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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DISCUSSION

This study aimed to refine the characterization of previously identified partial chromosomal abnormalities in EPLs from early pregnancy losses (EPLs) by employ- ing aCGH. Our findings significantly expand upon the initial QF-PCR and subtelomeric MLPA data, providing a detailed understanding of the genomic landscape in these cases. The identification of multiple abnormalities within individual samples, unidentified by the previous analy- ses underscores the complex genetic etiology of EPLs. For instance, in one sample we identified an additional abnormality located proximally to the expected single chromosomal abnormality on chromosome 7q36, which had not been previously detected using the QF-PCR and subtelomeric MLPA. In another sample, we discovered an additional duplication on the 1p36.32p36.31 chromosomal regions, despite the initial distal deletion and duplication on 1p and 1q regions respectively. Interstitial chromosomal abnormalities account for approximately 5–10% of chro- mosomal anomalies in early pregnancy losses (EPLs) [18, 19]. These abnormalities cannot be detected using methods such as the previously used QF-PCR and subtelomeric MLPA, underscoring the limitations of these techniques. This highlights the critical need for high-resolution ap- proaches, such as aCGH in EPLs with no chromosomal abnormality detected by subtelomeric MLPA. Our study’s findings are particularly noteworthy giv- en the large size of the CNVs detected (averaging 33.2 Mb), suggesting that these genetic alterations may disrupt multiple genes and are essential for normal embryonic development. The frequent involvement of chromosomes 1, 18, and 13 in these abnormalities is in line with their established association with pregnancy loss [20, 21]. These chromosomes have previously been implicated in recurrent pregnancy loss (RPL), particularly in studies of aneuploidy and large chromosomal rearrangements [22]. Chromosom- al copy number variations (CNVs) in key regions such as 1p36.33-p36.32, 9p24.3-p23, 11q24.2-q25, 13q32.3-q34, and 18q21.31-q23 have been strongly implicated in early pregnancy loss (EPL). These regions host genes critical for apoptosis, placental development, and cellular signaling. For example, 1p36.33-p36.32 harbors genes essential for apoptosis, while abnormalities in 11q24.2-q25 involve genes like ETS1, crucial for connective tissue integrity. Disruptions in 18q21.31-q23 affect placental function, and 13q abnormalities interfere with vascular development. Advances in next-generation sequencing have enhanced the identification of these CNVs in EPL cases, confirm- ing their significance in embryonic viability [23-26]. In live-born individuals, similar abnormalities may result in congenital disorders, developmental delays, and physical malformations, but often allow for survival past the pre- natal period. The key difference lies in the severity of the genetic disruption and the associated clinical outcomes, with EPL cases often involving more pronounced, lethal alterations. By contrast, live-born individuals may exhibit milder phenotypes due to mosaicism or less severe genetic disruptions [27]. Around 1/3 of all genes in the recurrent regions are associated with multisystem syndromes, as shown by the OMIM genes enrichment analysis (Supplementary Table 2). Some of the genes are strongly associated with EPLs due to their critical roles in embryonic development and placental function. For instance, PEX10 and PEX3, linked to peroxisomal biogenesis disorders, often result in embry- onic lethality due to metabolic dysfunction [28]. COL4A1 and COL4A2, involved in vascular integrity, are associated with placental abnormalities and pregnancy complications [29]. Additionally, CITED2 plays a vital role in placental development, and its deficiency is linked to embryonic le- thality [30]. The results of our Gene Ontology (GO) enrich- ment analysis provide additional insights into the biologi- cal processes potentially disrupted by these chromosomal abnormalities. Our data suggest that the recurrent genes identified are primarily involved in essential biological processes such as molecular binding, enzymatic activity, ATPase activity, growth, metabolism, reproduction, and developmental processes. Dysregulation of these genes could plausibly lead to early embryonic developmental abnormalities, contributing to pregnancy loss. This find- ing is consistent with previous studies highlighting the role of genetic dysregulation in critical pathways such as apoptosis, cell cycle control, and placental development in EPL [31-36]. It is essential to acknowledge the limitations of this study, including the retrospective design and relatively small sample size. These factors may restrict the generaliz- ability of our findings. The majority of the detected chro- mosomal abnormalities could have arisen from parental balanced chromosomal translocations [37]. Unfortunately, this cannot be confirmed at the time, since we were un- able to perform parental karyotypes. The probabilities of different reproductive outcomes for carrier individuals of reciprocal balanced translocations are commonly based on an estimate of the likelihood of a fetus to survive with chromosomal imbalances resulting from the adjacent-1 segregation, while conceptions with other unbalanced seg- regations may not be viable [38]. This can lead to a more precise risk assessment and proper genetic counselling for the next pregnancies of the couples. The focus on CNVs also does not exclude the pos- sibility of other genetic factors contributing to EPLs, such as single nucleotide variants (SNVs) or epigenetic changes that were not assessed in this study. Furthermore, while aCGH offers higher resolution than many traditional meth- ods, it does not capture all types of genomic variation [39]. Future studies should aim to integrate CNV data with whole-genome sequencing and epigenetic profiling to develop a more comprehensive understanding of the genetic landscape of EPLs. Functional validation studies using in vitro and in vivo models are critical to elucidating how these genetic changes affect cellular and develop- mental processes [40-42]. This comprehensive research approach will be essential for understanding the underlying mechanisms of EPLs.

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