Genotype-Phenotype Analysis of 8q24.3 Duplication and 21q22.3 Deletion in a Chinese Patient and Literature Review

Abstract

Introduction: Copy number variants (CNVs) are responsible for many patients with short stature of unknown etiology. This study aims to analyze clinical phenotypes and identify pathogenic CNVs in a patient with short stature, intellectual disability, craniofacial deformities, and anal imperforation. Methods: G-banded karyotyping and chromosomal microarray analysis (CMA) was used on the patient to identify pathogenic causes. Fluorescence in situ hybridization (FISH) was applied to explore the abnormal genetic origin. Literatures were searched using identified CNVs as keywords in the PubMed database to perform genotype-phenotype analysis. Results: Cytogenetic analysis revealed a normal karyotype 46,XY. CMA detected a 6.1 Mb duplication at 8q24.3 and a 3.6 Mb deletion at 21q22.3. FISH confirmed that the abnormal chromosomes were inherited from paternal balanced translocation. We compared phenotypes of our patient with 6 patients with 8q24.3 duplication and 7 cases with 21q22.3 deletion respectively. Conclusions: A novel 8q24.3 duplication and 21q22.3 deletion was identified in a Chinese patient. Genotype-phenotype analysis demonstrated that patients with 8q24.3 duplication and 21q22.3 deletion had specific facial features, intellectual disability, short stature, and multiple malformations.

© 2021 S. Karger AG, Basel

Introduction

Short stature is a common pediatric disorder with complex etiology and diverse clinical phenotypes [1]. Chromosomal aberration, especially genome copy number variations (CNVs), is an important cause of short stature, and these patients can also have intellectual disability, facial abnormalities, cardiac defects, bone malformations, and other multiple deformities [2]. Conventional cytogenetic analysis is the first choice for diagnosis of chromosomal diseases; however, it could not detect microscopic chromosomal deletions or duplications less than 5 Mb [3]. Chromosome microarray analysis (CMA) is an important approach to detect CNVs with higher resolution, sensitivity, and accurate positioning [4, 5]. It has been used as an important diagnostic tool for syndromic short stature of unknown cause [6].

We present a rare case with concurrent 8q24.3 duplication and 21q22.3 deletion using CMA in a child with short stature, intellectual disability, abnormal facial features, and anal imperforation. Fluorescence in situ hybridization (FISH) confirmed the alterations were derived from paternal balanced translocations [7]. The concurrent CNVs have not been reported worldwide. The study describes clinical manifestations, genotype-phenotype correlations of patients with 8q24.3 duplication and 21q22.3 deletion.

Materials and Methods Clinical Manifestations

The proband was an 8-year-and-9-month-old boy. He was referred to the Pediatric Department of Beijing Jishuitan Hospital in March 2017. He complained of short stature, intellectual disability, and facial deformity. His height was 115.2 cm (P <3th) and weight 18.2 kg (P <3th). His head circumference was 51.5 cm. His facial dysmorphic features were epicanthus, downslanted palpebral fissures, large ears, broad nasal bridge, large nose, broad mouth, multiple dental caries, short philtrum, maxillary protrusion, and receding micrognathia (Fig. 1). Other clinical manifestations included right accessory ear and scoliosis.

Fig. 1.

Facial deformity. a Epicanthus, downslanted palpebral fissures, large ears, broad nasal bridge, large nose, broad mouth, multiple dental caries, and short philtrum. b Maxillary protrusion, receding micrognathia, and accessory ear.

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The male patient, G3P3, was born at full term by caesarean section. He was a small for gestational age infant. His birth weight was less than 2500 g. He had no history of perinatal asphyxia. He had congenital anal atresia at birth and underwent surgical treatment. He had feeding difficulty and constipation. The patient had intellectual disability and his intelligence test was equivalent to about 2 years old. He was an introvert and quiet boy. His language development was delayed. He spoke his first words “baba” and “mama” at one year old. He had poor articulation and could only communicate with 3–5-word sentences incoherently at visit. His developmental milestones were normal. He raised his head at 2 months, rolled at 4 months, sat at 6 months, crawled at 8 months, and walked independently at 13 months.

