Introduction

Many human genetic disorders result from an unbalanced chromosomal abnormality in which there is a loss or gain of chromosomal material. Since the 1970s, such imbalances have traditionally been detected through the analysis of chromosomes by karyotype assessment. Chromosome G-banding patterns are visualised under the microscope leading to the identification of differences in chromosome number (aneuploidies), large balanced and unbalanced structural rearrangements and mosaic structural and numerical abnormalities. Karyotyping has been an integral tool in the genetic evaluation of children with congenital anomalies and developmental delay. However, chromosomal aberrations below approximately 5 megabases (Mb) in size cannot be detected by routine karyotype and therefore, a loss or gain of genetic material below this size (microdeletion or microduplication) cannot be visualised.

The diagnosis of chromosome abnormalities below 5 Mb can be improved using fluorescently labelled DNA probes, which bind to specific DNA sequences. This technique, called fluorescence in situ hybridisation (FISH), is valuable in the identification of chromosomal aberrations at predetermined locations. For example, the absence of a fluorescent probe signal on one copy of chromosome 22 at the q11.2 locus indicates 22q11.2 deletion syndrome (see table 1).1 While FISH is very useful, it is a targeted test that requires a specific diagnosis and chromosomal location to be considered. A more hypothesis-free approach is achieved by using microarray-based comparative genomic hybridisation (aCGH). A description of how aCGH is performed was recently published.2 In brief, thousands of probes spread across all chromosomes are used to interrogate chromosome copy number and any deviation from the expected number of copies is reported, such that a locus in which a group of probes are missing indicates a deletion of material, while extra copies are consistent with a gain of material. These variants are termed copy number variants (CNVs) collectively and may represent normal …