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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RESULTS

In the investigated group, pathogenic CNVs were found in 31 patients. In addition, in the majority of all surveyed individuals, we identified benign CNVs (58/81 patients) and variations of unknown clinical significance (66/81 patients). There were 280 CNVs detected, of which 41 were pathogenic (28 deletions, 13 duplications), 118 benign (91 deletions, 27 duplications) and 121 of unknown clinical significance (50 deletions, 71 duplications). Copy number variations have not been established in six of the patients. The size of all identified CNVs was from 100,021 to 13,881,527 bp. There were 169 deletions and 111 duplications. The largest duplication covered 13,881,527 bp, and the smallest included 100,021 bp. The region of the smallest deletion covered 102,202 bp, and the size of the largest in four (q34.3q35.2) region: arr 4q34.3q35.2 (178,213,959-190,896,645) ×1, was 12,682,687 bp. We revealed eight pathogenic variations associated with the phenotype in six patients from the total group. Variations were distributed over eight chromosomes (chromosomes 2, 4, 5, 10, 12, 15, 17, 22). In two of the analyzed patients, a combination of two pathogenic CNVs on different chromosomes was found, and four of the patients had a single pathogenic variation. Six of the aberrations were deletions and two of them were duplications. The amount of detected genomic pathogenic changes ranges from 300 kb to 13 Mb. In five patients of the total group, we discovered five pathogenic CNVs that were not associated with the observed phenotype (Table 1). As well as pathogenic variations, benign CNVs and CNVs of unknown clinical significance were found. There were 239 (an average of 2.9 per patient variations of the total group). These CNVs were distributed over 75 patients. All established benign and unknown CNVs ranged in size from 106,847 to 1,348,283 bp. From the total number of identified CNVs (239 without pathogenic CNVs), 179 (74.9%) covered 100-500 Kb, 52 (21.8%), from 500 Kb to 1 Mb and eight (3.3%) were larger than 1 Mb. There were 141 deletions and 98 duplications. One hundred and eighteen of the CNVs were benign. They were divided by size as follows: 90 (76.3%) covered 100-500 Kb; 21 (17.8%) were from 500 Kb to 1 Mb; seven (5.9%) were larger than 1 Mb. There were 27 duplications and 91 deletions (Table 2). The CNVs of unknown clinical significance numbered 121 and were of the following size: 89 (73.5%) from 100 to 500 Kb; 31 (25.6%) were from 500 Kb to 1 Mb; one (0.8%) was a size larger than 1 Mb. Copy number variations (excluding the pathogenic ones) were present in 74 patients. In 70 persons, the size of CNVs ranged from 100 to 500 Kb; in 39 CNVs were from 500 Kb to 1 Mb, and in seven larger than 1 Mb. In the majority of the cases, a combination of benign CNVs and CNVs of unknown clinical significance was defined. It is noteworthy that in our sample, CNVs ranging in size between 100 and 500 kb were of greater frequency.

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