He had normal liver and kidney function, myocardial enzyme, and blood electrolytes. Glycosylated hemoglobin was 5.3% (4.8–6.0%). Fasting insulin was normal 7.2 (2.6–24.9) U/mL. Fasting C-peptide was 1.20 ng/mL (1.10–4.40 ng/mL). ACTH (fasting 8 a.m.) was 14.31 (7.2–63.3) pg/mL and cortisol (fasting 8 a.m.) 12.38 (4.26–24.85) μg/dL. His thyroid function was normal. Growth hormone concentration response to pharmacological stimuli (levodopa) was as follows: 6.76 (0′), 8.99 (30′), 15.70 (60′), 11.80 (90′), and 3.65 (120′) ng/mL (normal >10 ng/mL). Fasting serum insulin-like growth factor was 134.00 (64–345) ng/mL. The abdominal sonography was normal. The pituitary magnetic resonance imaging showed no obvious abnormality. The spinal X ray radiography confirmed anterior curvature. His bone age was 5 years and 6 months old, delayed 3 years for his actual age.

Clinical manifestations of his parents were normal. His father’s height was 172 cm and mother’s 165 cm, respectively. Their first child, G1P1, was male and his phenotype was normal. The second son of the family, G2P2, had multiple malformations and died for unknown reasons at two months old.

Written informed consent was obtained from his parents. Clinical data and peripheral lymphocyte DNA were collected from the proband and his parents.

Cytogenetic Analysis

A 2 mL sample peripheral blood was collected from the proband and subjected to lymphocyte culture. Cytogenetic investigations on 20 metaphases obtained from PHA-stimulated peripheral lymphocytes were performed following standard protocols. We used routine cytogenetic analysis by G-banding techniques with a resolution of approximately 550 bands.

Chromosomal Microarray Analysis

DNA was extracted from blood lymphocytes using the QIAamp DNA Mini Kit (Qiagen Benelux B.V., Venlo, The Netherlands). CMA analysis was performed using standard Affymetrix CytoScan HD platform (Santa Clara, CA, USA) including 2.7 million probes (1.95 million copy number probes and 750,000 SNP probes) [8]. Labeling and hybridization were carried out according to the manufacture’s instruction. The raw data were collected and analyzed by Affymetrix Chromosome Analysis Suite Software (Santa Clara, CA, USA). The cutoffs for the detection criteria for CNVs were set at 50 kb for gains, 100 kb for losses, and 3,000 kb for regions of homozygosity.

Copy number changes were compared with database of genomic variants (http://projects.tcag.ca/variation/) and UCSC genome browser (http://genome.ucsc.edu/). The gene content of CNVs was determined using clinical genome resource browser (https://dosage.clinicalgenome.org/) and online mendelian inheritance in man (OMIM; https://omim.org/).

Fluorescence in situ Hybridization

To confirm origins of abnormal chromosomes, FISH analysis was performed using Agilent SureFISH probe according to a standard protocol. Double-color FISH was performed with region-specific probe (spectrum red) and internal reference probe (spectrum green). Microscope images of 10 metaphase cells were collected and analyzed using meta systems ISIS image analysis software.

Literature Review

We searched literatures using identified CNVs as keywords in PubMed to perform genotype-phenotype correlation analysis. The references of the retrieved articles were also further consulted to ensure clinical data were comprehensive. The inclusion literatures must provide sufficient information for genotype-phenotype analysis.

Results Cytogenetic and CMA Analysis

The karyotype of 20 cultured lymphocytes of the patient was 46,XY. Whole genome array analysis detected a 6.1 Mb duplication at 8q24.3 (chr8:140238896-14629577) and a 3.6 Mb deletion at 21q22.3 (chr21:44491199–48097372) as shown in Fig. 2; [9]. The duplicated and deleted region contained 158 and 113 genes respectively.

Fig. 2.

CMA detected a 6.1 Mb duplication at 8q24.3 (chr8:140238896-14629577) highlighted in the blue region (a) and a 3.6 Mb deletion at 21q22.3 (chr21:44491199–48097372) highlighted in the red region (b). CMA, chromosome microarray analysis.

