Choosing a prenatal diagnostic test: Microarray analysis shown equal to karyotyping

Jan 1st – Chromosomal microarray analysis was successful in 98.8% of fetal samples.[tabs tab1=”2MM Rundown” tab2=”Full 2MM Report” tab3=”About the Authors”]

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Image: PD

1. Chromosomal microarray analysis was successful in 98.8% of fetal samples.

2. All of the aneuploidies and unbalanced arrangements identified via karyotyping were likewise identified by microarray, except for cases of balanced translocations and fetal triploidy.

3. Microarray allowed for identification of additional clinically relevant deletions and duplications in samples with a normal karyotype.

Microarray analyses have proven to be equally efficacious in identifying aneuploidies and unbalanced rearrangements and provided additional clinically relevant findings (e.g. segmental aneuplodies, copy number variants). However, there are certain limitations and issues that warrants attention. The microarray analyses did not identify balanced translocations and triploidies. Moreover, “uncertain” findings occurred in 3.4% (130 of 3822) karyotypically normal samples, more than 72.3% (94 of 130) of these cases could not be dismissed as benign and will likely require additional interpretation among a team of clinical geneticists, counselors, and laboratory directors, in addition to causing anxiety for the patient. Furthermore, while 1.7% or 1 in 60 samples with advanced maternal age or positive aneuploidy screening produced clinically relevant copy number variants, the small size and the subsequent mild phenotypic effects of these variants must also be considered before pushing for more invasive testing.

At this point in time, additional studies are necessary to confirm the frequencies of clinically relevant deletions and duplications, and patients must be carefully counseled on the risks of invasive testing versus the frequency and expected clinical severity of such microarray findings.

Click to read the study in NEJM

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Image: PD

1. Chromosomal microarray analysis was successful in 98.8% of fetal samples.

2. All of the aneuploidies and unbalanced arrangements identified via karyotyping were likewise identified by microarray, except for cases of balanced translocations and fetal triploidy.

3. Microarray allowed for identification of additional clinically relevant deletions and duplications in samples with a normal karyotype.

Primer: Fetal karyotyping is used as a confirmatory test after positive prenatal screening for various genetic anomalies, including Down’s Syndrome. Karyotyping detects major chromosomal deletions or translocations while chromosomal microarray analysis can detect smaller genomic deletions or duplications. Microarray analyses have identified a genetic cause in an additional 12-15% of children already diagnosed with altered neurocognitive development, in comparison to regular karyotyping. To further evaluate the reliability of microarray analyses in detecting chromosomal abnormalities, including those not seen on karyotyping, a prospective study comparing karyotyping and microarray analyses on prenatal diagnostic samples was performed in the present study.     

Background reading:

1. Cytogenetic and molecular genetic diagnostic tools

2. Overview of prenatal screening and diagnosis of Down syndrome

3. Sagoo GS, Butterworth AS, Sanderson S, et al. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med 2009;11:139-46.

This [prospective cohort study]: A total of 4,406 of women underwent chorionic-villus sampling and amniocentesis for microarray analysis and subsequent confirmatory karyotyping. Microarrays identified all of the autosomal and sex chromosome aneuploidies (7.4 and 1.3% respectively) and unbalanced rearrangements seen via karyotyping. Among 3,822 fetal samples with normal karyotypes, 96 (2.5%) had deletions or duplications of clinical significance. Clinically relevant findings via microarray were reported in 6% of cases with suspected structural anomalies, 1.7% of with advanced maternal age, and 1.6% testing positive for Down’s, all of which had normal karyotypes.

In sum: Microarray analyses have proven to be equally efficacious in identifying aneuploidies and unbalanced rearrangements and provided additional clinically relevant findings (e.g. segmental aneuplodies, copy number variants). However, there are certain limitations and issues that warrants attention. The microarray analyses did not identify balanced translocations and triploidies. Moreover, “uncertain” findings occurred in 3.4% (130 of 3822) karyotypically normal samples, more than 72.3% (94 of 130) of these cases could not be dismissed as benign and will likely require additional interpretation among a team of clinical geneticists, counselors, and laboratory directors, in addition to causing anxiety for the patient. Furthermore, while 1.7% or 1 in 60 samples with advanced maternal age or positive aneuploidy screening produced clinically relevant copy number variants, the small size and the subsequent mild phenotypic effects of these variants must also be considered before pushing for more invasive testing. At this point in time, additional studies are necessary to confirm the frequencies of clinically relevant deletions and duplications, and patients must be carefully counseled on the risks of invasive testing versus the frequency and expected clinical severity of such microarray findings.

Click to read the study in NEJM

Written by [EP] and [RR]

© 2012 2minutemedicine.com. All rights reserved. No works may be reproduced without written consent from 2minutemedicine.com. Disclaimer: We present factual information directly from peer reviewed medical journals. No post should be construed as medical advice and is not intended as such by the authors or by 2minutemedicine.com. PLEASE SEE A HEALTHCARE PROVIDER IN YOUR AREA IF YOU SEEK MEDICAL ADVICE OF ANY SORT. 

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Elizabeth Park: Elizabeth is a 4th year M.D. Candidate at Boston University School of Medicine.

Rif Rahman: Rif is a 4th year M.D. candidate at Harvard Medical School, currently completing a research year investigating the use of conventional and advanced imaging techniques to assess treatment response of high grade gliomas.

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