Balkan Journal of Medical Genetics

DELINEATION OF PARTIAL CHROMOSOMAL ABNORMALITIES IN EARLY PREGNANCY LOSSES
Bozhinovski Gj1, Terzikj M1, Kubelka-Sabit K2,3, Plaseska-Karanfilska D1,*
*Corresponding Author: *Corresponding Author: Prof. Dijana Plaseska-Karanfilska, M.D., Ph.D. Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000, Skopje, Republic of North Macedonia. Tel: +389-2-3235-410 E-mail: dijana@manu.edu.mk
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RESULTS

General findings To investigate the genomic landscape of the previ- ously detected partial chromosomal abnormalities in EPLs with QF-PCR and subtelomeric MLPA methods, we have performed array CGH analysis on a total of 20 samples. All 30 previously detected chromosomal abnormali- ties among the 20 studied EPLs were confirmed and 2 additional chromosomal abnormalities previously not detected with QF-PCR and subtelomeric MLPA methods were revealed. These additional abnormalities were out of the ligation sites of the used subtelomeric MLPA probes, therefore they were not detected previously. Among the 20 investigated samples, the total num- ber of detected partial chromosomal abnormalities was 32, of which 18 (56% of all detected abnormalities) were deletions and 14 were duplications (44%). Nine samples had single partial chromosomal abnormality, 10 samples carried double abnormalities, while one sample carried three partial abnormalities. All the characterized abnor- malities were on distal chromosomal sites, except one sample which had an additional aberration located proxi- mally (7q22.1q34) of the expected single chromosomal abnormality on chromosome 7q36, previously not de- tected with the QF-PCR and subtelomeric MLPA meth- ods. Also, another sample with deletion on 1p region and duplication on 1q region detected previously by MLPA, was found to carry an additional duplication involving the 1p36.32p36.31 chromosomal region. Schematic presenta- tion of the detected chromosomal abnormalities among the affected chromosomes is shown on Figure 1. The sizes of the abnormalities ranged from 1.04 Mb to 150.21 Mb, with average size of 33.2 Mb. Detailed genomic locations of the detected partial chromosomal abnormalities is presented in Table 1 and the gene content of the detected abnormalities is described in Supplementary Table 1. Chromosome 1 exhibited the highest frequency of abnormalities, with six of the detected alterations mapped to this chromosome. Chromosome 18 was the second most affected, harboring four abnormalities, followed by chro- mosome 13 with three abnormalities. Recurrent chromosomal regions and GO enrichment analysis To identify significant CNV regions and to determine the molecular functions and biological processes of the genes contained in these regions who are associated with early pregnancy loss (EPL), we first focused on recurrent regions (>2) among the 32 detected partial chromosomal alterations determining the SOR regions. With this approach, we identified a total of six recur- rent events. The most common recurrent event was on the terminal part of the chromosome 1p, with SOR of 1.78 Mb in the 1p36.33-p36.32 regions, shared by five deletions/ duplications Common recurrent events were found on the terminal part of chromosomes 18q (SOR of 22.1 Mb in the 18q21.31-q23 region) and chromosome 13q (SOR of 14.02 in the 13q32.3-q34 region). With two recurrent events were chromosomes 6q, 9p and 11q, with SOR of 48.26 Mb in the 6q22.31-q27 region, SOR of 8.88 Mb in the 9p24.3- p23 region and SOR of 7.38 Mb in the 11q24.2q25 region. Schematic presentation of the SOR regions is presented on Figure 2. The OMIM genes in every recurrent abnormality were identified and the respective diseases caused by those genes were paired. The most common disorders caused by the identified genes were multisystem syndromes, which may explain their pathogenicity in early human develop- ment. The OMIM genes and the associated disorders are shown in Supplementary Table 2. Gene Ontology (GO) enrichment analysis was con- ducted using Panther, and significantly enriched GO terms were visualized through bar plots (Figures 3 and 4). The analysis revealed that the genes are predominantly associ- ated with molecular binding activities, enzymatic functions as catalytic molecules, or ATPase activity. In terms of biological processes, the recurrent genes identified in this study primarily encode proteins involved in essential functions such as biological regulation, cellular processes, and metabolic processes (Figure 4). Further- more, several genes within the affected regions were linked to developmental processes, indicating that their dysfunc- tion could contribute to early developmental abnormalities, potentially leading to pregnancy loss.

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