Profiling of DNA Copy Number Microaberrations Associated with Congenital Disorders Among Malaysian Children Using Array Comparative Genomic Hybridisation

Copy number gains or losses of various chromosomal regions, whole chromosomes or subtelomeric rearrangements have been known to cause human mental retardation syndromes and congenital malformations. This study characterised chromosomal abnormalities associated with congenital disorders in Malaysian patients and identified novel microdeletions or microduplications that correlate with the phenotype. A high resolution method, array comparative genomic hybridization (aCGH) was used. DNA was extracted from blood and then quantified and qualified before proceeding with the technique. Samples with satisfactory DNA quality and quantity were then chosen to be analysed with aCGH. The DNA was labelled, combined, pre-hybridised, hybridised and scanned. The identification of genes located in the region of duplication and deletion was conducted using ENSEMBL!. The correlation between the genotype and phenotype was done using OMIM. One hundred patients were analysed in this study. Chromosome specific deletions and duplications occurred most frequently in chromosomes 1 and 3. The reasons probably are because these chromosomes are large and harbour many loci and genes that are susceptible to changes. In this study, 496 clones harboured copy number changes. Of this, 88 copy number changes were found in more than one individual. A comparison of the most frequent changes associated with phenotypes was also executed. For example, chromosome 17q21.31 was identified as major cause for global delays observed in the patients within this study based on the comparitive analysis, previous literature and CRHR1 and MAPT genes functions. Furthermore, 10 patients were selected for an in depth analysis to identify the possible causal gene(s). Seven novel genes speculated to have significant effect on the phenotypes were identified. Amongst them were FBN2 gene for abnormal pinna, FUZ for holoprosencephaly, TMEM1 and ARFGEF2 for microcephaly, TM2D2 for developmental delay, SH3GL2 for autism and INPP5A for severe psychomotor delay and failure to thrive as observed in these patients. This study proves the importance of aCGH as a tool that refines birth defects diagnosis. However, due to the high-resolution output of the technique, the copy-number variable nature of the genome as well as the massive gaps in the knowledge of many regions of the genome and gene function; conclusive delineation of the genotype-phenotype correlation remains an arduous task. Nonetheless, aCGH helps to provide better insight into the patient diagnosis and helps greater understanding of the disease molecular pathogenesis.

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