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There were 61 OMIM genes in the 8q24.3 duplication region: KCNK9, TRAPPC9, CHRAC1, AGO2, PTK2, GPR20, PTP4A3, ADGRB1, ARC, JRK, PSCA, SLURP1, LYNX1, LY6D, GML, CYP11B1, CYP11B2, LY6E, LY6H, GPIHBP1, GLI4, TOP1MT, RHPN1, MAFA, NAPRT, EEF1D, TSTA3, FAM83H, SCRIB, PUF60, EPPK1, PLEC, MIR661, PARP10, GRINA, SPATC1, EXOSC4, GPAA1, CYC1, SHARPIN, MAF1, BOP1, SCXA, HSF1, DGAT1, SCRT1, FBXL6, SLC52A2, CPSF1, SLC39A4, VPS28, TONSL, FOXH1, PPP1R16A, GPT, RECQL4, ZNF34, RPL8, ZNF7, COMMD5, and ZNF16. It was uncertain whether these genes were of triplosensitivity.

There were 39 OMIM genes in the 21q22.3 deletion region: CBS, U2AF1, CRYAA, SIK1, HSF2BP, RRP1B, PDXK, CSTB, RRP1, TRAPPC10, PWP2, C21orf33, ICOSLG, DNMT3L, AIRE, PFKL, C21orf2, TRPM2, TSPEAR (thrombospondin-type laminin G domain and EAR repeats), UBE2G2, SUMO3, PTTG1IP, ITGB2, LINC00163, ADARB1, POFUT2, COL18A1, SLC19A1, PCBP3, COL6A1, COL6A2, FTCD, SPATC1L, LSS, MCM3AP, PCNT, disconnected-interacting protein homolog 2A (DIP2A), S100B, and PRMT2. Deletions of 6 genes, including CBS, CSTB, TSPEAR, ITGB2, FTCD, and DIP2A, could lead to haploinsufficiency.

Fluorescent in situ Hybridization

Metaphase FISH results of the proband and his parents are shown in Fig. 3. Chromosome 8 was detected using Agilent SureFISH 8q24.3 probes (R) and centromeric probe chr8CEP (G). His father had 1 red signal and 1 green signal located in different chromosomes illustrating 8q24.3 translocation. The result of his mother was normal. The proband inherited from his father 1 normal chromosome 8 and 1 8q24.3 translocation chromosome resulting in 8q24.3 duplication. Chromosome 21 was detected using Agilent SureFISH 21q22.3 probe (R) and centromeric probe chr21CEP (G). The father of the proband had 1 red signal and 1 green signal located in different chromosomes. It was illustrated that he had 21q22.3 translocation. His mother was normal. The proband inherited from his father 1 chromosome 21 with 21q22.3 deletion. FISH results confirmed that the proband had 8q24.3 duplication and 21q22.3 deletion, inherited from his father’s balanced reciprocal translocation.

Fig. 3.

FISH analysis of metaphase in the family. a–c 8q24.3-specfic probe (red) and chr8 centromeric probe (green). a The proband’s father was abnormal. He had 1 red signal (yellow arrow) and 1 green signal (white arrow) located in different chromosomes. b The proband’s mother was normal. c The proband inherited from his father 1 normal chromosome 8 and 1 derivative chromosome with 8q24.3 translocation (yellow arrow). d–f 21q22.3-specfic probe (red) and chr21 centromeric probe (green). d The proband’s father was abnormal. He had 1 red signal (white arrow) and 1 green signal (yellow arrow) located in different chromosomes. e The proband’s mother was normal. f The proband inherited from his father 1 chromosome 21 with 21q22.3 deletion (yellow arrow). FISH, fluorescence in situ hybridization.

/WebMaterial/ShowPic/1337799 Patients with 8q24.3 Duplication and 21q22.3 Deletion

Both 8q24.3 duplication and 21q22.3 deletion have been rarely reported and most literatures were published in case report form. We have compared phenotypes of these individuals with 8q24.3 duplication and 21q22.3 deletion respectively. We have screened 6 trisomic 8q24.3 cases reported in the literature [10-15]. Six patients with detailed clinical manifestations and our proband were summarized in Table 1. One patient with incomplete clinical data was not included in the table [16]. Seven patients with 21q22.3 deletion and our proband are shown in Table 2 [17-22]. We excluded 2 fetuses who were terminated before pregnancy [23, 24].

Table 1.

Phenotype comparison of patients with 8q24.3 duplication

/WebMaterial/ShowPic/1337807 Table 2.

