title: 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.
authors.affiliation: Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, 117152 Russia ; Russian National Research Medical University named after N.I. Pirogov, Separated Structural Unit "Clinical Research Institute of Pediatrics", Ministry of Health of Russian Federation, Moscow, 125412 Russia ; Department of Medical Genetics, Russian Medical Academy of Postgraduate Education, Moscow, 123995 Russia.
authors.forename: Ivan Y
authors.initials: IY
authors.lastname: Iourov
authors.affiliation: Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, 117152 Russia ; Russian National Research Medical University named after N.I. Pirogov, Separated Structural Unit "Clinical Research Institute of Pediatrics", Ministry of Health of Russian Federation, Moscow, 125412 Russia.
authors.forename: Svetlana G
authors.initials: SG
authors.lastname: Vorsanova
authors.affiliation: Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, 117152 Russia ; Russian National Research Medical University named after N.I. Pirogov, Separated Structural Unit "Clinical Research Institute of Pediatrics", Ministry of Health of Russian Federation, Moscow, 125412 Russia.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Demidova
authors.affiliation: Russian National Research Medical University named after N.I. Pirogov, Separated Structural Unit "Clinical Research Institute of Pediatrics", Ministry of Health of Russian Federation, Moscow, 125412 Russia.
authors.forename: Galina A
authors.initials: GA
authors.lastname: Aliamovskaia
authors.affiliation: Russian National Research Medical University named after N.I. Pirogov, Separated Structural Unit "Clinical Research Institute of Pediatrics", Ministry of Health of Russian Federation, Moscow, 125412 Russia.
authors.forename: Elena S
authors.initials: ES
authors.lastname: Keshishian
authors.affiliation: Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, 117152 Russia ; Russian National Research Medical University named after N.I. Pirogov, Separated Structural Unit "Clinical Research Institute of Pediatrics", Ministry of Health of Russian Federation, Moscow, 125412 Russia.
authors.forename: Yuri B
authors.initials: YB
authors.lastname: Yurov
keywords: 5p13 duplication; Aneuploidy; Bioinformatics; Chromosome instability; Mosaicism