; PECS, Picture Exchange
Communication Systems; t, translocation; TEACCH, Treatment and Education
for Autistic and other Communication Handicapped Children; VSD, Ventricular
septal defect; WAIS, Wechsler intelligence scales; WISC, Wechsler Intelligence
Scale for Children.
clinical features: MR, ASD, ADHD, CHD, previously described
separately for different duplicated chromosomal segments.
•The 8p23.1 region was associated with facial dysmorphism,
especially prominent forehead, an important sign, noticed
during infancy, that could guide investigations toward the
identification of 8p duplication.
•We hypothesized that our patient’s phenotype was entirely
determined by the large duplication of 8p21.3→p23.1 region.
CLINICAL PRESENTATION AND
FAMILY HISTORY
We report the case of a 7-year-old female patient, referred for
genetic counseling due to dysmorphic features, psychomotor
retardation, and noncyanotic CHD. She was the first child of
an apparently healthy, non-consanguineous couple. Both parents
were 28 years old when the patient was born. Pregnancy was
uneventful; the mother denied any exposure to alcohol, radiation,
or infectious agents. Family history was negative for mental
retardation and congenital defects and the karyotype of the
parents was normal. However, the mother had two miscarriages
before the proband was born. The patient has two healthy
younger sisters, the prenatal diagnosis was performed during
both pregnancies.
Medical History
Clinical examination at birth revealed systolic murmur gr 3/6,
heard over second, third, and fourth intercostal spaces at the
left sternal border. Echocardiography performed 1 month later
revealed noncyanotic CHD with ventricular septal defect (VSD)
and patent foramen ovale. Developmental milestones acquisition
delay was noticed at 20 months. There was also a delayed
acquisition of language milestones; the patient had not verbally
spoken a word. Nonetheless, nonverbal communication was
relatively good, she smiled, but could not concentrate, did not
establish visual contact, and did not respond when her name
was called. She was referred for genetic counseling at this age
due to mild dysmorphic facial features (prominent forehead,
flat nasal bridge, low-set ears), psychomotor retardation, and
noncyanotic CHD. aCGH was performed and showed a 22.3Mb
duplication of the 8p21.3→p22 region. The karyotype revealed
the translocation of the duplicate fragment on chromosome
4q, terminal. The FISH analysis confirmed the duplication and
translocation and showed that the 4q telomeres were preserved.
At 2 years and 10 months, the first psychological assessment
was performed. Low or average levels of all skills (cognitive,
emotional, social, personal autonomy) were recorded. At 3 years
and 9 months Early Childhood Inventory-4 screening used to
assess common symptoms of psychiatric disorders in children
aged 3–7 years, indicated ADHD characterized by hyperactive
and impulsive inattentive behavior, in which attention deficit
with medium-high severity prevailed. Other findings were
physical and symbolic aggression, with specific phobia, selective
mutism, and elimination disorders. The psychological evaluation
using the Portage-Scale indicated that at the chronological age
of 4 years and 8 months she had a mental age of 3 years and 9
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Gug et al. 8p Duplication With t(4;8)
months and DQ =81 (developmental quotient). The pediatric
neuropsychiatrist monitored the evolution, establishing mild
mental retardation at the age of 5 years (IQ =75 BS; Binet-Simon
Intelligence scale), ASD, and ADHD.
METHODOLOGY
Clinical Evaluation
The patient underwent a multidisciplinary evaluation, involving
health professionals from the following specialities: genetics,
cardiology, pediatrics, pediatric neuropsychiatry, speech
pathology, and psychology.
The patient’s parents gave written informed consent
(including for publication of images) considering the Declaration
of Helsinki. This study was approved by the Ethics Committee
for Scientific Research of the Emergency Hospital for Children
“Louis Turcanu,” Timisoara.
Neuropsychiatric Evaluation
The neuropsychiatric diagnoses were put through clinical
examination, assessment of the diagnostic criteria after
the Diagnostic and Statistical Manual of Mental Disorders
(DSM5) and confirmed through Kiddie Schedule for Affective
Disorders and Schizophrenia (K-SADS). The patient was also
evaluated considering the Childhood Autism Rating Scale
(CARS), Autism Diagnostic Interview-Revised (ADI-R), Autism
Diagnostic Observation Schedule (ADOS), the Portage-Scale
and ADHD-Rating Scale.
