What you need to know before ordering chromosomal microarray

What does chromosomal microarray detect?

Chromosomal microarray (CMA) testing looks for extra (duplicated) or missing (deleted) chromosomal segments, sometimes called copy number variants (CNVs). These include:

• Microdeletions and microduplications of chromosome segments, which are too small to see under a microscope but may contain multiple genes (see illustration below)
• Most abnormalities of chromosome number (trisomy, monosomy, etc.), including Down syndrome
• Most unbalanced rearrangements of chromosome structure (translocations, etc.)

Depending on the platform, CMA may also detect:

• Excessive homozygosity, suggestive of risk for recessive disease or imprinting disorders (see Apply Results for more information)
• Triploidy and other duplications of the entire chromosome set (tetraploidy, etc.)

As with traditional karyotype, mosaicism (a mixture of normal and abnormal cells) of greater than 20-25% can be detected by CMA testing. Detection rates vary with the specific testing platform ms).

What does CMA not detect?

No test can rule out all genetic diseases. Some types of variants require a different test, and some regions are technically difficult to isolate and analyze.

CMA does not detect:

• Small changes in the sequence of single genes (point mutations)
• Tiny duplications and deletions of DNA segments within a single gene (Fragile X syndrome, for example)
• Balanced chromosomal rearrangements (balanced translocations, inversions)

The limitations of CMA testing also vary with the methodology used. Most CMA cannot detect mosaicism below 20-25%. Some platforms do not detect excessive homozygosity or triploidy as well as others. (See the section on Ordering for more information on the different CMA platforms.)

How does CMA work?

“Microarray” refers to a microchip-based testing platform that allows high-volume, automated analysis of many pieces of DNA at once. CMA chips use labels or probes that bond to specific chromosome regions. Computer analysis is used to compare a patient’s genetic material to that of a reference sample. A difference between a patient’s DNA and the reference sample is called a variant.

Which patients could benefit from it?

CMA is clearly useful for individuals who don’t fit a specific known syndrome (such as Down syndrome), but demonstrate any of the following:

Developmental delay/intellectual impairment
• Autism spectrum disorders
• Multiple congenital anomalies, including dysmorphic facial features

CMA may also be the most cost-effective test when your differential includes more than one condition that could be detected by the technology. It is possible for patients to have more than one genetic condition, and this could be considered if a patient shows features not typically related to an established diagnosis.  A genetic specialist can help determine if additional testing, such as CMA, would be useful.

CMA is being investigated for use in other patient populations, and its uses will expand over time. In these cases it may be especially useful when other tests have failed to yield a diagnosis:

• Unexplained seizure disorder
• Growth delay
• Psychiatric illness
• Neuromuscular conditions

How are results used clinically?

CMA testing may be a gateway to getting more help for families of children with previously undiagnosed conditions.  A variant found on CMA may not only provide a long-awaited explanation for a patient’s clinical findings, but also impact management in the following ways:

• Specific cognitive, developmental and functional profiles associated with some variants guide prognosis, management and educational interventions.
• Evaluations or referrals may be indicated for syndromes to screen for complications that may otherwise have been missed.
• Family studies inform reproductive planning and screening for at-risk family members.

A CMA diagnosis can also provide psychosocial benefit for the family, including access to a new support community of individuals with a similar diagnosis. See the case examples below, and the Apply Results section, for examples and resources related to the clinical utility of CMA results.

Should CMA replace traditional chromosome analysis or other genetic tests?

In 2010, the American College of Medical Genetics recommended CMA as first-tier testing in the population of individuals with developmental delay, intellectual impairment, autism spectrum and multiple congenital anomalies.

CMA leads to a diagnosis in 10-15%, which is significantly better than the ~3% yield with traditional chromosome analysis. CMA can also detect most gross chromosome abnormalities detected by standard karyotype.

Karyotype is still appropriate for patients who strongly fit the features of a specific chromosomal abnormality diagnosis, such as Down syndrome.  Targeted molecular genetic testing is appropriate for conditions such as Fragile X syndrome that are not detected by CMA. However, CMA may be useful when those tests have failed to yield a diagnosis, when a patient has a diagnosis but an unusual course, or when the differential includes multiple conditions with overlapping features.

Findings suggestive of a specific diagnosis indicating targeted testing may include:

• Characteristic physical features
• Specific constellations of congenital malformations
• Certain cognitive/developmental profiles
• Clear pattern of inheritance in the family

When in doubt, consult with a clinical or laboratory genetics specialist (see How do I get help?).

What are the costs and risks?

In general, genetic testing costs more than routine lab tests. While CMA is currently more expensive than traditional chromosome analysis, the diagnostic yield is significantly higher in patients with certain indications. Costs are decreasing as technology improves.

There is a risk of uncertain, uninformative or unexpected findings. However, a negative result is not necessarily unhelpful in a diagnostic search. The potential clinical and psychosocial impact of various results must be weighed on a case-by-case basis. See the sections on pre- and post-test counseling for tips for this process.