Chromosomal microarray (CMA) test

Chromosomal microarray (CMA) test allows the detection of clinically significant microdeletions or microduplications that are bigger than 50,000 to 100,000 DNA bases, a resolution that is 50-100 x higher than that of conventional karyotype. It detects most gross chromosomal abnormalities detected by standard karyotype. Since 2010, the American College of Medical Genetics has recommended CMA test (instead of karyotype) as the first tier testing in individuals with with developmental delay, intellectual impairment, autism spectrum disorders and multiple structural abnormalities). Increasingly, this is now accepted as the minimum level of resolution of genetic testing, and not the lower resolution associated with the karyotype, that has to be offered in the investigation of fetal abnormalities in developed countries. The turn around time is about 2 weeks. While the true incidence of individuals with microdeletions and microduplications is not known in the general population, it has been estimated that 1-2% of the general population has individuals with microdeletions and microduplications, and that this incidence does not appear to increase or decrease with maternal age. As this higher resolution genetic test is now increasingly used in centres around the world, higher rates of chromosomal abnormalities than the baseline rate of 1-2% in the general population have been described in newer studies where there are major or minor ultrasound markers. The yield of an abnormal chromosomal microarray test depends on the ultrasound marker detected. Possible results on CMA test

1. Normal including only benign variants - read <limitations of CMA test point 1(a-c)>.

2. Abnormal / pathogenic variants - could cause serious or variable genetic conditions involving intellectual impairment, autism spectrum disorders, structural abnormalities, and others including seizure disorder, growth disorders, psychiatric illness and muscle weakness; read <limitations of CMA test point 2>.

3. Variation of unknown significance (VOUS) - read <limitations of CMA test point 3>.

Limitations of CMA test: 1. No single test can rule out all genetic diseases. CMA does not detect: a) Small changes in the sequence of single genes (smaller than 50-100 thousand DNA bases) which could still cause serious genetic diseases e.g. point mutations like most autosomal recessive, autosomal dominant, sex-linked recessive conditions, and Fragile X syndrome.

b) Structural chromosomal abnormalities like balanced and translocation and inversions with no loss/gain of DNA sequence larger than 50-100 thousand DNA bases

c) Low level chromosomal mosaicism below 20-25%

2. Even if a chromosomal microdeletion or microduplication is detected in a fetus, it may not, however, allow an accurate prediction of the outcome of the fetus. Many of the microdeletions / microduplications may be associated with a spectrum of outcomes ranging from very mild to severe disturbances of intellectual impairment / autism spectrum disorder / structural abnormality. Some microdeletions / microduplications, on the other hand, may be more consistently associated with severe disturbances of intellectual impairment / autism spectrum disorder / structural abnormality.

3. As more clinical data gets correlated with the genetic findings, there may be further reclassification of the results in the future e.g. some VOUS may be reclassified as benign, some VOUS may reclassified as pathogenic, and some benign may be reclassified as VOUS.