Peripheral Blood Karyotype
Peripheral blood lymphocytes were cultured in a growth
medium (PB-MAXTM Karyotyping Medium, Gibco). Metaphase
chromosomes were harvested, and slides were made for analysis.
GTG banding was used for staining (at the 550-band level).
Chromosomal analysis was performed using LUCIA Karyo-G
software, and the aberrations and karyotypes were classified
according to the ISCN 2016 system.
Fluorescence in situ Hybridization (FISH)
Aquarius R
Cytocell FISH probes were applied to metaphases.
The probes were: (a) Subtelomere Specific Probes 8p (DJ580L5-
red) and (d) 8q (489D14-green), (b) Wolf-Hirschhorn Syndrome
Critical Region (WHSCR) Probe with Subtelomere Specific
Probe red, which corresponds to 4p16.3, and (DJ963k6-
green), which corresponds to 4q35.2, (c) alpha-satellite 8
probe (D8Z2-green) and Whole Chromosome Painting
Probe (wcp4-red).
Array Comparative Genomic Hybridization (aCGH) analysis
was performed using CytoChip Focus Constitutional BAC
array (Illumina Inc., U.S.) and the used reference was the
normal human male genomic DNA (Promega, WI). The
DNA probes were derived from BAC (Bacterial Artificial
Chromosomes) DNA clones from human genome collection.
The selected BACs were replicated to a high degree, 3×
and 4×, providing a more robust signal for each data point.
The target solution was hybridized to the 2×180K array
and data were acquired using the InnoScan 710 microarray
scanner. A composite image was obtained and imported into
the Blue Fuse Multi Software (v.3.1) microarray software,
Genome Assembly NCBI Build 37hg19, for data analysis.
The average whole-genome resolution was approximately
1Mb. The DGV (Database Genomic Variation), Decipher
(Database of Chromosomal Imbalance and Phenotype in
Human using Ensembl Resources), ISCA (International
Standards for Cytogenomic Arrays), OMIM (Online Mendelian
Inherited in Man) international databases were used to interpret
the results.
RESULTS
Clinical evaluation at the ages of 1 and 5 years showed mild
dysmorphic facial features: prominent forehead, flat nasal bridge,
and diastema (Figure 1). In the differential diagnosis of the
prominent forehead, the most striking dysmorphic feature,
Crouzon syndrome, Hurler syndrome, Pfeiffer syndrome,
Rubinstein–Taybi syndrome, and Russell–Silver syndrome have
been considered. They were ruled out due to the absence of other
specific clinical features.
At the age of 6 years and 11 months, she was evaluated
by the pediatric neuropsychiatrist, her diagnosis being ASD,
ADHD, delay in psychomotor acquisitions with mild delay in
the expressive language acquisition with polymorphic dyslalia,
motor coordination disorder and instrumental disorders, liminal
intellect with cognitive disharmony (IQ =83 WISC; Wechsler
Intelligence Scale for Children), minimal brain lesions indices,
organic brain background. Related to the diagnosis of ASD, the
patient showed qualitative deterioration of social interaction and
cognition, communication, lack of emotional reciprocity and
empathy, no make-believe play, lack of imaginative play, and also
stereotyped, repetitive behavioral patterns and mannerisms and
also resistance to change.
In the first stage of the differential diagnosis for ASD, we
excluded organic disorders, which could show an “autistic-like”
behavior, through the neurological examination and paraclinical
investigations. In the second stage, we made an accurate
differential diagnosis with all the psychiatric disorders, revealing
an “autistic-like” behavior–mental retardation, language
development disorders, ADHD, sensory disorders, reactive
attachment disorders, early-onset schizophrenia. The clinical
evaluation, the psychiatric exam, the psychological evaluations,
and the applied scales guided us.
We also made a differential diagnosis of ADHD, ruling
out other medical and psychiatric disorders with cognitive,
attentional and executive functioning deficits and hyperkinetic
impulsive behavior or agitation, restlessness–anxiety disorders,
attachment disorders, posttraumatic stress disorder, and mood
disorders, including depressive or bipolar disorders. In children,
ADHD and bipolar disorders can have overlapping symptoms.
Both can present with distractibility, increased energy, and
mood lability, and, therefore, a thorough history is essential for
the diagnosis.
