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首页> 外文期刊>Journal of Molecular Genetics >Establishing an Array CGH Platform for Molecular Diagnosis of Saudi Patients with Intellectual Disability
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Establishing an Array CGH Platform for Molecular Diagnosis of Saudi Patients with Intellectual Disability

机译：建立用于沙特智力障碍患者分子诊断的阵列CGH平台

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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.
机译：导致遗传物质净增加或减少的基因组不稳定是遗传障碍（例如与拷贝数变异（CNV）和结构染色体异常相关的精神发育迟缓（MR））的明显特征。识别脆弱的基因组区域和其中包含的基因对于特异性诊断遗传疾病至关重要。传统的核型分析和荧光原位杂交（FISH）是检测此类异常的常用技术。但是，每种技术都有其自身的局限性。核型分析可以检测到大约5个兆碱基（Mb）的微观重排。 FISH可以定位特定DNA序列在染色体上的位置，但它依赖于单个靶标或所研究区域的先验知识。比较基因组杂交（CGH）是一种用于在全基因组范围内鉴定CNV的技术。但是，使用中期染色体扩展的传统CGH受较低的分辨率和大约5-10 Mb的灵敏度限制。开发高分辨率CGH（通常称为阵列CGH（aCGH））来克服此类限制，方法是将杂交靶标替换为点样形式的基因组片段。建立和验证aCGH作为检测特发性智力低下，畸形特征和/或畸形的特定沙特患者中已知和新型隐秘遗传变化的先进技术。使用高分辨率的2x105 K安捷伦微阵列扫描仪对从两名3岁和14岁的沙特女性患者的血液样本中获得的基因组DNA（gDNA）进行aCGH，这些患者表现出类似于Angelman综合征（AS）和William's综合征的临床特征（WS）。灵敏度阈值为6.0的像差检测方法2（ADM-2）算法用于数据分析。在AS患者（患者1）中，aCGH结果显示15号染色体上没有缺失，但除了4号，8号，11号，14号，16号染色体上的扩增外，在4号，6号和17号染色​​体上观察到较小的非特异性间质缺失。参见图17和19。在WS患者（患者2）中，在7号染色体上检测到了预期的缺失。但是，在7号和15号染色体上观察到了其他非特异性间质缺失，在14号和22号染色体上也观察到了扩增。当将这些患者的aCGH结果与来自阿卜杜勒阿齐兹国王大学（KAU）的诊断基因组医学部门（DGMU）的FISH数据进行比较时，研究人员观察到两种方法在15号和7号染色体上的一致性很高;在患者1的15号染色体上没有观察到FISH缺失，在患者2的7号染色体中观察到了缺失。高分辨率aCGH和FISH技术显示出与aCGH高度相关，从而导致了更广泛的CNC。这种增加的频谱可以改善大批患者的智力低下的预后。因此，研究人员建议将aCGH广泛用作筛查沙特阿拉伯西部智障患者的常规诊断平台。

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