Skip to main content
Download PDF

Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability

Italian Journal of Pediatrics volume 48, Article number: 207 (2022) Cite this article

Abstract

Background

Developmental delay and intellectual disability represent a common pathology in general population, involving about 3% of the pediatric age population, the genetic etiology being often involved. The aim of this study was to determine the clinically relevant copy number variants in patients diagnosed with global developmental delay/intellectual disability in our population, using the chromosomal microarray analysis.

Methods

We analyzed 189 patients diagnosed with global developmental delay/intellectual disability, presented in Clinical Emergency Hospital for Children, Cluj-Napoca. The patients were completely clinically investigated, including dysmorphic and internal malformations evaluation, psychiatric, neuropsychological and metabolic evaluation, standard karyotyping. Genomic analysis was done using chromosomal microarray analysis.

Results

Pathogenic findings (including uniparental disomy) and variants of unknown significance were detected in 53 of 189 patients (28.04%). Pathogenic copy number variants and uniparental disomy were observed in 35 of 189 patients (18.51%). Two patients presented uniparental disomy for chromosome 15, one with clinical phenotype of Prader-Willi syndrome and the other with clinical phenotype with Angelman syndrome. Within the category of pathogenic findings, the recurrent copy number variants were seen in 21 of 35 patients (60%).

Conclusions

The increased percentage of pathogenic structural variants observed in patients with global developmental delay/intellectual disability analyzed by chromosomal microarray technique supports its use in patients with a non-specific phenotype such as these neurodevelopmental disorders. The high percentage of recurrent pathogenic variants between these findings is a finding that support their initial evaluation when a genetic testing algorithm could be a useful option.

Background

Developmental delay and intellectual disability represent a common pathology, affecting 1–3% of children, the etiology being represented by genetic factors in more than a half of these patients [1,2,3]. Global developmental delay (GDD) is a diagnosis reserved for a child under five years, being defined as a significant delay, under two standard deviations (SD), in two or more developmental domains (gross or fine motor abilities, speech/language, cognition, social/personal and activities of daily living) [4]. Intellectual disability (ID) is a diagnosis established beginning with the age of five years, when the following three criteria are met simultaneously: defective intellectual function (usually measured by intellectual coefficient), defective adaptative function (conceptual, social, or practical skills) and onset of these deficits during the developmental period [5]. Not all the patients with GDD diagnosis will fulfill the criteria for ID diagnosis after the age of five years.

With advanced genomic technologies, as chromosomal microarray analysis (CMA) and exome/genome sequencing, the genetic etiology in GDD/ID is now identified in more than 50% of these patients [3, 5].

The G-bands karyotype identified numerical or structural chromosomal abnormalities in approximately 5% of GDD/ID patients (in some studies, up to 15% of cases) [5,6,7,8], 21 trisomy being the most frequently seen (in about 70% of these patients) [6, 8]. Recurrent microdeletions/microduplications (mainly involving 22q11.2, 7q11.23, 17p11.2, 15q11–13, 16p11.2, 1q21.1 and other regions) are observed in about 5% of cases, usually being identified by Fluorescent In Situ Hybridization (FISH), Multiplex Ligation-dependent Probe Amplification (MLPA) or quantitative Polymerase Chain Reaction (qPCR) techniques [8, 9]. A first-tier test in genetic investigations in GDD/ID is now represented by CMA, due to an important diagnostic yield, of 15–25% in patients with GDD/ID [10,11,12,13], preferred over G-bands karyotype, FISH, MLPA or qPCR techniques, due to a higher sensitivity and better genomic resolution for copy number variants (CNVs) detection [10].

Pathogenic single nucleotide variants (SNVs) or indels variants, in monogenic or oligogenic disorders, are identified by exome/genome sequencing in 15–30% of GDD/ID patients, tests usually performed after a negative CMA analysis [10, 12,13,14,15].

The other unexplained causes in GDD/ID patients could be related to environmental teratogens (including the fetal alcohol exposure, valproate exposure or infections), perinatal factors (prematurity, asphyxia, or other neonatal complications) or postnatal causes (as CNS infections, traumatisms, toxic, psychosocial environment).

The aim of this study was to determine the clinically relevant CNVs in Romanian children diagnosed with GDD/ID, using Single Nucleotide Polymorphism (SNP) array technology.