The prognosis is guarded and symptomatic
psychopharmacologic treatment, psychological therapies,
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Gug et al. 8p Duplication With t(4;8)
FIGURE 1 | Patient face and profile at the age of 1 year (A,B) and 6 years (C,D). Mild facial dysmorphism with prominent forehead, flattened nose base, and low set
ears can be noticed.
psycho-sensorial stimulation, preschool special education,
occupational, physical, speech, developmental, and behavioral
therapies were helpful for the management of this complex case.
Antipsychotic, mood-stabilizing, and neurotrophic medication
but also behavioral therapies, like ABA (Applied Behavioral
Analysis), PECS (Picture Exchange Communication Systems),
or TEACCH (Treatment and Education for Autistic and
Communication Handicapped Children) were recommended
and might improve the prognosis and the clinical evolution of
the patient.
Echocardiography revealed noncyanotic CHD with restrictive
perimembranous DSV with a left to right shunt, covered
by excess tissue from the tricuspid valve, patent foramen
ovale, and bicuspid aortic valve with gr I aortic insufficiency.
Cardiological monitoring was recommended and performance
sports were contraindicated.
Cytogenetic analysis of the proband revealed a female
karyotype with derivative chromosome 4. The following
karyotype was revealed: 46,XX,der(4),t(4;8)(q35;p21.3). Hence,
a partial trisomy of chromosome 8p, from band p21.3 to
p23.3, resulted (Figures 2A,B). The duplicated fragment was
translocated to chromosome 4q, terminal. The abnormality was
found in all metaphases. The karyotype of the parents was
normal; therefore, the abnormality is de novo.
FISH result was 46,XX,der(4),t(4;8)(q35;p21.3).ish
der(4),t(4;8)(q35;p21.3)(wcp4+,WHSCR+,DJ963k6+,DJ580L5+).
The duplication of the 8pter region and translocation to the
telomeric region 4q were confirmed by FISH analysis (DJ580L5
probe) (Figures 2C,D).
Array CGH showed: arr[GRCh37]
8p23.3p21.3(125733_22400607)×3. It identified a terminal
duplication, a 22.3 Mb copy number gain of chromosome
8p23.3–p21.3, between 125,733 and 22,400,607. Duplication
limits using array platforms are illustrated in Figure 3.
In the cytogenetic location delimited by the genomic
coordinates (GRCh37-Genome Reference Consortium
Human Build 37), there are 134 genes, located as follows:
1 gene in band 8p21; 30 genes in band 8p21.3; 39 genes in
band 8p22; 57 genes in band 8p23.1; and 6 genes in band
8p23.3 (12).
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Gug et al. 8p Duplication With t(4;8)
FIGURE 2 | Karyotype (A,B) and metaphase FISH (C,D) of our patient revealed: (A) de novo duplication (p21.3→p23.3) with translocation t(4;8)(q35;p21.3) (arrow);
(B) diagram of partial trisomy 8p with the large arrow indicating the location of the duplicate segment; (C) Kit Aquarius®Specific Probes Red (DJ580L5) mark
subtelomeric 8p and Green (489D14) mark subtelomeric 8q; 3 copies are noticed for 8p of which 2 correctly positioned and the third translocated to the telomeres of
chromosome 4q, ish der(4)dup(4)t(4;8)(489D14+,DJ580L5++)(D) Kit Aquarius®Specific Probes Red (WHSCR) mark subtelomeric 4p16.3 and Green (DJ963k6)
mark subtelomeric 4q35.2; the image prove s the presence of 4q telomeres: ish der(4)t(4;8)(WHSCR+,DJ963k6+). (E) Kit Aquarius®Whole Chromosome Painting
Probes wcp 4 Red and Kit Aquarius®Satellite Enumeration Probes α-satellite 8 (D8Z2).
DISCUSSION
Chromosome 8p duplication is a rare chromosomal aberration
with unknown prevalence. Phenotypic features may be
nonspecific and a combination of complementary tests that
include karyotype, FISH analysis, and microarray are required
for diagnosis. Table 1 summarizes the main information about
8p21.3→p23.3 microduplication syndrome. The present study
shows a rare case with a de novo duplication of the entire region
8p21.3–p23.3, which has not been reported before.
More than 50 cases with 8p inverted duplication/deletion
syndrome have been described but, direct duplications of
chromosome 8p are less common (5,6,11).
