Nörogelişimsel Bozukluğu Olan Bireylerde Kopya Sayısı Değişikliği Bulguları

Abstract

Amaç: Kromozomal mikrodizin analizi (CMA), nedeni açıklanamayan nörogelişimsel bozukluklarda (NDDs) birinci basamak genetik testlerden biridir. Bu çalışmada, nörogelişimsel fenotipler nedeniyle CMA istenen Türk bireylerde yöntemin tanısal katkısının değerlendirilmesi amaçlandı. Materyal ve metod: Bu retrospektif iki merkezli çalışmaya, Ocak 2023-Ocak 2026 tarihleri arasında gelişimsel gecikme, entelektüel yetersizlik, otizm spektrum bozukluğu, dikkat eksikliği/hiperaktivite bozukluğu ve eşlik eden konjenital anomaliler nedeniyle CMA yapılan 517 birey dahil edildi. Kopya sayısı değişiklikleri (CNV), ACMG/ClinGen kriterlerine göre sınıflandırıldı.
Bulgular: Kohort 289 erkek ve 228 kadın bireyden oluşmaktaydı. Raporlanabilir CNV’ler, 111 bireyde (yaklaşık %21,5) saptandı. Toplamda 74 CNV patojenik, 10 CNV muhtemel patojenik ve 49 CNV klinik anlamı belirsiz varyant olarak sınıflandırıldı. En az bir patojenik veya muhtemel patojenik CNV, 67 bireyde saptandı ve tanısal verim yaklaşık %13 olarak hesaplandı. Delesyonlar, tüm CNV’ler arasında duplikasyonlardan daha sıktı. On dokuz bireyde birden fazla CNV saptandı.
Sonuç: CMA, yönlendirilen yaklaşık her sekiz bireyden birinde klinik açıdan anlamlı moleküler tanı sağlamıştır. Bulgularımız, CMA’nın NDDs'nin rutin tanısal değerlendirmesinde kullanılmasını desteklemektedir; ancak yorumlama fenotip, gen içeriği, kalıtım durumu ve gerektiğinde tamamlayıcı sitogenetik veya sekanslama verileri ile birlikte yapılmalıdır.

Keywords

• Kromozomal mikrodizin analizi
• Kopya sayısı değişikliği
• Nörogelişimsel bozukluklar
• Entelektüel yetersizlik
• Otizm spektrum bozukluğu

Ethical Statement

The study was approved by the Ordu University Ethics Committee for Non-Interventional Scientific Research (approval no: 2026/184, date: July 3, 2026).

Copy Number Variant Findings in Individuals with Neurodevelopmental Disorders

Abstract

Background: Chromosomal microarray analysis (CMA) is widely used as a first-tier test in individuals with unexplained neurodevelopmental disorders (NDDs). This study aimed to evaluate the diagnostic contribution of CMA in a Turkish cohort referred for the evaluation of neurodevelopmental phenotypes.
Materials and Methods: This retrospective, two-center study included 517 individuals referred for CMA between January 2023 and January 2026 because of developmental delay, intellectual disability, autism spectrum disorder or attention-deficit/hyperactivity disorder, with or without congenital anomalies. Copy-number variants (CNVs) were classified according to ACMG/ClinGen criteria.
Results: The cohort included 289 males and 228 females. Reportable CNVs were identified in 111 individuals (21.5%). Overall, 74 CNVs were classified as pathogenic, 10 as likely pathogenic, and 49 as variants of uncertain significance. At least one pathogenic or likely pathogenic CNV was detected in 67 individuals, corresponding to a diagnostic yield of 13%. Deletions were more frequent than duplications among identified CNVs. Multiple CNVs were observed in 19 individuals.
Conclusions: CMA yielded a clinically relevant molecular diagnosis in approximately one in eight referred individuals. These findings support the continued use of CMA in the routine diagnostic evaluation of NDDs, particularly when interpreted together with phenotype, gene content, inheritance, and complementary cytogenetic or sequencing-based data.

Keywords

• Chromosomal microarray analysis
• Copy number variation
• Neurodevelopmental disorders
• Intellectual disability
• Autism spectrum disorder

Ethical Statement

The study was approved by the Ordu University Ethics Committee for Non-Interventional Scientific Research (approval no: 2026/184, date: July 3, 2026).

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed, text rev. Washington, DC: American Psychiatric Association Publishing; 2022.
2. Olson L, Bishop S, Thurm A. Differential diagnosis of autism and other neurodevelopmental disorders. Pediatr Clin North Am. 2024;71(2):157-77.
3. Martinez de Lagran M, Bascon-Cardozo K, Dierssen M. Neurodevelopmental disorders: 2024 update. Free Neuropathol. 2024;5:20.
4. Gao S, Shan C, Zhang R, Wang T. Genetic advances in neurodevelopmental disorders. Med Rev (2021). 2025;5(2):139-51.
5. Bonti E, Zerva IK, Koundourou C, Sofologi M. The high rates of comorbidity among neurodevelopmental disorders: reconsidering the clinical utility of distinct diagnostic categories. J Pers Med. 2024;14(3):300.
6. Awuah WA, Shah MH, Sanker V, Mannan KM, Ranganathan S, Nkrumah-Boateng PA, et al. Advances in chromosomal microarray analysis: transforming neurology and neurosurgery. Brain Spine. 2025;5:104197.
7. 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.
8. Waggoner D, Wain KE, Dubuc AM, Conlin L, Hickey SE, Lamb AN, et al. Yield of additional genetic testing after chromosomal microarray for diagnosis of neurodevelopmental disability and congenital anomalies: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20(10):1105-13.

9. Li W, Xie X, Chai H, Chen C, Fu F, Huang H, et al. Copy number variants of uncertain significance by chromosome microarray analysis from consecutive pediatric patients: reevaluation following current guidelines and reanalysis by genome sequencing. Genes (Basel). 2025;16(8):874.
10. Sanri A, Mutlu MB, Sezer O. Diagnostic utility of chromosomal microarray analysis in a Turkish pediatric cohort: insights from 1,022 patients with neurodevelopmental disorders and congenital anomalies. Cytogenet Genome Res. 2025.
11. Gerik-Celebi HB, Aydin H, Bolat H, Unsel-Bolat G. Clinical and genetic characteristics of patients with unexplained intellectual disability/developmental delay without epilepsy. Mol Syndromol. 2023;14(3):208-18.
12. Ceylan AC, Citli S, Erdem HB, Sahin I, Arslan EA, 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;11:54.
13. Kılıçaslan F, Öz Ö, Mutlu MB. Investigation of chromosomal anomalies and copy number variations in children diagnosed with autism spectrum disorder by array CGH method. Int J Dev Neurosci. 2025;85(1):e10397.
14. Chaves TF, Ocampos M, Barbato IT, Bortoli MMC, Ribeiro EM, Li X, et al. A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD. Sci Rep. 2024;14(1):3762.
15. Ravel JM, Renaud M, Muller J, Becker A, Renard E, Remen T, et al. Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study. Genome Med. 2023;15(1):39.
16. Wen T, Rudd MK, Manning MA. Addendum: Yield of additional genetic testing after chromosomal microarray for diagnosis of neurodevelopmental disability and congenital anomalies: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025;27(3):101335.