Phenotype comparison of patients with 21q22.3 deletion

/WebMaterial/ShowPic/1337805 Discussion

In our study, the patient had short stature, intellectual disability, facial anomalies, scoliosis, and congenital anal atresia. His abnormal facial features included downslanted palpebral fissures, epicanthus, hypertelorism, large ears, right accessory ear, large nasal bridge, broad mouth, multiple dental caries, maxillary prognathism, and receding micrognathia. His clinical manifestations were unspecific and cytogenetic analysis did not detect any abnormal chromosomes. With the development of molecular techniques, CMA has been used as a first-line test for patients with unexplained developmental disability, intellectual disability, and congenital anomalies [25]. It has a significantly increased accurate molecular diagnosis rate from 3% to about 20% for these patients. CMA detected a 6.1 Mb duplication at 8q24.3 and a 3.6 Mb deletion at 21q22.3 in the proband. FISH results were concordant with array analysis. The abnormal chromosomes were inherited from his father’s balanced reciprocal translocations between chromosomes 8 and 21. To date, this is the first report of patient with concordant 8q24.3 duplication and 21q22.3 deletion. We performed genotype-phenotype analysis in patients with 8q24.3 duplication and 21q22.3 deletion respectively, both of which were rare cases and have obvious phenotypic heterogeneity.

We compared phenotypes of 7 cases with 8q24.3 duplications in the literature. Their duplicated segments and phenotypes were different from each other. Concolino et al. described a “pure” de novo duplication of chromosome 8q22.2-8q24.3 and suggested that mental retardation and facial dysmorphism such as hypertelorism, microretrognathia, and telecanthus are key features of 8q22.2-q24.3 duplication syndrome [12]. Except for these features, more clinical manifestations were identified in 8q24.3 duplication patients in our study. Almost all of the patients (5/5) had intellectual disability and some had epilepsy (2/5) [10, 11, 14]. Most of them (3/5) had growth retardation and short stature [10, 12]. Main facial features were prominent forehead (4/6), hypertelorism (4/6), large nasal bridge (5/6), and low-set ears (3/6). Other facial dysmorphism included microretrognathia (2/6), anteverted nares (2/6), broad mouth (2/6), and long philtrum (2/6) [12, 14]. Multiple specific malformations were detected in these patients: congenital heart disease (3/7), anal atresia (3/7), cleft lip and palate (2/7), and cryptorchidism (2/4) [13, 15].

Two patients with 8q24.3 duplication had sudden death of unknown causes [15, 16]. Farcas et al. [15] found a rare case with 8q24.12-q24.3 duplication (27 Mb) and 8q24.3 deletion (237 kb). She had sudden death in the first day after birth. Toruner et al. [16] detected 8q24.3qter duplication and 22q13.3qter deletion in a case of unclassified sudden infant death who had left hydroureter and hydronephrosis. The second child of the family in this study also had unexplained sudden death. As he had multiple deformities and his genomic DNA was unavailable, we hypothesized that the deceased child might have had 8q24.3 duplication. The etiology of unexplained sudden death in 8q24.3 duplication needs further research.

Shrimpton et al. [11] reported a boy with concurrent 3p26 deletion and 8q24.3 duplication. His phenotypes were only mild cognitive deficit and delayed speech and language skills, which were considered to be the result of 8q24.3 duplication. He had no manifestations of dysmorphic features and short stature. His stuttering problem was common to our patient. Intensive training and specialized education were needed to improve the speech of these patients [11].

Hilger et al. [13] found that a male patient of VACTERL association had a 120 kb microduplication of 8q24.3. His phenotypes included butterfly vertebra (V), anal atresia (A), congenital subvalvular aortic stenosis and ventricular septal defect (C), esophageal atresia (TE), high-grade bilateral vesico-ureteral reflux (R), and bilateral cryptorchidism. It was not clear whether the patient had intellectual disability, facial abnormalities, and short stature. Similar to this patient, clinical symptoms of our proband included vertebral abnormalities and anal atresia. The common duplicated genes of both patients were EPPK1, PLEC, MIR661, PARP10, GRINA, and SPATC1. The pathogenesis of EPPK1, MIR661, and SPATC1 were not seem to be associated with the patient's phenotype. Plectin-1 encoded by PLEC is an intermediate filament-binding protein. It is believed to provide mechanical strength to cells and tissues by acting as a cross-linking element of the cytoskeleton. PLEC mutations have been found to be associated with epidermolysis bullosa simplex with pyloric atresia, suggesting an important function in gastrointestinal development [26, 27]. It remains to be confirmed by function study whether abnormal expression level caused by PLEC duplication was related with anal atresia. Poly (ADP-ribose) polymerases, PARP10, regulate gene transcription by altering chromatin organization by adding ADP-ribose to histones and also function as transcriptional cofactors [28]. The pathogenic function of PARP10 alterations should be studied in further detail.

