WHOLE GENOME ANALYSIS BY ARRAY-BASED COMPARATIVE GENOMIC HYBRIDIZATION IN PATIENTS WITH CONGENITAL MALFORMATIONS
Dimova I1, Vazharova R1, Nikolova D1, Tincheva R2, Nesheva D1, Uzunova Y3, Toncheva D1,*
*Corresponding Author: Professor Draga Toncheva, Department of Medical Genetics, Medical University Sofia, 2, Zdrave str., 1431 Sofia, Bulgaria; Tel./Fax: +359-2-952-0357; E-mail:dragatoncheva@yahoo.com
page: 33

DISCUSSION

 

We used the technique of array-CGH to screen micro-structural whole genome copy number changes in four patients with congenital malformations. We detected a specific genomic abnormalities in one of the four patients and different copy number polymorphisms in all four patients. This technique permits identification at a high resolution of micro-structural abnormalities in human chromosomes [7]. In comparison to fluorescent in situ hybridization (FISH) and classical cytogenetic diagnostics, the method has a much higher sensitivity and permits screening of the whole genome simultaneously for unbalanced micro-structural rearrangements [8]. It is also applicable for effective screening of new dose-dependent genes, which are important for the emergence of many human diseases [9]. The use of the BAC clones ensures strong and large signals that can be measured over a broad range – from deletions to amplifications [9,10]. We established copy number polymorphisms in all of our patients. According to recent publications [11-13], more than half of the variability between human genomes is due to copy number variations (CNVs) of small regions of DNA. It is hypothesized that these CNVs are responsible for some complex diseases and are more frequent than single nucleotide polymorphisms [11-13]. There are more than 6,000 known regions of CNV, and there may be many more [13,14]. The impact of CNVs in the development of congenital malformations remains to be seen.Our most interesting finding was the loss of genetic material from chromosome 18 in patient 3. This deletion comprises the region 18q21.1-q23 and encompassed 48 deleted BAC clones. The 18q syndrome (OMIM #601808) is characterized by mental retardation, facial dysmor phism, congenital malformations and deformities of the feet, depending on the size of the deleted region [15]. The critical region in the ‘typical’ 18q phenotype is one of 4.3 Mb located within 18q22.3-q23. A recent study investigated partial deletions of the long arm of chromosome 18 and identified critical regions for microcephaly (18q21.33), short stature (18q21.- -q21.33, and 18q22.3-q23), white matter disorders (18q22.3-q23) and CAA (congenital aural atresia) (18q22.3) [15]. These observations are consistent with the clinical symptoms in our patient. During investigation of the deleted region in the long arm of chromosome 18 by genome browser, we delineated 149 genes, of which some have no known function. Other genes in this region may also be related to the abnormal phenotype. Among these we found genes with regulatory function (ZNF236, zinc finger protein 236), transcription coactivators and regulators [DCC, deleted in colorectal carcinoma; RAX, retina and anterior neural fold homeo box; TSHZ1, teashirt family zinc finger 1), translation regulators 38 (NARS, asparaginyl-tRNA synthetase), transporters (CCBE1, collagen and calciumbinding EGF domains 1), inducte of apoptosis (PMAIP1, phorbol- 12-myristate-13-acetate-induced protein 1), regulators of cell growth (SOCS6, suppressor of cytokine signaling 6; PARD6G, par-6 partitioning defective 6 homolog gamma (C. elegans)] and others. These genes may be good candidates for further functional studies, as candidate genes for the human development and congenital anomalies. Our concurrent array CGH analysis and karyotyping in the patient with 18q deletion, showed that microarray technology is useful for the detection of low level mosaicism.




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