Iourov Ivan Y, Vorsanova Svetlana G, Demidova Irina A, Aliamovskaia Galina A, Keshishian Elena S, Yurov Yuri B
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.
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.
Springerplus. 2015 Oct 15;4:616. doi: 10.1186/s40064-015-1399-3. eCollection 2015.
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.
分子细胞遗传学的最新进展使得能够以前所未有的水平检测基因组重排，从而发现先前未知的染色体失衡（合子性和合子后/镶嵌性）。这些失衡可能伴随着另一种病理性基因组变异，即染色体不稳定（CIN），表现为染色体结构重排和低水平镶嵌非整倍体。幸运的是，将全基因组和单细胞分子细胞遗传学技术与生物信息学相结合，为将基因组变化与特定分子或细胞病理学联系起来提供了机会。对一名15个月大、患有发育迟缓、先天性畸形、喂养问题、耳聋、癫痫样活动和眼部病变的男孩进行了高分辨率染色体SNP微阵列分析。此外，通过荧光原位杂交（FISH）分析了体细胞染色体突变（CIN）。在索引患者中发现了5号染色体间质13.3p13.2重复。此外，检测到CIN几乎仅表现为染色体丢失和增加（非整倍体）。通过对SNP阵列数据和FISH结果的生物信息学分析，提出了CIN与重复导致的基因组失衡之间的关联。相互作用组学分析表明，该重复被证明包含与细胞周期、程序性细胞死亡、染色体分离和基因组稳定性维持途径相关的基因。还观察到了基因型与表型的相关性。据我们所知，现有文献中尚未报道过相同的重复。除了基因型与表型的相关性外，还可能提出重复与CIN（非整倍体）之间的联系。该案例研究表明，结合SNP阵列基因组分析、生物信息学和体细胞基因组变异的分子细胞遗传学评估，能够以个性化的方式提供对细胞和分子病理学的见解。因此，可以推测，针对个体间和细胞间基因组变异的类似方法可能有助于更好地理解疾病机制和与疾病相关的生物学过程。