GRINA encodes a glutamate-binding subunit of NMDA receptor ion channels and is associated with function, gene regulation, and neuronal survival of cAMP response element-binding protein [29-31]. This receptor acts on cAMP response element-binding protein to promote brain-derived neurotrophic factor gene expression, which plays an important role in neuronal survival, differentiation, growth, and development. GRINA abnormal expression was considered to be correlated with intellectual disability and growth retardation of 8q24.3 patients.

Partial deletion of chromosome 21q is a rare chromosomal disorder with heterogeneous phenotype because of unique breakpoint and genetic background [32]. Clinical manifestations of 21q22.3 deletion individuals varied from mild, moderate, severe to lethal depending on the deleted region and concordant chromosomal aberrations [17, 19, 20]. We present phenotypes of a new case and 7 previously reported cases with 21q22.3 deletion. Except for 1 deceased newborn, all of them (7/7) had intellectual disability [20]. Four cases (4/6) had congenital cardiac defects, 2 of which were severe type of hypoplastic left heart [18, 20]. About half of the reported patients (3/6) exhibited short stature. Hypertelorism (6/7) and epicanthus (5/7) were the most common facial features. Large nose (4/6), broad mouth (3/6), and large ears (3/7) were frequently identified in these patients. Retrognathia (3/4) and strabismus (2/3) were also detected as important features of these patients. Two (2/4) cases had downslanted palpebral fissures. Two (2/4) patients presented with upslanted palpebral fissures, which is similar to trisomy 21 syndrome [21, 22]. One patient had small palpebral fissures [20].

It is demonstrated that 21q22.3 deletion were frequently associated with diverse congenital heart defects. Velinov et al. [18] found a female infant with hypoplastic left heart with aortic atresia and hypoplastic aortic arch, ventricular septal defect, and a nonrestrictive atrial communication. Ciocca et al. [20] reported a syndromic female newborn of 21q22.3 deletion with severe stenosis of the aortic valve and ascending aorta, mitral valve atresia, and hypoplastic left ventricle, who died of cardiopulmonary insufficiency after birth. A Colombian girl with 21q22.3 deletion and 7q35q36.3 duplication manifested an atrial septal defect, dilated coronary sinus, and interventricular communication [21]. The deleted location and size of 21q22.3 were similar with our case who had no cardiac anomaly. Sgardioli et al. identified a pure 21q22.3 deletion female with mitral valve prolapse with discrete valve regurgitation [22]. It is speculated that gene expression in the 21q22.3 region was correlated with cardiac development. The heterogeneous phenotypes were considered to be caused by genetic background and environmental factors.

Patients with 21q22.3 deletion were summarized as intellectual disability, congenital heart disease, short stature, and specific facial abnormalities including hypertelorism, epicanthus, abnormal palpebral fissures, strabismus, large nose, broad mouth, large ears, and retrognathia. It is very complicated to identify pathogenic genes leading to specific phenotypes in 21q22.3 as deletion of the gene enrichment area had complex and unknown functions.

