Chromosomal Microarray (CMA / aCGH)
Definition
A high-resolution test that detects copy number variations (CNV) across the genome, that is, deletions and duplications too small to be seen under a microscope. It is also called "molecular karyotyping".
Comparison with karyotype, International Consensus (ISCA) data:
| Microarray (CMA) | G-banded Karyotype | |
|---|---|---|
| Diagnostic yield | 15–20% | ~3% (excluding Down syndrome and recognizable syndromes) |
| Strength | High sensitivity for submicroscopic deletions/duplications | Sees the whole chromosome structure |
| What it cannot see | Truly balanced rearrangements and low-level mosaicism | Small (submicroscopic) changes |
Conclusion of the consensus:
Current evidence strongly supports the use of CMA in place of G-banded karyotype as the first-tier cytogenetic diagnostic test in patients with unexplained developmental delay/intellectual disability, autism spectrum disorder or multiple congenital anomalies.
When karyotype is preferred:
- If an obvious chromosomal syndrome is suspected (e.g. Down syndrome)
- If there is a family history of chromosome rearrangement
- If there is a history of recurrent pregnancy loss
This last point is important: microarray cannot see balanced translocations, yet the main genetic cause of recurrent pregnancy loss is precisely balanced translocation carrier status (see the Chromosome Abnormalities entry). This is why a karyotype is requested in recurrent pregnancy loss.
Relationship with FISH: FISH is a targeted test; it looks at a single predetermined region (e.g. 22q11 DiGeorge, 15q11 Prader-Willi) and gives a rapid result. Microarray, on the other hand, scans genome-wide and requires no target. If the clinical suspicion points to a specific syndrome, FISH is appropriate; if it is unclear, microarray is appropriate.
Risks and Limitations
The balanced rearrangements and low-level mosaicism that CMA cannot see are relatively rare causes of an abnormal phenotype in this patient group (<1%), so the limitation is real but leaves only a small gap in practice.
CMA can generate a large number of VUS; the clinical significance of some copy number variations is uncertain.