Balkan Journal of Medical Genetics

BENIGN, PATHOGENIC AND COPY NUMBER VARIATIONS OF UNKNOWN CLINICAL SIGNIFICANCE IN PATIENTS WITH CONGENITAL MALFORMATIONS AND DEVELOPMENTAL DELAY
Mihaylova M1,*, Staneva R1,2, Toncheva D1, Pancheva M1,2, Hadjidekova S1,2
*Corresponding Author: Dr. Marta Mihaylova, Department of Medical Genetics, Medical Faculty, Medical University of Sofia, 2 Zdrave Street, 1431 Sofia, Bulgaria. Tel: +3592-9172-735. E-mail: marta.mih@gmail.com
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INTRODUCTION

A high percentage of genetic diseases manifest themselves in the first 28 days after birth, but the full clinical symptoms may not be evident in newborns. Conventional diagnostic tests are with low resolution. They are also time-consuming, labor-intensive and are difficult to automate, therefore, the etiology of congenital anomalies (CAs) in 40.0-60.0% of the cases remains unclear. Molecular and molecular cytogenetic techniques such as FISH (fluorescent in situ hybridization), QF-PCR (quantitative fluorescence-polymerase chain reaction), MLPA (multiplex ligation-dependent probe amplification), have enhanced the diagnosis, but they require preliminary information on the suspected chromosomal abnormality and on the location. The new genomic technologies such as micro- array comparative genomic hybridization (aCGH) and nextgeneration sequencing (NGS), combine the advantages of conventional technologies, enabling whole-genome screening in high resolution. At present, great interest has arisen in a newly discovered variation known as copy number variations (CNVs), which, in 2007, was indicated to be the “breakthrough” of the year [1]. Currently, CNVs are defined as a ubiquitous segment of DNA longer than 1 kb, presented at a variable copy number, compared to the reference genome. The great interest in CNVs was aroused by the observation that they can affect transcriptional activity and translational levels of adjacent genes [2-8]. An association was found between certain CNVs and predisposition to multifactorial diseases [3,9-15]. Copy number variations differ in type and frequency in different populations and can be used as a valuable source of information for the study of genetic characteristics of the nations [16-20]. With the accumulation of huge amounts of data for different CNVs, certain phenotype-genotype correlations have been defined [21]. It is therefore possible for CNVs that have been initially considered benign to later be proved as increasing sensitivity to multifactorial disease or causing genetic disease with late onset or incomplete penetrance. Therefore, the term CNVs is generally used to describe the CNVs both in patients and in healthy controls, as well as to describe the genomic imbalances, causing known microdeletion/ micro-duplication syndromes. Consequently, CNVs can be divided into benign, pathogenic and CNVs of unknown clinical significance [22-25] and can be polymorphic with frequency greater than 1.0% or rare, less than 1.0%. They can also arise as de novo anomalies or be inherited, multiallelic or biallelic [26]. According to the data from two large studies in healthy populations, the human genome contains 12 CNVs on average [27,28]. Another study revealed that 12.0% of the human genome is represented by CNVs covering hundreds of genes, disease loci, functional elements and segmental duplications [29]. Sequencing of the human genome revealed that insertions and deletions in absolute terms are responsible for 22.0% of the variations and cover 74.0% of the affected nucleotides [30]. Recent data indicate that the genomes of two individuals may vary between 1.0 and 3.0% [31]. Caramaschi et al. [32] carried out a survey of 116 patients. The detected CNVs were analyzed for genotype/ phenotype correlations with the clinical features of the patients. Pathogenic CNVs (21 deletions, three duplications and three cases with both of them) were observed in 27 patients (23.3%). The analysis showed a significant association between pathogenic CNVs and the first appearance of the symptoms before the age of 1 year and the presence of malformations [32]. According to another study on CNVs in 2500 individuals, it was found that in 65.0 to 80.0% of the cases, CNVs were greater than 100 kb, in 5.0-10.0% greater than 500 kb, and in 1.0-2.0% greater than 1 Mb [19]. In addition, the biggest part of the genomic variations were found with a frequency of 0.02 to 1.0%, comprising 6.0% of our genome. At the same time, polymorphic CNVs represented 0.09%. Another study conducted by Pinto et al. [20] on a healthy population detected that 160 Mb (~5.0%) was represented by CNVs, from which 96.0% were rare, less than 2.0%, while others were common. In this study, we present our findings with regard to the distribution, frequency and clinical significance of the detected CNVs. MATERIALS AND METHODS The present study focuses on 81 patients of both sexes with dysmorphic features, with or without intellectual disability, behavioral problems, failure to thrive, neurological disorders. All of them presented a normal karyotype. The blood was taken in compliance with the standard procedures for good laboratory practice. The genomic screening, arraybased comparative genomic hybridization (aCGH) was performed by standard protocol using the CytoChip ISCA oligo microarray, 4 × 44 k (BlueGnome Ltd., Cambridge, Cambridgeshire, UK), resolution 70 kb. Data were analyzed with the BluefuseMulti v.4.2 software (BlueGnome Ltd.).

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