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Understanding chromosomal microarrays

December 15, 2012 8:12 am

The advantages and disadvantages of chromosomal microarrays are highlighted in a recent article and a related editorial (NEJM 2012; 367: 2175-84, 2249-51).

Chromosomal microarrays can detect almost all of the chromosomal imbalances detected with conventional cytogenetic analysis. They are recommended as a first-tier test for postnatal developmental delays, autism spectrum, or with multiple congenital anomalies. Clinically significant findings occur in 15% of those with normal conventional karyotypes.

Specific advantages of microarrays:

Higher resolution
Faster turnaround due to automation
Does not require dividing cells (useful in fetal death)
Eliminates need to culture amniocytes or chorionic villi

Major downside:

In a few percent, may detect copy-number variant of uncertain clinical significance
Increased cost

The referenced study compared chromosomal microarray to karyotyping and enrolled 4406 women at 29 centers who were undergoing prenatal diagnosis. Indications for screening included advanced maternal age (47%), abnormal result on Down’s syndrome screening (19%), structural abnormalities on ultrasonography (25%), and other indications (9%) (some had multiple indications).

The microarrays were of two varieties. The first microarray (71% of cases) consisted of a fourplex array with each array consisting of 44,000 oligonucleotide probes. The second platform (29% of cases) contained 1.8 million oligonucleotide probes.

Key Findings:

Microarray identified all of the abnormalities on conventional karyotyping except for balanced translocations (no loss of genetic material).
There were 94 of 3822 fetal samples with copy-number variants of uncertain clinical significance (see blog reference below). Subsequently, 30 of these were classified as pathogenic and 8 as benign.
In samples with normal karyotypes, microarray identified clinically relevant findings in 6% of those with a structural abnormality and 1.7% of those with advanced maternal age or positive Down’s syndrome screening.

The implications of this study and related studies are that microarray has a role in prenatal evaluation of structural abnormalities. Ultimately, whole-exome sequencing will likely supersede microarray analysis and further the conundrum of interpreting abnormalities of uncertain clinical significance.

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