Zada, Almira and Faradz, Sultana MH and Mundhofir, Farmaditya EP (2013) DETECTION OF COPY NUMBER VARIATIONS IN INTELLECTUALLY DISABLED PATIENTS IN INDONESIA USING HIGH RESOLUTION GENOME WIDE ARRAY ANALYSIS. Masters thesis, Universitas Diponegoro.

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Abstract

Background: Intellectual disability (ID) is a neurodevelopmental disorder that is characterized by an intelligence quotient (IQ) of 70 or below, and deficits in at least two behaviors related to adaptive functioning diagnosed by 18 years of age. The etiology of ID can be classified as genetic and non-genetic factors. Chromosomal abnormality is a frequent genetic cause of ID. Routine cytogenetic analysis remained the major diagnostic test for ID patients in Indonesia. However, it cannot detect the submicroscopic chromosomal rearrangement termed copy number variation (CNV). The use of genome wide array analysis to detect CNVs might increase the rate of diagnostic yield in ID patients in Indonesia.
Methods: Eighteen patients with ID who had normal results after karyotyping, CGG repeat analysis in the FMR1 gene and subtelomeric MLPA testing were included. Detection of CNVs were done by using high resolution genome wide array analysis (Affymetrix CytoScan HD Array platform) with an average test resolution of approximately 20 kb then analyzed by using
Chromosome Analysis Suite (ChAS) Software V.2.0. The various CNV detected were classified by comparing in house and international normal and affected individual datasets, gene contents and literature studies. FISH studies were performed for carrier testing and the possible presence of a balanced chromosome rearrangement in the parents and/or mosaic imbalance.
Results: Three out of 18 patient with ID were found to carry pathogenic CNV i.e one patient with 14q32.2q32.31 microdeletion of 1.1 Mb and 2 patients with 7q11.23 microdeletion of 1.4 Mb (Williams-Beuren Syndrome). One patient with 1p36.11p35.3 microduplication of 1.7 Mb were found to carry likely pathogenic CNV. In addition, there is one patient carried large homozygous regions totaling ~7% of the autosomal genome which one of these homozygous stretches harbours a mutated recessive disease gene.
Conclusion: The genome wide array analysis in this study has an additional detection rate of 16.7% (3 out of 18 patients) causative CNVs in selected ID patients after routine karyotyping combined with subtelomeric MLPA and CGG(n) repeat analysis in the FMR1 gene.
Keywords: Intellectual disability, copy number variation, genome wide array analysis

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