Research Article
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Copy Number Variations in a Turkish Cohort of Children with Intellectual Disability

Year 2023, Volume: 13 Issue: 3, 263 - 275, 28.12.2023
https://doi.org/10.26650/experimed.1380210

Abstract

Objective: Intellectual disability (ID) is a complex, variable, and clinically heterogeneous neurodevelopmental disorder that affects 1% – 3% of the global population. Copy number variations (CNVs) contribute to approximately 15%–20% of ID cases. Array comparative genomic hybridization (aCGH) is the first-line test for diagnosing patients with ID with/without multiple congenital anomalies (MCAs). This study aimed to present CNVs identified in a retrospective aCGH cohort of Turkish patients with ID with/without other medical conditions.
Materials and Methods: The study population consisted of 210 patients (139 male, 71 female) aged 2–18 years. aCGH analysis was performed using oligo and bacterial artificial chromosome (BAC)-based microarray platforms. CNVs were interpreted using public databases and literature mining and categorized according to international guidelines.
Results: Forty-five CNVs were detected in 38 (18%) patients. Among these CNVs, 21 (46.6%) were pathogenic, 4 (8.8%) were likely pathogenic, and 8 (17.7%) were variants of uncertain clinical significance (VUS). Nineteen CNVs corresponded to rare microdeletion/ microduplication syndromes.
Conclusions: This study reports rare CNVs or syndromes among Turkish patients with ID with/without other medical conditions. Data revealed an overall diagnostic rate of 11.43%, which confirms aCGH as the first-line technology allowing geneticists to diagnose complex phenotypes, identify candidate genes involved in ID, and explore novel CNV effects.

Ethical Statement

Ethics Committee Approval: Ethical approval of the study was obtained from the Human Subjects Research Ethical Committee of the Kocaeli University (2009/102).

Supporting Institution

The authors declare that this study has received no financial support.

References

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  • 21. Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, Poddighe P, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet 2009; 52: 161-9. google scholar
Year 2023, Volume: 13 Issue: 3, 263 - 275, 28.12.2023
https://doi.org/10.26650/experimed.1380210