Methods

We analyzed 189 patients diagnosed with GDD/ID, presented in Clinical Emergency Hospital for Children Cluj-Napoca, between January 1st 2015 and July 1st 2017. The age of the patients was between 1 and 18 years. The inclusion criteria was the diagnosis of GDD or ID. An exclusion criteria was the presence of 21 trisomy confirmed by karyotype. GDD/ID diagnosis was based on the intelligence quotient evaluated by Wechsler Intelligence Scale for Children test (WISC-IV) and development quotient (for children younger than 6 years), evaluated by Portage test and A Developmental NEuroPSYchological Assessment test (NEPSY). The patients were completely clinically investigated, including dysmorphological evaluation, internal malformations evaluation, psychiatric and neuropsychological examinations, metabolic evaluation, standard karyotyping. Brain imaging and electroencephalogram (EEG) were indicated by the neurologist. Other investigations was performed depending on clinical indication of each patient.

The research was approved by Ethics Committee of Clinical Emergency Hospital for Children, Cluj-Napoca. Written informed consent was obtained from the parents of all the participants in the study.

High density SNP array analysis

The deoxyribonucleic acid (DNA) was purified by Wizard® Genomic DNA Purification Kit (Promega, Madison, WI, USA), using 3 ml peripheral blood, sample collected for each patient. Then, a SNP array analysis was done using Infinium OmniExpress-24 BeadChip array kit (Illumina, San Diego, CA, USA) and the platform iScan System (Illumina, San Diego, CA, USA). The SNP array kit allowed the analysis of about 700,000 markers. For bioinformatic analysis it was use the Genome Studio software version 2.0 (Illumina, San Diego, CA, USA). The interpretation of each CNV was done using the recommendations of American College of Medical Genetics [16, 17].

Results

The study group included 189 patients, 91 girls (48.14%) and 98 boys (51.85%), with an age between three and 18 years (Table 1). The average age was 11.17 years and 28 of 189 patients (14.81%) were five years old and under the age of five years (with the GDD diagnosis), the others 161 patients (85.19%) were older (with ID diagnosis). Pathogenic findings (including pathogenic CNVs and uniparental disomy - UPD) and variants of unknown significance (VOUS) were detected in 53 of 189 patients (28.04%). Pathogenic CNVs and UPD were observed in 35 of 189 patients (18.51%). Clinical characteristics are described in Table 1.

Table 1 Clinical characteristics in patients with GDD/ID
Full size table

The pathogenic CNVs detected in our patients are described in Table 2. Two patients presented UPD for chromosome 15, one with clinical phenotype of Prader-Willi syndrome and the other with clinical phenotype of Angelman syndrome (patients 76 and 78). Among pathogenic CNVs, 22 patients (66.7%) presented deletions and 11 patients (33.3%) had duplications.

Table 2 Pathogenic CNVs observed in our GDD/ID patients
Full size table

Recurrent pathogenic CNVs were observed in 21 of 35 patients (60%) with pathogenic findings, thus: 15q11.2-q31.1 deletion (two patients), 4p16 deletion (two patients), 22q11.21 deletion (two patients), 22q11.21 duplication (one patient), 16p11.2 proximal deletion (two patients), 16p11.2 proximal duplication (one patient), 18p11 duplications (two patients), 18p11 deletion (one patient), 7p11.23 deletion (one patient), 5q35 deletion (one patient),1q21 deletion (two patient), 1p36 deletion (one patient), 17p11.2 duplication (one patient), 17q21.31 deletion (one patient), Xp22.31 deletion (one patient) (Table 2). The clinical phenotype was suggestive for the etiological diagnosis in four of 189 patients (2.11%) and confirmed by SNP array analysis, thus: Wolf-Hirschhorn syndrome (4p16 deletion), Williams syndrome (7p11.23 deletion), Sotos syndrome (5q35 deletion) and Prader-Willi syndrome (15q11.2-q31.1 deletion). For most patients, the clinical phenotype was not suggestive for a particular etiology.

The patients observed with VOUS in our study group are described in Table 3.

Table 3 VOUS observed in our GDD/ID patients
Full size table

Discussions

In this study group of Romanian patients with GDD/ID we identified pathogenic CNVs, UPD or VOUS in 28% of patients. Pathogenic CNVs and UPD were seen in 18.5% of patients. The recurrent pathogenic CNVs were seen in 60% of patients with pathogenic findings (CNVs or UPD).

