5p13.3p13.2 duplication associated with developmental delay, congenital malformations and chromosome instability manifested as low-level aneuploidy

Abstract

Recent developments in molecular cytogenetics allow the detection of genomic rearrangements at an unprecedented level leading to discoveries of previously unknown chromosomal imbalances (zygotic and post-zygotic/mosaic). These can be accompanied by a different kind of pathological genome variations, i.e. chromosome instability (CIN) manifested as structural chromosomal rearrangements and low-level mosaic aneuploidy. Fortunately, combining whole-genome and single-cell molecular cytogenetic techniques with bioinformatics offers an opportunity to link genomic changes to specific molecular or cellular pathology. High-resolution chromosomal SNP microarray analysis was performed to study the genome of a 15-month-aged boy presented with developmental delay, congenital malformations, feeding problems, deafness, epileptiform activity, and eye pathology. In addition, somatic chromosomal mutations (CIN) were analyzed by fluorescence in situ hybridization (FISH). Interstitial 5p13.3p13.2 duplication was revealed in the index patient. Moreover, CIN manifested almost exclusively as chromosome losses and gains (aneuploidy) was detected. Using bioinformatic analysis of SNP array data and FISH results, CIN association with the genomic imbalance resulted from the duplication was proposed. The duplication was demonstrated to encompass genes implicated in cell cycle, programmed cell death, chromosome segregation and genome stability maintenance pathways as shown by an interactomic analysis. Genotype-phenotype correlations were observed, as well. To the best our knowledge, identical duplications have not been reported in the available literature. Apart from genotype-phenotype correlations, it was possible to propose a link between the duplication and CIN (aneuploidy). This case study demonstrates that combining SNP array genomic analysis, bioinformatics and molecular cytogenetic evaluation of somatic genome variations is able to provide a view on cellular and molecular pathology in a personalized manner. Therefore, one can speculate that similar approaches targeting both interindividual and intercellular genomic variations could be useful for a better understanding of disease mechanisms and disease-related biological processes.

Ontogenetic and Pathogenetic Views on Somatic Chromosomal Mosaicism

“…Thus, to obtain an integrated view on CIN and SCM, which includes all exogenous and endogenous elements, a “multidimensional” evaluation of genomic changes at genomic, epigenomic, proteomic and metabolomic levels are required [11,12,161,168]. To get an example of a chromosomal imbalance disrupting molecular pathways to genome instability, one can address our previous case-report on 5p13.3p13.2 duplication, which has been associated with CIN manifested as aneuploidy [169]. Finally, somatic aneuploidy per se may produce instability in transmitting genetic information during the cell cycle and become, thereby, a source for CIN leading to a wide spectrum of pathologic conditions [11,157,170].…”

Svetlana G. Vorsanova (1945–2021)

“…In total, the body of Svetlana's bioinformatic research yielded new biomedical direction of systems cytogenomics [101]. Moreover, these studies provided for ground-breaking achievements in medical cytogenetics (cytogenomics) -the treatment of chromosomal disorders, which are presumably incurable genetic conditions [102,103]. Finally, paying a tribute to our time, the latest bioinformatic research of Svetlana was focused on the impact of COVID-19 on biomedical publishing [104] and cellular genomes [105].…”

Yuri B. Yurov (1951-2017)

“…Additionally, it became a basis for original algorithms of fusion and network-based classification of molecular cytogenetic data [ 125 ] as well as proposing global pathways of neuropsychiatric diseases for therapeutic interventions [ 126 ]. These algorithms were successfully used for uncovering mechanisms of chromosomal instability and somatic mosaicism [ 127 , 128 ]. Moreover, in silico approaches to chromosomal imbalances are applicable for developing successful treatments of chromosomal abnormalities, which are considered incurable genetic conditions [ 129 ].…”