Abstract

References

  • 1. Pereira RR, Pinto IP, Minasi LB, de Melo AV, da Cruz e Cunha DM, Cruz AS, et al. Screening for intellectual disability using high-resolution CMA technology in a retrospective cohort from Central Brazil. PLoS One 2014; 9: e103117. google scholar
  • 2. Quintela I, Eirfs J, Gömez-Lado C, Perez-Gay L, Dacruz D, Cruz R, et al. Copy number variation analysis of patients with intellectual disability from North-West Spain. Gene 2017; 626: 189-99. google scholar
  • 3. Vianna GS, Medeiros PF, Alves AF, Silva TO, Jehee FS. Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil. Genet Mol Res 2016; 15. google scholar
  • 4. Wolfe K, Strydom A, Morrogh D, Carter J, Cutajar P, Eyeoyibo M, et al. Chromosomal microarray testing in adults with intellectual disability presenting with comorbid psychiatric disorders. Eur J Hum Genet 2016; 25: 66-72. google scholar
  • 5. 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: 415-22. google scholar
  • 6. Lee CL, Lee CH, Chuang CK, Chiu HC, Chen YJ, Chou CL, et al. Array-CGH increased the diagnostic rate of developmental delay or intellectual disability in Taiwan. Pediatr Neonatol 2019; 60: 453-60. google scholar
  • 7. Moorhead PS, Nowell PC, Mellman WJ, Battıps DM, Hungerford DA. Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Cell Res 1960; 20: 613-6. google scholar
  • 8. 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 2011; 13: 680-5. google scholar
  • 9. 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: 245-57. google scholar
  • 10. Türkyılmaz A, Geckinli BB, Tekin E, Ates EA, Yarali O, Cebi AH, et al. Array-based comparative genomic hybridization analysis in children with developmental delay/intellectual disability. Balkan J Med Genet 2022; 24: 15-24. google scholar
  • 11. Chen CP, Wang LK, Chern SR, Wu PS, Chen SW, Wu FT, et al. Prenatal diagnosis and molecular cytogenetic characterization of mosaic ring chromosome 21 associated with low PAPP-A and low PlGF in the first-trimester maternal serum screening. Taiwan J Obstet Gynecol 2022; 61: 359-63. google scholar
  • 12. Conti V, Carabalona A, Pallesi-Pocachard E, Parrini E, Leventer RJ, Buhler E, et al. Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene. Brain 2013; 136: 3378-94. google scholar
  • 13. Jang W, Chae H, Kim J, Son JO, Kim SC, Koo BK, et al. Identification of small marker chromosomes using microarray comparative genomic hybridization and multicolor fluorescent in situ hybridization. Mol Cytogenet 2016; 9: 61. google scholar
  • 14. Sifakis S, Eleftheriades M, Kappou D, Murru R, Konstantinidou A, Orru S, et al. Prenatal diagnosis of proximal partial trisomy 1q confirmed by comparative genomic hybridization array: molecular cytogenetic analysis, fetal pathology and review of the literature. Birth Defects Res A Clin Mol Teratol 2014; 100: 284-93. google scholar
  • 15. Quintela I, Barros F, Fernandez-Prieto M, Martinez-Regueiro R, Castro-Gago M, Carracedo A, et al. Interstitial microdeletions including the chromosome band 4q13.2 and the UBA6 gene as possible causes of intellectual disability and behavior disorder. Am J Med Genet A 2015; 167A: 3113-20. google scholar
  • 16. Kirchhoff M, Bisgaard AM, Stoeva R, Dimitrov B, Gillessen-Kaesbach G, Fryns JP, et al. Phenotype and 244k array-CGH characterization of chromosome 13q deletions: an update of the phenotypic map of 13q21.1-qter. Am J Med Genet A 2009; 149A: 894-905. google scholar
  • 17. Lennon PA, Boerkoel CF, Plunkett K, Soukam S, Cheung SW, Patel A. A novel 8.5 MB dup(1)(p34.1p34.3) characterized by FISH in a child presenting with congenital heart defect and dysmorphic features. Am J Med Genet A 2006; 140A: 1864-70. google scholar
  • 18. Jacher JE, Innis JW. Interstitial microdeletion of the 1p34.3p34.2 region. Mol Genet Genomic Med 2018; 6: 673-7. google scholar
  • 19. Rosenfeld JA, Patel A. Chromosomal microarrays: understanding genetics of neurodevelopmental disorders and congenital anomalies. J Pediatr Genet. 2017; 6: 42-50. google scholar
  • 20. 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: 749-64. google scholar
  • 21. Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, Poddighe P, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet 2009; 52: 161-9. google scholar
There are 21 citations in total.

Details

Primary Language English
Subjects Clinical Sciences (Other)
Journal Section Research Article
Authors

Deniz Sünnetçi Akkoyunlu 0000-0001-9297-8222

Bülent Kara 0000-0003-3780-6596

Naci Çine 0000-0001-9063-1073

Seda Eren Keskin 0000-0002-8315-646X

Buket Doğruoğlu 0000-0002-1138-7680

Zeynep İlkay 0000-0001-7256-6992

Tolgahan Özer 0000-0001-5427-3811

Hakan Savlı 0000-0003-2836-9881

Publication Date December 28, 2023
Submission Date October 24, 2023
Acceptance Date November 27, 2023
Published in Issue Year 2023 Volume: 13 Issue: 3

Cite

Vancouver Sünnetçi Akkoyunlu D, Kara B, Çine N, Eren Keskin S, Doğruoğlu B, İlkay Z, Özer T, Savlı H. Copy Number Variations in a Turkish Cohort of Children with Intellectual Disability. Experimed. 2023;13(3):263-75.