A similar percentage of pathogenic findings analyzing patients with GDD/ID was also seen in other studies [18,19,20,21,22,23,24,25], supporting the important diagnosis yield given by this analysis, indicated as first-tier test in GDD/ID [10]. A genomic approach for the patients with an unspecific phenotype such as isolated or syndromic GDD/ID is useful, in our research, the clinical etiological diagnosis was indicated in only 2% of cases, similar with other study [9].

Recurrent CNVs were identified in 60% of pathologic findings, the same percentage being observed by other study [26], these CNVs having in some cases a potential recognizable phenotype, even if quite variable in some patients, compared to the classical clinical picture. This could be an argument to continue giving an importance to the phenotype evaluation, which could bring a diagnosis in some patients, that can be confirmed more easily and less expensive by MLPA technique. The same recurrent CNVs seen in our study, described above, were also noted by other studies [26, 27]. Chromosome 18 was often involved in pathogenic CNVs, four patients presenting large deletion/duplication: 18q21.2-q23 duplication, 18p11.32-p11.21 duplication and 18p11.32-p11.21 deletion.

Some patients presented some very rare and particular CNVs, which will be described below. The patient 3, a 12-year-old boy with isolated GDD/ID, presented as a particularity a pathogenic 22q11.1-q11.21 duplication of 1.5 Mb (cat eye syndrome) associated to a pathogenic Xq27.1-q27.3 duplication of 7.4 Mb duplication, the last one including more OMIM genes, SOX3 being a known morbid OMIM gene, coding for a transcription factor implicated in neurodevelopment, which is associated with X-linked intellectual disability and panhypopituitarism or growth hormone deficiency. These features were described for other patients in literature, our patient presenting isolated GDD/ID without endocrine or other features [28,29,30,31]. The patient 5, a 18-year-old girl with GDD/ID and dysmorphic signs, presented 29.4 Mb duplication of 1q41-1q44 region, which included 43 morbid OMIM genes (including ZBTB18), a similar CNV being described in other patients, most of them also presenting short stature or associated internal malformations [32,33,34,35], features not observed in our patient.

In patient 6, a 11-year-old boy with GDD/ID, epilepsy, autism spectrum disorder (ASD) and obesity was detected a 16p13.2-16p13.13 duplication (3.8 Mb), including GRIN2A gene -known to be associated with epilepsy and GDD/ID- and also 16p13.2 region -known to be associated with 16p13.2 duplication syndrome - USP7 gene usually involving ASD and GDD/ID- these features were also described in our patients [27]. The pathogenic CNVs described in patient 45 – a 3-year-old girl with GDD/ID, short stature and dysmorphic features - is a 14q32.2 deletion (1.3 Mb), which included genes involved in ID, as YY1 gene, responsible of Gabriela de Vries syndrome [36], overlapping CNVs were described in Decipher patients (260,834, 291,402), with similar phenotypes as our patient, the cases with this CNV are very rare. 6q15-q21 deletion of 20.3 Mb seen in patient 71 is another rare CNV already noted in association with GDD/ID [37,38,39], including an important number of OMIM genes involved in neurodevelopment. In patient 153, presenting with GDD/ID and dysmorphic features, was observed the 7p15.3-p21.1 deletion (4.7 Mb), also described in association with ID [40], for this patient it is interesting that TWIST1 gene, associated with Saetre-Chotzen syndrome, is also included in this deletion, being responsible for dysmorphic features presented in our patient. The deletion in 4q22.2-q24 region in patient 166, who presents GDD/ID, dysmorphic features and language delay is also a very rare CNVs, it was described in patients with similar features [41, 42].

Conclusion

The pathogenic findings, as pathogenic CNVs or UPD, were observed in 18.5% patients, thus supporting the use of chromosomal microarray technique in patients with a non-specific phenotype such as GDD/ID. Recurrent CNVs were observed in 60% patients of those with pathogenic findings, as: 15q11.2-q31.1 deletion, 4p16 deletion, 22q11.21 deletion, 22q11.2 duplication, 16p11.2 deletion, 16p11.2 duplication, 18p11 duplications, 18p11 deletion, 7p11.23 deletion, 5q35 deletion,1q21 deletion, 1p36 deletion, 17p11.2 duplication, 17q21.31 deletion, Xp22.31 deletion.

