While there has admittedly been a lot of hype around genetics, most people may not realize that there are many instances in which the technology is being used on a daily basis – such as prenatal testing. We recently had the opportunity to correspond with Mark McDonough, the CEO of CombiMatrix, about how his company is leveraging chromosomal microarrays to replace the traditional karyotype during pregnancy.
Shiv Gaglani, Medgadget: How many women are affected by miscarriage each year?
Mark McDonough: First trimester pregnancy losses are thought to occur in approximately 20% of all recognized pregnancies. In 2013 there were 4.4 million pregnancies in the United States, of which approximately 880,000 resulted in miscarriage. In addition, between 100,000 and 200,000 women included in that number are victims of recurrent pregnancy loss (three or more miscarriages).
Medgadget: How are miscarriage tests typically performed today? What are the limitations of this technology?
McDonough: We know that half of early pregnancy losses are caused by a major chromosomal abnormality in the baby, and miscarriage analysis can be particularly important for women suffering from recurrent pregnancy loss so they can better understand why they miscarried and if they are at risk for subsequent miscarriages.
In the past, if a clinician offered testing it would be a routine karyotype. This type of testing requires living fetal cells to be grown in culture, and up to 50% of the time karyotyping will not provide a result as the cells failed to grow in culture. This can be particularly frustrating because most labs will attempt to culture the cells for up to three or four weeks before determining that the miscarriage test is a failure. Furthermore, when cells are grown in culture, it is also possible that new chromosomal abnormalities develop that were not originally present (culture artifact), which is problematic because recurrence risk counseling is based on the type of chromosomal abnormality identified.
Today we have a better technology for miscarriage testing – chromosomal microarray –that is much quicker that traditional karyotype and that does not require that you culture cells; you simply extract the DNA. We are now seeing a tremendous migration from karyotyping to microarray.
Medgadget: Please describe CombiMatrix’s testing technology and its advantages compared to traditional karyotyping.
McDonough: At CombiMatrix, we use single nucleotide polymorphism (SNP) microarray technology (Illumina) to quantify the presence or absence of hundreds of thousands of unique regions throughout the fetal genome, and we employ a mathematical algorithm to derive precise, objective data. One criticism of karyotyping is that is it dependent on the expertise of technician and the cytogeneticist who are interpreting the results, so it is, by nature, subjective test.
Instead of relying on living cells, microarray evaluates fetal DNA directly and is able to provide a result 95% of the time, versus 50% of the time for karyotyping, and is not subject to culture artifact. We are also able to turn around the analysis in ten days, as opposed to three weeks, providing the patient with an answer as quickly as possible.
Furthermore, because the microarray evaluates chromosomal information at a much higher resolution than traditional karyotyping, we can identify a whole host of chromosomal disorders caused by microdeletions and microduplications that are too small to be detected by microscopic evaluation of the chromosomes used in karyotyping. While the more obvious chromosomal abnormalities, like an extra or missing chromosome such as a trisomy 13 or a monosomy X, are the usual culprits in early trimester losses, microdeletion and microduplication disorders that are missed by karyotyping are more likely to be associated with later pregnancy losses.
A secondary benefit of using our SNP microarray technology is that we are able to test formalin-fixed paraffin-embedded (FFPE) tissue. We can therefore look at both tissue from the most recent loss and archived tissue from any previous losses to determine if there are any trends in the genetic abnormalities that might inform our risk counseling.
Medgadget: Beyond miscarriage analysis, where is CombiMatrix applying its microarray technology? What are the indications?
Microarray analysis has been the standard of care for the evaluation of children and adults with intellectual disabilities, developmental delay and general abnormalities in autism for over five years. By using microarray technology to replace standard genetic testing, such as karyotyping and fluorescence in situ hybridization (FISH), the diagnosis rates for these have more than doubled. One of the biggest surprises early on was that approximately 7% of children with an autism spectrum disorder actually have a chromosomal microdeletion or microduplication. By identifying the cause of autism, the families now have valuable knowledge that not only assisted them in their care but also helps with family planning and recurrent risks and of course the most important question: why did this happen to my child?
We also offer prenatal microarray testing for expecting parents following amniocentesis or chorionic villus sampling (CVS). The American College of Obstetricians and Gynecologists (ACOG) released practice guidelines in December 2013 that recommend the use of chromosomal microarray in lieu of traditional karyotyping for any pregnancy affected by fetal anomalies detected by ultrasound. A landmark multicenter, prospective study sponsored by the National Institute of Child Health and Human Development (NICHD) found that microarray analysis identified clinically significant results and abnormalities that were missed by karyotyping in 6% of women, which is 1 in 17.
Medgadget: Prenatal genetic testing is a hot area for companies with noninvasive tests that only require blood draws. Isn’t your microarray testing, which requires samples obtained through invasive amniocentesis and CVS, in danger of becoming obsolete?
McDonough: Today’s non-invasive prenatal screening (NIPS) tests that use a simple blood draw from the mother, while a vast improvement to the screening tests of the past three decades, are still that – screening tests, and that’s what people need to remember with these non-invasive tests. Screening tests by definition have false positives and false negatives, and we’ve had many of these samples come through our laboratory with a positive non-invasive prenatal screening result that ended up being normal. A recent paper published this month in Genetics in Medicine highlighted the high discordant rate between NIPS tests and cytogenomic analysis. There is a significant potential for false positives with NIPS, and so it is important that patients and physicians consider the ACOG recommendation to confirm positive NIPS tests with an invasive procedure to ensure accuracy.Microarray testing is complementary to NIPS, and we have established a partnership with Sequenom to broaden and confirm the results of their MaterniT21 non-invasive prenatal testing. Any expecting mother who receives a positive result from MaterniT21 is then reflexed to microarray testing.In addition, something that is not always well understood today is that CVS and amniocentesis actually have a low risk associated with them when performed by an experienced provider. ACOG published practice bulletin in 2007, which was reaffirmed in 2012, indicating that a review of the literature showed the true risk associated with CVS and amniocentesis was less than between the window of 1/300 and 1/500, which is a much smaller number than traditionally quoted. Based on this number, all women, regardless of their age, should be offered the option of invasive testing. This recommendation has supplanted the long-standing notion that only women of advanced maternal internal (age 35 and older) should be offered invasive testing.
Medgadget: Where do you see your technology taking CombiMatrix in the future?
McDonough: We are dedicated to using the best technology in the market to help improve the lives of individuals by providing them with information that they can use to help manage their health and the health of their families. Microarray testing is where our company started; we originated as a tools organization, and we have tremendous human capital in that regard.