Retrospective evaluation of regions with loss of heterozygosity in clinical samples evaluated by the single nucleotide polymorphism array (SNP Array)

Loss of heterozygosity (LOH) is defined as the loss of the structure or function of one of the two alleles inherited from the parents at a specific locus in a diploid genome due to genetic or epigenetic mechanisms. The LOH process, caused by chromosome segregation errors, occurs during gametogenesis and early embryo development. Chromosomal deletions, uniparental disomy, mitotic recombination, and gene conversion lead to loss of heterozygosity. Uniparental disomy (UPD) occurs when both homologous chromosomes are inherited from a single parent. It can involve the entire chromosome (complete UPD) or just a segment (segmental UPD). UPD effectively decreases the genome's allelic diversity, leading to homozygosity. Additionally, loss of heterozygosity (LOH) is another key mechanism responsible for various clinical phenotypes. This study aims to analyze the chromosomal distribution of loss-of-heterozygosity (LOH) regions and identify any LOH regions that could be linked to clinical outcomes through retrospective analysis. In this thesis, SNP array data from 572 patients examined between 2020 and 2023 using the SNP array method (Thermo Fisher CytoScan™ Optima 315K) were analyzed retrospectively to determine the distribution of loss of heterozygosity (LOH) regions. The participants were divided into clinical subgroups based on their diagnoses. The analyses were conducted using the Chromosome Analysis Suite Software (ChAS) program. For the analysis of LOH regions, the genome was divided into 10-megabase segments. Pandas, NumPy, Seaborn, and Matplotlib tools were used to create these segments and generate heat maps illustrating the distribution of LOH regions. In this study, at least one LOH segment was detected in 115 (20.1%) of the 572 individuals analyzed using the SNP array method. The detection rate of LOH regions varied significantly among clinical subgroups. The groups with the highest LOH detection rates included cases of abortion and developmental delay, and LOH was more frequently detected on chromosomes 2, 5, 6, 11, and X. Copy-neutral LOH occurred frequently in segments containing genes associated with neurodevelopmental disorders, such as epilepsy, autism, and dysmorphic phenotypes. These genes include PHIP (6q14.1), TCF4 (18q21.2), RORB (9q21.13), and SYNGAP1 (6p21.32). The genomes of the 115 individuals carrying LOH segments also included genes linked to epigenetic regulation and synaptic plasticity. These genes include DNMT1 (19p13.2), NTRK2 (9q21.33), and SYNE1 (6q25.2). The presence of these genes suggests that LOH may affect phenotype through both epigenetic mechanisms and structural changes. In conclusion, understanding the distribution of LOH regions within the genome can substantially enhance our understanding of the potential pathogenesis across a broad clinical spectrum, including prenatal anomalies, neurodevelopmental disorders, dysmorphic syndromes, and congenital malformations. The genes located within these segments and their positioning may inform the molecular mapping of prospective disease mechanisms.