Availability of data and materials

Relevant data generated or analyzed during this study are included in this published article. The other datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

GDD:

Global developmental delay

SD:

Standard deviation

ID:

Intellectual disability

CMA:

Chromosomal microarray analysis

FISH:

Fluorescent in situ hybridization

MLPA:

Multiplex ligation-dependent probe amplification

qPCR:

Quantitative polymerase chain reaction

CNVs:

Copy number variants

SNVs:

Single nucleotide variants

Indels:

Insertion and/or deletion of nucleotides into genomic DNA (deoxyribonucleic acid), less than 1 kb in lenght

CNS:

Central nervous system

SNP array:

Single nucleotide polymorphism array

WISC-IV:

Wechsler Intelligence Scale for Children

NEPSY:

Developmental NEuroPSYchological Assessment

EEG:

Electroencephalogram

DNA:

Deoxyribonucleic acid

UPD:

Uniparental disomy

VOUS:

Variant of unknown significance

Del:

Deletion

Dup:

Duplication

Chr:

Chromosome

Kb:

Kilobase

ASD:

Autism spectrum disorder

Mb:

Megabase

References

  1. Zablotsky B, Black LI, Maenner MJ, Schieve LA, Danielson ML, Bitsko RH, et al. Prevalence and trends of developmental disabilities among children in the United States: 2009-2017. Pediatrics. 2019;144(4):e20190811.

    Article  Google Scholar 

  2. Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the quality standards Subcommittee of the American Academy of neurology and the practice Committee of the Child Neurology Society. Neurology. 2003;60(3):367–80.

    Article  CAS  Google Scholar 

  3. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil. 2011;32(2):419–36.

    Article  Google Scholar 

  4. American Psychiatric Association. Neurodevelopmental disorders. In: Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) 5th ed. text rev. Washington, DC; Edited by: American Psychiatric Association; 2022.

  5. Jimenez-Gomez A, Standridge SM. A refined approach to evaluating global developmental delay for the international medical community. Pediatr Neurol. 2014;51(2):198–206.

    Article  Google Scholar 

  6. Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380(9854):1674–82.

    Article  CAS  Google Scholar 

  7. Belkady B, Elkhattabi L, Elkarhat Z, Zarouf L, Razoki L, Aboulfaraj J, et al. Chromosomal abnormalities in patients with intellectual disability: a 21-year retrospective study. Hum Hered. 2018;83(5):274–82.

    Article  CAS  Google Scholar 

  8. Rauch A, Hoyer J, Guth S, Zweier C, Kraus C, Becker C, et al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet Part A. 2006;140A(19):2063–74.

    Article  Google Scholar 

  9. Miclea D, Szucs A, Mirea A, Stefan DM, Nazarie F, Bucerzan S, et al. Diagnostic usefulness of MLPA techniques for recurrent copy number variants detection in global developmental delay/intellectual disability. Int J Gen Med. 2021;14:4511.

    Article  Google Scholar 

  10. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–64.

    Article  CAS  Google Scholar 

  11. Moeschler JB, Shevell M, Saul RA, Chen E, Freedenberg DL, Hamid R, et al. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014;134(3):e903–18.

    Article  Google Scholar 

  12. Lee JS, Hwang H, Kim SY, Kim KJ, Choi JS, Woo MJ, et al. Chromosomal microarray with clinical diagnostic utility in children with developmental delay or intellectual disability. Ann Lab Med. 2018;38(5):473–80.

    Article  Google Scholar 

  13. Pereira RR, Pinto IP, Minasi LB, De Melo AV, Da Cruz E, Cunha DM, et al. Screening for intellectual disability using high-resolution CMA Technology in a Retrospective Cohort from Central Brazil. Plos one. 2014;9(7):e103117.

    Article  Google Scholar 

  14. Gieldon L, Mackenroth L, Kahlert AK, Lemke JR, Porrmann J, Schallner J, et al. Diagnostic value of partial exome sequencing in developmental disorders. Plos one. 2018;13(8):e0201041.

    Article  Google Scholar 

  15. Fitzgerald TW, Gerety SS, Jones WD, Van Kogelenberg M, King DA, McRae J, et al. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519(7542):223.

    Article  CAS  Google Scholar 

  16. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. Working Group of the American College of medical genetics laboratory quality assurance committee. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med Off J Am Coll Med Genet. 2011;13(7):680–5.

    Google Scholar 

  17. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the clinical genome resource (ClinGen). Genet Med. 2020;22(2):245–57.

    Article  Google Scholar 

  18. Di Gregorio E, Riberi E, Belligni EF, Biamino E, Spielmann M, Ala U, et al. Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes. Clin Genet. 2017;92(4):415–22.

