Comparative Genomic Hybridization in the Study of Human Disease

Microarray-based comparative genomic hybridization (CGH) has made a significant impact on the ability to diagnose human constitutional disease by detecting genomic copy number changes that were previously undetectable by other types of cytogenetic and molecular technologies. Not only can hundreds of well-characterized genetic syndromes be detected in a single assay, but new genomic disorders and disease-causing genes are also being discovered through the utilization of this technology. Clinical implementation of array CGH Hybridization has been extended to the prenatal setting, where it is also proving to enhance the diagnostic capabilities in the perinatal period. However, the clinical interpretation of the increasing number of copy number variations detected as the resolution of the microarrays is improved still poses a formidable challenge to laboratorians, health care providers and families. Key Concepts: Array comparative genomic Hybridization (aCGH) has several advantages over traditional cytogenetic methods for diagnosing human diseases: higher resolution, more robust and automated, and shorter turn around time since no cell culture is required. Copy number variation (CNV) is common in the genome making it challenging for the clinical significance to be determined. Parental testing and utilisation of several internet-based databases assist with the interpretation of CNVs. The detection rate for clinically relevant CNVs by aCGH (10–20%) is significantly higher than traditional chromosome analysis (3%) making it the recommended first-tier cytogenetic diagnostic test for patients with unexplained developmental delay/intellectual disability, autism spectrum disorders and multiple congenital anomalies by the International Standard Cytogenomic Array Consortium. The resolution of aCGH has evolved to be sensitive enough to aid in the diagnosis of single gene disorders. Array CGH is a useful tool for discovering new disease-causing genes. Array CGH has led to the recognition of many new genomic disorders, many of which cannot be diagnosed clinically due to lack cardinal features, variable expressivity and reduced penetrance. CNVs, particularly those that occur de novo, are increasingly being recognised as important in the etiology of both syndromic and nonsyndromic autism as well as other neuropsychiatric disorders. SNP-based microarrays can be used to diagnosis uniparental disomy. Array CGH is increasingly being used in prenatal diagnosis and has demonstrated its usefulness in clarifying the significance of karyotype findings and providing diagnoses not identifiable by chromosome analysis alone. It is the opinion of The American College of Obstetrician and Gynecologists (2009) that aCGH not currently replace classic cytogenetics for prenatal diagnosis, but that targeted aCGH can be offered as an adjunct tool in prenatal cases with abnormal anatomical findings and normal karyotype, as well as in cases of fetal demise with congenital anomalies and the inability to obtain a conventional karyotype. Keywords: array comparative genomic Hybridization; copy number variation; genomic disorders; autism; uniparental disomy; prenatal diagnosis; microarray; microdeletion; microduplication