Balkan Journal of Medical Genetics

ARRAY-BASED COMPARATIVE GENOMIC HYBRIDIZATION ANALYSIS IN CHILDREN WITH DEVELOPMENTAL DELAY/INTELLECTUAL DISABILITY
Türkyılmaz A, Geckinli BB, Tekin E, Ates EA, Yarali O, Cebi AH, Arman A
*Corresponding Author: Ayberk Türkyılmaz, M.D., Assistant Professor, Department of Medical Genetics, Karadeniz Technical University Faculty of Medicine, Farabi Street, 61080 Ortahisar, Trabzon, Turkey. Tel: +90-505-812-03-34. Fax: +90-462-377-51-06. E-mail: ayberkturkyilmaz@gmail.com
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MATERIALS AND METHODS

Patients. The study included 139 patients diagnosed with isolated or syndromic DD/ID (78 females, 62 males) at the Department of Pediatric Neurology, Giresun University, Giresun, Turkey; Department of Medical Genetics, Karadeniz Technical University, Trabzon, Turkey; Department of Medical Genetics, Erzurum City Hospital, Erzurum, Turkey and Department of Medical Genetics, Marmara University, Istanbul, Turkey. All patients were evaluated a by medical geneticist for dysmorphologic phenotyping. Patients with abnormal metabolic and thyroid function test results, brain tumor, brain infection, and signs of hypoxic ischemic encephalopathy, were excluded from the study. All cases were evaluated using prenatal history, family history, anthropometric measurements, detailed dysmorphological examination, hearing examination, eye examination and cardiac analysis (echocardiography). Electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) tests were performed in cases where it was deemed necessary. For genetic analysis, blood samples were obtained from all patients whose parents provided written informed consent. Ethics Statement. All experimental procedures were conducted in accordance with the principles of the Declaration of Helsinki, and informed written consent was obtained from patients or their guardians. This was a retrospective clinical study approved by Erzurum Research and Training Hospital Ethics Committee, Erzurum, Turkey [Approval #2020/23-219]. Genetic Analysis. All patients first underwent standard karyotyping using the G-banding technique. At least 20 metaphases were analyzed at 450-500 band resolution for each patient. Chromosomal abnormalities were reported according to the recommendations of the International System for Human Cytogenetic Nomenclature 2016 [12]. For aCGH analysis, genomic DNA was isolated from peripheral blood leukocytes using Siam® DNA Mini Kit (Qiagen GmbH, Hilden, Germany). Affymetrix CytoScan Optima 315K arrays (Thermo Fisher Scientific, Waltham, MA, USA) were used according to the manufacturer’s instructions for detecting CNVs. The aCGH results were evaluated using Chromosome Analysis Suite version 3.1.0 (Thermo Fisher Scientific). Technical specifications of the aCGH platform are available on the manufacturer’s website (https://www.thermofisher.com/tr/en/home/lifesci ence/microarray-analysis/affymetrix.html). All CNVs were called and based on human assembly GRCh37 (hg19). Chromosomal abnormalities detected by aCGH analysis were confirmed using available FISH probes in available index cases and/or parents. The detected CNVs were evaluated according to the criteria of American College of Medical Genetics (ACMG) and were divided into three categories according to their size, gene content, inheritance pattern, presence in the literature, and population databases: pathogenic, variants of uncertain clinical significance (VUS) and benign [13]. Prevalent and known micro-deletion/microduplication syndromes and CNVs reported in several publications were considered pathogenic. Copy number variations that were reported in a single case report in the literature and explained the patient’s phenotype including the genes, were considered VUS that were likely pathogenic. The CNVs that were identified in a small number of individuals in the general population and did not involve genes, were considered VUS that were likely benign. Copy number variations involving genes but having unclear dosage sensitivity status, with different opinions about its pathogenicity in the literature, were considered as VUS with no subclassification. Additionally, common polymorphisms in population databases and/or CNVs reported as benign in more than one publication, were considered benign. Pathogenicity of novel CNVs were analyzed by referring to current literature (PubMed), Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER, https:// deciher. sanger.ac.uk/), Online Mendelian Inheritance in Man (OMIM, http://omim.org/), the Database of Genomic Variants (DGV, http://dgv.tcag.ca/dgv/app/home), and Clinical Genome Resource (ClinGen, https://dosage.clinicalge nome.org/index.html).

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