What is the main advantage of chromosomal microarray over karyotyping?

It detects copy-number gains and losses across the genome at much higher resolution than chromosome banding, identifying many submicroscopic deletions and duplications that a karyotype cannot see.

Why can microarray miss a balanced translocation?

Microarray and CGH measure the relative amount of genomic material, so they detect gains and losses but not rearrangements that move material without changing copy number; a balanced translocation therefore requires karyotyping or FISH to detect.

Chromosomal Microarray and Comparative Genomic Hybridization

Comparative genomic hybridization (CGH) and chromosomal microarray analysis are molecular cytogenetic methods that detect genomic copy-number gains and losses by comparing a test genome against a reference. By moving the comparison onto an array of thousands of genomic targets, microarray-based approaches map deletions and duplications across the whole genome at resolutions far finer than chromosome banding, making them a high-resolution tool for detecting submicroscopic imbalances.

Definition

Chromosomal microarray with comparative genomic hybridization is a copy-number analysis method in which differentially labelled test and reference DNA compete to hybridize to defined genomic targets, so that fluorescence ratios reveal gains and losses of genomic material across the genome.

Scope

This topic covers the principle of competitive hybridization underlying CGH, its evolution from metaphase CGH to array CGH and SNP arrays, what copy-number information these platforms provide, and their characteristic limitation regarding balanced rearrangements. It is a methodological reference and does not provide clinical management guidance.

Core questions

How does competitive hybridization of test and reference DNA reveal copy-number change?
What did the move from metaphase CGH to array-based platforms change about resolution?
How do array CGH and SNP arrays differ in the information they provide?
Why can microarray not detect balanced rearrangements or low-level mosaicism?

Key concepts

Copy-number variation (CNV)
Competitive (ratio) hybridization
Metaphase CGH versus array CGH
Single-nucleotide polymorphism (SNP) array
Genomic resolution and probe density
Genome-wide copy-number profiling
Detection of regions of homozygosity (SNP arrays)
Limitation for balanced rearrangements

Mechanisms

In comparative genomic hybridization, test and reference DNA are labelled with different fluorophores and hybridized together to a common target; where the test genome has a copy-number gain or loss, the fluorescence ratio departs from the balanced reference value, mapping the imbalance. In the original method the target was a normal metaphase spread, which limited resolution; replacing it with an array of mapped genomic clones or oligonucleotides (array CGH) raised resolution by orders of magnitude and allowed precise localisation of gains and losses. SNP arrays additionally interrogate polymorphic sites, providing genotype information that can reveal regions of homozygosity and aid detection of uniparental disomy. Because these platforms measure only the relative amount of genomic material, they detect unbalanced changes (deletions and duplications) at high resolution but cannot detect balanced rearrangements that do not alter copy number, and they have limited sensitivity for low-level mosaicism.

Clinical relevance

Chromosomal microarray is used to identify submicroscopic copy-number gains and losses in the evaluation of developmental disability, congenital anomalies, and certain cancers, detecting many imbalances below the resolution of karyotyping. Consensus guidance has recommended it as a first-tier test for unexplained developmental disability or congenital anomalies, while noting that karyotyping or FISH remains needed when a balanced rearrangement is suspected. This entry describes how microarray findings are generated; it is not a basis for individual diagnostic or treatment decisions.

Evidence & guidelines

An international consensus statement led by Miller and colleagues (2010) recommended chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies, while recognising the continuing role of karyotyping for balanced rearrangements. Copy-number findings are reported using International System for Human Cytogenomic Nomenclature (ISCN) conventions.

History

Comparative genomic hybridization was introduced by Kallioniemi and colleagues in 1992 as a way to survey copy-number changes across the genome of solid tumours using a single hybridization to metaphase chromosomes. Solinas-Toldo and colleagues in 1997 demonstrated matrix- (array-) based CGH, replacing the metaphase target with an array of genomic clones and greatly improving resolution. Array CGH and, later, SNP arrays then became routine high-resolution tools, and by 2010 consensus had positioned chromosomal microarray as a first-tier diagnostic test in defined clinical settings.

Key figures

Anne Kallioniemi
Daniel Pinkel
Joe W. Gray
Peter Lichter
David T. Miller

Seminal works

kallioniemi-1992
solinas-toldo-1997
miller-2010

Frequently asked questions

What is the main advantage of chromosomal microarray over karyotyping?: It detects copy-number gains and losses across the genome at much higher resolution than chromosome banding, identifying many submicroscopic deletions and duplications that a karyotype cannot see.
Why can microarray miss a balanced translocation?: Microarray and CGH measure the relative amount of genomic material, so they detect gains and losses but not rearrangements that move material without changing copy number; a balanced translocation therefore requires karyotyping or FISH to detect.