The deleted 21q22.3 region in our patient encompasses 39 OMIM genes including 6 dosage sensitive genes: CBS, CSTB, TSPEAR, ITGB2, FTCD, and DIP2A. Cystathionine beta-synthase deficiency, due to biallelic CBS mutations, caused homocystinuria [33]. Clinical features of this metabolic disorder usually manifest myopia, ectopia lentis, mental retardation, skeletal anomalies, and thromboembolic events. The incidence of vascular disease should be further investigated because of CBS heterozygous deletion [34, 35]. Loss of function mutations in CSTB, encoding cystatin B, was responsible for progressive myoclonus epilepsy [36]. Mutations in the gene TSPEAR, a regulator of Notch signaling, cause disorders of congenital sensorineural deafness and ectodermal dysplasia 14 in autosomal recessive inheritance [37, 38]. Mutations in ITGB2, beta-2 subunit of the leukocyte cell adhesion molecule, have been found to cause an autosomal recessive disorder of leukocyte adhesion deficiency characterized by recurrent bacterial infections [39, 40]. Biallelic mutations in the FTCD gene, which encodes the enzyme formiminotransferase cyclodeaminase, were associated with glutamate formiminotransferase deficiency featured by intellectual disability and megaloblastic anemia [41, 42]. The patient in our study had no manifestations of homocystinuria, epilepsy, congenital sensorineural deafness, leukocyte adhesion deficiency, and FTCD deficiency illustrating these genes in the other allele may be normal. Next generation sequencing for evaluation of another allele is needed for phenotype prediction and genotype-phenotype correlation analysis.

DIP2A, which is localized to dendritic spines in excitatory neurons and involved in acetylated coenzyme A synthesis, has been reported to be a candidate gene for autism spectrum disorder [43]. It was shown that a genetic variant rs2255526 in the DIP2A gene was associated with increased developmental dyslexia risk in the Chinese population [44]. The animal model demonstrated Dip2a knockout mice presented synaptic dysfunction and autism-like behavioral impairments, which resemble the core symptoms of patients with autism spectrum disorder [43]. The proband in our study had intellectual disability and social communication difficulty, which may be affected by synaptic dysfunction of DIP2A deletion.

Our study revealed a karyotype of 46,XY,der(21)t(8;21)(q24.3;q22.3) in the proband. His father’s karyotype was 46,XY,t(8;21)(q24.3;q22.3), who was a balanced reciprocal translocation. Malsegregation of chromosomes in the germ cells of the father could form 18 types of gametes including 1 normal gamete, 1 balanced translocation, and 16 unbalanced translocations [45]. The pathogenesis of chromosomal aberrations provides important diagnostic basis and genetic counseling. The phenotype of the proband’s brother (G1P1) was normal; however, his karyotype may be normal or a carrier of balanced translocation. Further analysis was not performed due to his unavailable genomic DNA. The second boy (G2P2) in the family had multiple malformations and was considered to have unbalanced translocation.

Conclusion

Individuals with 8q24.3 duplication and 21q22.3 deletion both have abnormal facial features, intellectual disability, short stature, and multiple malformations. Genotype-phenotype analysis suggested that special facial features of our proband had both features of 8q24.3 duplication and 21q22.3 deletion. Craniofacial development of the patient was suggested to be attributed to a combination of 8q24.3 duplication and 21q22.3 deletion. His vertebral abnormalities and congenital anal atresia were considered to be associated with 8q24.3 duplication [13]. The pathogenic genes of the duplicated region and deleted region leading to specific features remains to be further studied at the molecular level.

This is a novel concordant 8q24.3 duplication and 21q22.3 deletion inherited from paternal reciprocal translocation. We analyzed genotype-phenotype correlations to provide basis for precision diagnosis, targets for molecular treatment, and genetic counseling. In patients of short stature with suspicion of chromosomal disorder, CMA is warranted to confirm diagnosis.

Acknowledgements

We would like to thank all members of the family participating in the study for agreeing to publish their available clinical data in medical journals.

Statement of Ethics

The study was conducted in accordance with the Declaration of Helsinki and the Ethics Committee of Beijing Jishuitan Hospital. Written informed consents were obtained from the participants and parents of the proband for publication of this article and any accompanying images in the study.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was supported by research grants from Beijing Jishuitan Hospital Nova Program (XKXX201608). H.S. designed the study. N.W. collected clinical data of patients.

Author Contributions

N.W. interpreted the patient data. H.S. wrote the manuscript. Both authors have read and approved the final manuscript.

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Naijun Wan, wann6971@163.com

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Abstract of Research Article

Received: August 13, 2020
Accepted: February 28, 2021
Published online: July 15, 2021

Number of Print Pages: 11
Number of Figures: 3
Number of Tables: 2

ISSN: 1662-4246 (Print)
eISSN: 1662-8063 (Online)

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