8p23.1 duplication syndrome defined as a 3.75 Mb
duplication, most of band 8p23.1, has a prevalence of 1–9/100,000
(15,22). The core 3.68 Mb duplication contains 32 genes of which
five were considered candidates for the phenotypic features.
Barber et al. (20) suggested that 8p23.1 duplication syndrome
is an oligogenic condition, largely caused by the duplication
and interactions of the SOX7 and GATA4 transcription factors.
They noticed that eight genes led to developmental delay and
dysmorphism including macrocephaly, prominent forehead,
and arched eyebrows. Centromeric 8p23.1 microduplications
including the GATA4 gene could enable the development of
non-syndromic congenital heart defects (15,20). An evaluation
of 1645 pediatric patients with different developmental disorders
by high-resolution microarray based CGH found four cases
with a ≈4.0 Mb interstitial duplication of 8p23.1 (18). A patient
with delayed motor and speech development and intellectual
disability had a 1.80 Mb duplication in 8p23.1. SOX7 and TNKS1
genes and possibly MIR124-1 and MIR598, located within this
interval, were probably responsible for the pathognomonic
features of the syndrome (19).
Direct 8p21.3→p23.3 duplication has been
reported in one case with the following karyotype:
46,XX,der(16)t(8;16)(p21;q24)mat. Unlike our patient who
had a de novo duplication, the other case resulted from a
balanced maternal translocation (21).
The duplicated region in our case included 134 genes
(12). The identified copy number variation was associated
with 8p21.3→p23.3 microduplication syndrome, being a
genomic imbalance, described in international databases as
having pathological significance. The duplicated region has an
important gene content associated with the development of
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Gug et al. 8p Duplication With t(4;8)
FIGURE 3 | (Right) Chromosome view of a 22.3 Mb duplication of the 8p23.3-21.3 bands, arr[GRCh37] 8p23.3p21 (125733_22400607)×3 detected by aCGH
analysis and ideogram of chromosome 8. (Left) The genes within this region were marked with different colors, depending on their intolerance to mutations. Known
pathogenic genes are marked in red (according to DECIPHER v9.31 database).
pathological conditions, particularly with growth retardation,
dysmorphic features, skeletal abnormalities, which may
predispose to restrictive lung disease and congenital heart defects
(23,24). Other phenotypic consequences are developmental
delay, mental retardation, and behavioral problems. Our
patient had facial dysmorphism, mild mental retardation/in
dynamics liminal intellect with cognitive disharmony, delay
in psychomotor acquisitions, developmental language delay,
cognitive disharmony, instrumental and motor coordination
disorder, ASD, and ADHD. The chromosomal segment
8p21.1→p21.3 seems to be the critical region for 8p duplication
syndrome (5). A mild clinical outcome for trisomy 8p22→8pter
was reported in a study, in contrast to the severe findings when
the duplication involved a longer, more proximal segment (25).
An 8p23.1→8p23.2 duplication spread over 6.8 Mb has been
reported in a child with speech delay and autism and his mother,
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Gug et al. 8p Duplication With t(4;8)
TABLE 1 | 8p21.3→p23.3 Duplication syndrome (in chronological order of the reports).
Region with
duplication
Size Mb Type of
duplication
±Translocation Pattern Abnormality References
8p21.3→p23.3 Unknown Duplication der(12),
t(8;12)(p12;pl3)
Familial
3 cases
MR, simian crease, CHD
(atrial septal defect,
ventricular septal defect)
(13)
8p12→8p21.1 Unknown Direct duplication No Familial
(3 cases)
mild MR (6)
8p21.3→23.1 Unknown Direct duplication
in 7 cases
No Familial
(6 cases)
sporadic
(1 case)
Normal to moderate MR in
the affected individuals,
ADHD (1 case), CHD (2
cases including 1 prenatal)
(5)
8p21→p23 Unknown Duplication No De novo ASD, mild dysmorphic
features, and moderate
learning disability, MR
(14)
8p23.1 3.75 Mb Duplication No Sporadic prominent forehead, mildly
arched eyebrows, slightly
upward slanting palpebral
fissures
(15)
8p21→8p23.1 12 Mb Direct duplication
8p +deletion
8p23.1
Rearrangement 8p
with
der(8)dirdup(8)(p21p23.1)
del(8)(p23.1pter)
De novo global developmental
delays, seizures,
Dandy–Walker variant
(10)
8p23.1→8p23.2 6.8Mb Duplication No Maternal Child: speech delay, ASD,
mother: epilepsy and
learning problems
(16)
8p21 6.14 Mb Duplication no De novo Cognitive and motor
development severely MR,
facial dysmorphic features,
ASD, self-mutilation
(17)
8p23.1. Minimum
3.79 Mb
Interstitial
duplication
no 4 cases
including 2
familial
(maternal)
CHD (aortic stenosis)
prominent forehead
(18)
Maximum
5.26 Mb
Terminal
duplication
6.83 Mb Terminal
duplication
der(8)t(8;15)(p22;q24.1) 1 case Prominent forehead
CHD (aortic dilatation)
8p23.1. 1.8 Mb Interstitial
duplication
no Familial Delay of motor and speech
development, MR, ASD.
