Product Description:
Genome-wide oligonucleotide microarrays have been successfully implemented in clinical cytogenetic diagnostics. These arrays have a 10-100 fold improvement in resolution compared to G-banding analysis. Clinical interpretation of the chromosomal imbalances detected by arrays in individuals with abnormal phenotypes has been aided by studies of copy number variation in normal populations. We have analyzed data from 8,738 whole-genome arrays from three clinical diagnostic laboratories that are members of the International Standard Cytogenomic Array (ISCA) consortium. Goals of this consortium include the standardization of cytogenetic array testing and deposition of data into a public database for use by the clinical and research communities. In accordance with ISCA standards, arrays were custom designed with genome-wide backbone coverage in addition to high density coverage of known clinically relevant regions and genes. Array analysis was carried out on individuals with phenotypes including mental retardation, autism, developmental delay, dysmorphic features, and/or multiple congenital anomalies. Of the 3,084 imbalances detected within the reporting criteria, we found pathogenic abnormalities in 53.5% (15.9% of patients) based on known clinically relevant regions, gene content, inheritance, and size. We observed many of the recently described recurrent disorders such as 16p11 microdeletions (38 cases) and 17q12 imbalances (5 deletions and 7 duplications). For 23.4% of the imbalances (7.6% of patients), the abnormality was of uncertain clinical significance at this time. For example, duplications of 16p11.2 were considered uncertain since evidence is still emerging for their association with an increased risk of autism. As expected, many common, known benign copy number variants were identified, including imbalances within segmental duplications, such as the DEFB gene cluster on 8p23.1. Of the 881 imbalances with known inheritance, 347 imbalances (39.4%) were determined to be de novo and most likely pathogenic. Of the inherited cases, many were inherited from a similarly affected parent or a parent carrying the balanced form of the rearrangement. Comparison of data such as these generated from clinical testing of individuals with abnormal phenotypes to that generated in normal populations will help to establish a gene dosage map of copy number variation for normal and abnormal human development.