    Article  Google Scholar 

  19. Kessi M, Xiong J, Wu L, Yang L, He F, Chen C, et al. Rare copy number variations and predictors in children with intellectual disability and epilepsy. Front Neurol. 2018;9:947.

    Article  Google Scholar 

  20. Chaves TF, Baretto N, Freitas de Oliveira L, Ocampos M, Tremel Barbato I, Anselmi M, et al. Copy number variations in a cohort of 420 individuals with neurodevelopmental disorders from the South of Brazil. Sci Rep. 2019;9(1):17776.

    Article  Google Scholar 

  21. Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, Van Kogelenberg M, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2015;385(9975):1305–14.

    Article  Google Scholar 

  22. Fan Y, Wu Y, Wang L, Wang Y, Gong Z, Qiu W, et al. Chromosomal microarray analysis in developmental delay and intellectual disability with comorbid conditions. BMC Med Genet. 2018;11(1):49.

    Google Scholar 

  23. Yang EH, Shin YB, Choi SH, Yoo HW, Kim HY, Kwak MJ, et al. Chromosomal microarray in children with developmental delay: the experience of a tertiary Center in Korea. Front Pediatr. 2021;9:944.

    Article  Google Scholar 

  24. Ceylan AC, Citli S, Erdem HB, Sahin I, Acar Arslan E, Erdogan M. Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders. Mol Cytogenet. 2018;11(1):1–9.

    Article  Google Scholar 

  25. Wang R, Lei T, Fu F, Li R, Jing X, Yang X, et al. Application of chromosome microarray analysis in patients with unexplained developmental delay/intellectual disability in South China. Pediatr Neonatol. 2019;60(1):35–42.

    Article  Google Scholar 

  26. Wayhelova M, Smetana J, Vallova V, Hladilkova E, Filkova H, Hanakova M, et al. The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay. BMC Med Genet. 2019;12(1):111.

    Google Scholar 

  27. Tiaki Uehara D, Hayashi S, Okamoto N, Mizuno S, Chinen Y, Kosaki R, et al. SNP array screening of cryptic genomic imbalances in 450 Japanese subjects with intellectual disability and multiple congenital anomalies previously negative for large rearrangements. J Hum Genet. 2016;61(4):335–43.

    Article  Google Scholar 

  28. Nambisan AKR, Kapoor R, Ajzensztejn M, Hulse T, Buchanan CR. SOX3 gene duplication (OMIM 313430) associated with midline CNS malformations, hypopituitarism and neurodevelopmental abnormalities: 3 unrelated cases. Endocr Abstr. 2017;50:PL1.

  29. Stagi S, Lapi E, Pantaleo M, Traficante G, Giglio S, Seminara S, et al. A SOX3 (Xq26.3-27.3) duplication in a boy with growth hormone deficiency, ocular dyspraxia, and intellectual disability: a long-term follow-up and literature review. Hormones. 2014;13(4):552–60.

    Google Scholar 

  30. Tasic V, Mitrotti A, Riepe FG, Kulle AE, Laban N, Polenakovic M, et al. Duplication of the SOX3 gene in an sry-negative 46,XX male with associated congenital anomalies of kidneys and the urinary tract: Case report and review of the literature. Balk J Med Genet. 2019;22(1):81–8.

    Article  CAS  Google Scholar 

  31. Hureaux M, Ben Miled S, Chatron N, Coussement A, Bessières B, Egloff M, et al. SOX3 duplication: a genetic cause to investigate in fetuses with neural tube defects. Prenat Diagn. 2019;39(11):1026–34.

    Article  CAS  Google Scholar 

  32. Watanabe S, Shimizu K, Ohashi H, Kosaki R, Okamoto N, Shimojima K, et al. Detailed analysis of 26 cases of 1q partial duplication/triplication syndrome. Am J Med Genet A. 2016;170(4):908–17.

    Article  CAS  Google Scholar 

  33. Morris MLM, Baroneza JE, Teixeira P, Medina CTN, Cordoba MS, Versiani BR, et al. Partial 1q duplications and associated phenotype. Mol Syndromol. 2016;6(6):297–303.

    Article  Google Scholar 

  34. Davis KA, Chernos J, Thomas MA. MG-130 pure duplication of 1q42.11-q44(QTER): further clinical delineation of a rare terminal duplication syndrome. J Med Genet. 2015;52:A8.

