Abstract: Genomic instability that results in a net gain or loss of genetic material is an obvious feature of genetic disorders such as Mental Retardation (MR) that are associated with Copy Number Variations (CNVs) and structural chromosomal abnormalities. It is crucial to identify fragile genomic regions and the genes contained in them to specifically diagnose genetic disorders. Conventional karyotyping and Fluorescent in situ Hybridisation (FISH) are commonly used techniques for detecting such abnormalities. However, each technique has its own limitations. Karyotyping can detect microscopic rearrangements as small as approximately five Mega bases (Mb). FISH can locate the position of specific DNA sequences on a chromosome but it relies on a single target or prior knowledge of the region under investigation. Comparative Genomic Hybridisation (CGH) is a technique used to identify CNVs on a genome-wide scale. However, traditional CGH which uses a metaphase chromosome spread is limited by lower resolution and a sensitivity of approximately 5-10 Mb. High resolution CGH, commonly known as array CGH (aCGH) was developed to overcome such limitations by substituting a hybridisation target with a genomic segment spotted on an array format. To establish and validate aCGH as an advanced technique for detecting known and novel cryptic genetic changes in selected Saudi patients with idiopathic mental retardation, dysmorphic features and/or malformations. A high-resolution 2x105 K Agilent microarray scanner was used to perform aCGH on genomic DNA (gDNA) obtained from blood samples of two Saudi female patients, aged 3 and 14 years who showed clinical features resembling Angelman Syndrome (AS) and William’s Syndrome (WS), respectively. The Aberration Detection Method 2 (ADM-2) algorithm with a sensitivity threshold of 6.0 was used for data analysis. In the AS patient (patient 1), the aCGH results revealed no deletions in chromosome 15 but smaller non-specific interstitial deletions were observed in chromosomes 4, 6 and 17 in addition to amplifications in chromosomes 3, 8, 11, 14, 16, 17 and 19. In the WS patient (patient 2), the expected deletion was detected in chromosome 7. However, other non-specific interstitials deletions were observed in chromosomes 7 and 15 and amplifications in chromosomes 14 and 22 were also observed. When the aCGH results of these patients were compared with FISH data from the Diagnostic Genomic Medicine Unit (DGMU) of King Abdulaziz University (KAU), the researchers observed a high concordance between the two methods with respect to chromosomes 15 and 7; no deletion was observed by FISH in chromosome 15 of patient 1 and a deletion in chromosome 7 was found in patient 2. High resolution aCGH and FISH techniques demonstrated a high degree of correlation with aCGH resulting in a wider spectrum of CNCs. This increased spectrum may ameliorate the prognosis of mental retardation in large cohorts of patients. Therefore, the researchers recommend using aCGH extensively as a routine diagnostic platform for screening patients with intellectual disabilities in Western Saudi Arabia.