(19)
8p23.1. 3.68 Mb Duplications no Familial Developmental delay,
dysmorphism including a
prominent forehead and
arched eyebrows.,
macrocephaly and, but not
CHD
(20)
8p21.3→p23.3 Unknown Duplication der(16),
t(8;16)(p21;q24)
Maternal CHD (transverse aortic arch
hypoplasia)
(21)
8p21.3→p23.3 22.3 Mb 8p terminal
duplication
der(4),t(4;8)(q35;p21.3) De novo Proeminent forehead, mild
MR, ASD, ADHD,
noncyanotic CHD
(ventricular septal defect)
Present case,
2020
ADHD, Attention Deficit Hyperactivity Disorder; ASD, Autism Spectrum Disorder; CHD, congenital heart defect; der, derivative; Mb, megabase; MR, mental retardation; t, translocation.
with epilepsy and learning problems. The interval included 41
known genes and 32 new genes among which the MCPH1
gene was thought to be the only plausible candidate gene for
autism (16).
Papanikolaou et al. (14) described a patient with partial
trisomy 8p(21-23) associated with autism, mild dysmorphic
features, and moderate learning disability. Pinto et al. (26)
suggested that the DLGAP2 gene, located on chromosome
8p23.3, could be a novel candidate gene for ASD. Further
evidence for the DLGAP2 gene as a strong candidate gene
has been provided by Poquet et al. (27) based on several
cases with de novo duplications involving the DLGAP2 gene
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Gug et al. 8p Duplication With t(4;8)
and presenting with ASD. Our patient also had a de novo
duplication that included 8p23.3, DLGAP2 gene, respectively.
Different chromosomal interstitial 8p rearrangements,
including duplications, have been associated with
ASD (17,28,29).
The size of the duplicated region correlated with the degree of
cognitive deficiency in a patient with severe developmental and
intellectual disability, severe impairment of expressive speech,
and language (30).
CHDs were found only in a few patients with 8p23.1
duplication containing the GATA4 gene (18). These defects
are different, even within the same family there were cases
with aortic stenosis or aortic dilatation (18). Transverse aortic
arch hypoplasia has been reported in two fetuses prenatally
diagnosed with 8p23.3–p21.3 trisomy and with direct duplication
of 8p21.3–p23.1, respectively (5,21). Cardiac defects can
manifest in unexpected forms in different syndromes, but
they are always an important element in assessing complex
cases (31).
Only extremely rarely, the 8p duplicate material is
translocated to another chromosome. In our patient
the cytogenetic analysis identified the translocation
t(4;8)(q35;p21.3), therefore karyotyping remains a useful
method to detect chromosomal rearrangements (32–34). The
trisomic fragment 8p has been translocated to the end of 4q
with the complete preservation of 4q telomeres. FISH analysis
indicated preservation of telomeres; therefore, we hypothesize
that our patient’s phenotype is determined entirely by the large
duplication of 8p21.3→p23 region.
A search of PubMed using the keywords: “chromosome
8p duplication” and “translocation” revealed several reports
referring to various chromosomal rearrangements involving
chromosome 8. We excluded cases that had combined
chromosome anomalies, and we found three reports of 8p
duplication in offspring of carriers of balanced translocations
involving chromosome 8. A report presented a family with
t(8;12)(p12;pl3) carriers and affected descendants with
8p21.3→p23.3 duplication, associated with MR and CHD
(13). Translocation t(8;15)(p22;q24.1) and duplication
8p associated with CHD and prominent forehead in the
offspring have been found in another family, as well. In
the third family, a pregnant woman was a carrier of a balanced
translocation t(8;16)(p21;q24), while the fetus had an unbalanced
translocation 46,XX,der(16)t(8;16)(p21;q24)mat, associated with
CHD (21).