    Article  Google Scholar 

  35. Coccé MC, Villa O, Obregon MG, Salido M, Barreiro C, Solé F, et al. Duplication dup(1)(q41q44) defined by fluorescence in situ hybridization: delineation of the ‘trisomy 1q42→qter syndrome’. Cytogenet Genome Res. 2007;118(1):84–6.

    Article  Google Scholar 

  36. Gabriele M, Vulto-van Silfhout AT, Germain PL, Vitriolo A, Kumar R, Douglas E, et al. YY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunction. Am J Hum Genet. 2017;907-925:2017.

    Google Scholar 

  37. Klein OD, Cotter PD, Moore MW, Zanko A, Gilats M, Epstein CJ, et al. Interstitial deletions of chromosome 6q: genotype–phenotype correlation utilizing array CGH. Clin Genet. 2007;71(3):260–6.

    Article  CAS  Google Scholar 

  38. Gilhuis HJ, Van Ravenswaaij CMA, Hamel BJC, Gabreëls FJM. Interstitial 6q deletion with a Prader-Willi-like phenotype: a new case and review of the literature. Eur J Paediatr Neurol. 2000;4(1):39–43.

    Article  CAS  Google Scholar 

  39. Turleau C, Demay G, Cabanis M-O, Lenoir G, de Grouchy J. 6q1 monosomy: a distinctive syndrome. Clin Genet. 1988;34(1):38–42.

    Article  CAS  Google Scholar 

  40. Fryssira H, Makrythanasis P, Kattamis A, Stokidis K, Menten B, Kosaki K, et al. Severe developmental delay in a patient with 7p21.1-p14.3 microdeletion spanning the TWIST gene and the HOXA gene cluster. Mol Syndromol. 2011;2(1):45–9.

    Article  CAS  Google Scholar 

  41. Hilhorst-Hofstee Y, Tümer Z, Born P, Knijnenburg J, Hansson K, Yatawara V, et al. Molecular characterization of two patients with de novo interstitial deletions in 4q22-q24. Am J Med Genet A. 2009;149A(8):1830–3.

    Article  CAS  Google Scholar 

  42. Strehle E-M, Yu L, Rosenfeld JA, Donkervoort S, Zhou Y, Chen T-J, et al. Genotype-phenotype analysis of 4q deletion syndrome: proposal of a critical region. Am J Med Genet A. 2012;158A(9):2139–51.

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Molecular Sciences, “Iuliu Hatieganu” University of Medicine and Pharmacy, Pasteur Street, No 6, 400349, Cluj-Napoca, Romania

    Diana Miclea, Sergiu Osan, Delia Stefan & Radu Popp

  2. Emergency Clinical Hospital for Children, Pasteur Street, No 6, 400349, Cluj-Napoca, Romania

    Diana Miclea, Simona Bucerzan, Monica Mager & Camelia Alkhzouz

  3. Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Simona Bucerzan & Camelia Alkhzouz

  4. Department of Neuroscience, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Monica Mager

  5. “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania

    Maria Puiu & Adela Chirita-Emandi

  6. Polytechnic University, Timisoara, Romania

    Cristian Zimbru

Authors
  1. Diana Miclea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sergiu Osan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simona Bucerzan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Delia Stefan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Radu Popp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Monica Mager
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria Puiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cristian Zimbru
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Adela Chirita-Emandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Camelia Alkhzouz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DM (conceptualization, methodology, validation, investigation, manuscript writing, manuscript supervising), SO (methodology, validation, investigation, manuscript writing), SB (methodology, investigation), DS (methodology, investigation), RP (methodology, investigation), MM (methodology, investigation), MP (methodology, investigation), CZ (methodology, investigation), ACE (methodology, investigation), CA (methodology, validation, investigation, manuscript supervising). All authors read and approved the final manuscript.

Corresponding author

Correspondence to Diana Miclea.

Ethics declarations

Ethics approval and consent to participate

All methods and genetic testing were carried out in accordance with the ethical standards on human experimentation, of the hospital committee and with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. The research was approved by Ethic Committee of Clinical Emergency Hospital for Children, Cluj-Napoca. Written informed consent was obtained from the legal guardians of all the participants in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miclea, D., Osan, S., Bucerzan, S. et al. Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability. Ital J Pediatr 48, 207 (2022). https://doi.org/10.1186/s13052-022-01397-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13052-022-01397-1

Keywords

Italian Journal of Pediatrics

ISSN: 1824-7288

Contact us