Clinico-cytogenetic correlations revealed associations
between phenotypic features and certain duplicate regions.
Thus, 8p12 region was associated with MR (6), 8p23.1 region
was associated with MR, ASD (16,19), facial dysmorphism,
especially prominent forehead (15,18,20), and CHD (18).
8p21.3→p23.1 region was associated with MR (5,13,14,17),
ADHD (5,17), ASD (27) and CHD (5,13,21). This study shows
only one case that has a large duplication involving the entire
8p21.3→p23.1 region, associated with mild facial dysmorphism
with a prominent forehead, MR, ADHD, ASD, and CHD. This is
preliminary evidence that indicates that all patient’s symptoms
are caused by this de novo duplication.
The origin of the duplicated segment has not been determined
in our study. A report of 52 cases of de novo unbalanced
translocations indicated that the primary driver for their
occurrence was a maternal meiotic non-disjunction, followed by
partial trisomy rescue (35).
A FISH analysis study found a direct tandem 8p duplication
and, unlike inv dup del(8p), this was not derived from parental
submicroscopic inversion (10). FISH method alone or in
combination with other tests is highly informative (36). The
phenotype of inverted duplications 8p is distinct from and much
more severe than the clinical effect of partial trisomy 8p due to
direct duplications known so far (6). Genetic counseling must
consider that gonadal mosaicism cannot be excluded (37,38).
For this reason, prenatal diagnosis was performed in subsequent
pregnancies (39–41).
CONCLUSIONS
We present a mildly affected phenotype correlated with a de
novo 22.3Mb copy number gain of chromosome 8p21.3–
p23.3, in a patient with liminal intellect with cognitive
disharmony, autism spectrum disorder, attention deficit
hyperactivity disorder, delay in psychomotor acquisitions and
a noncyanotic congenital heart defect. Our results suggest
that our patient’s phenotype can be explained by the large
duplication of 8p21.3→p23.1 region. Our report emphasizes
the diagnostic value of molecular cytogenetics in children
with an autism spectrum disorder. It also provides additional
data regarding neuropsychiatric features in chromosome
8p duplication.
DATA AVAILABILITY STATEMENT
All datasets generated for this study are included in the
article/supplementary material.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by Ethics Committee for Scientific Research of
Emergency Hospital for Children ‘Louis Turcanu,’ Timisoara,
Romania. Written informed consent to participate in this
study was provided by the participants’ legal guardian/next
of kin. Written informed consent was obtained from the
minor(s)’ legal guardian/next of kin for the publication
of any potentially identifiable images or data included in
this article.
AUTHOR CONTRIBUTIONS
CG and DSto are the co-first authors. CG performed the
cytogenetic analysis, the genetic counseling, and wrote the
first draft of the manuscript. DSto coordinated and supervised
data collection and interpretation, and critically reviewed the
manuscript for important intellectual content. GD is the
cardiologist who followed the child throughout the evaluation
Frontiers in Pediatrics | www.frontiersin.org 8July 2020 | Volume 8 | Article 375

Gug et al. 8p Duplication With t(4;8)
and made essential contributions to the manuscript writing. LN,
MC, DSta, and AP collected the data, analyzed, and interpreted
the findings, critically revised, and reviewed the manuscript
for important intellectual content. IM revised and improved
the first draft of the manuscript and is the corresponding
author. All authors have read and approved the final manuscript
for publication.
ACKNOWLEDGMENTS
We gratefully acknowledge the participation of the parents and
for allowing us to learn from their stories. We would like to
thank Vasilica Plaiasu MD, PhD, and biologist Ozunu Diana for
excellent technical support in the cytogenetic laboratory for the
FISH method.
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2020 Gug, Stoicanescu, Mozos, Nussbaum, Cevei, Stambouli, Pavel and
Doros. This is an open-access article distributed under the terms of the Creative
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are credited and that the original publication in this journal is cited, in accordance
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