Sometime between the 16th and 20th week of pregnancy, expectant women are given the option of having an amniocentesis, a prenatal test that involves taking a sample of amniotic fluid primarily to determine if the baby has a chromosomal abnormality, such as Down syndrome, or a genetic disorder such as cystic fibrosis (CF) or sickle cell anemia.
Only amniocentesis or chronic villus sampling (CVS) can diagnose these problems in the womb. Both tests are invasive and carry a risk of miscarriage so most women do not have them done unless they are at an increased risk. If, for example, screening tests indicated that both parents are carriers of a recessive genetic disorder, than the woman's risk of having a baby with a genetic disorder would be higher.
It appears, however, that science may be on the brink of reducing the use of these invasive prenatal tests.
Last week Sequenom (San Diego) reported that breakthrough data from a collaborative project with the Chinese University of Hong Kong, supporting the noninvasive prenatal diagnosis of monogenic diseases, were published online in the early edition of the Proceedings of the National Academy of Sciences. Monogenic diseases, which include cystic fibrosis, thalassemia and sickle cell anemia, could only be definitively diagnosed prenatally through invasive procedures following extensive carrier screening testing on both parents.
"There's a whole range of monogenic disorders ... probably several thousand of these disorders," Harry Stylli, PhD, president/CEO of Sequenom, told Diagnostics & Imaging Week. "The only way we could ascertain the conditions they represent in the fetus is through amniocentesis or CVS."
Both amniocentesis and CVS are invasive procedures, he said, which carry a "small but real risk" of miscarriage and cost up to $2,500.
According to Sequenom, data from the collaborative project show for the first time that when individual mutant or normal DNA sequences are counted in maternal plasma using digital PCR technology, the number of mutant genes inherited by an unborn fetus, and hence its disease status, can be determined. The authors further demonstrated that a "molecular counting" strategy can be made more efficient by taking into account the length of the DNA molecules in maternal plasma, as fetal DNA molecules are known to typically be shorter than the maternally derived molecules in maternal plasma.
Through the use of this digital counting approach, the authors were able to noninvasively diagnose thalassemia and hemoglobin E disease from maternal plasma – forms of inherited anemia that affect millions of people worldwide. This molecular counting strategy can in principle be applicable to all forms of monogenic diseases, namely paternally or maternally inherited autosomal dominant diseases and autosomal recessive diseases with any combination of parental mutations. Thus, the complete diagnosis of monogenic diseases can be achieved noninvasively, the company said.
"This approach that we announced is a way of actually determining whether a fetus has these disorders noninvasively by a simple blood test," Stylli said, adding that the discovery is "truly revolutionary."
If a prenatal test was available to determine monogenic disorders noninvasively, Stylli said a wider population of women would be screened.
When asked about potential next steps for the company, Stylli said, "I think what you'll see is first of all we're going to commercialize these other tests ... move it from being a science work to being a diagnostic."
With any luck, he said, the products should be emerging by the end of 2010.
"This new study addresses a problem that has been puzzling investigators in the field of noninvasive prenatal diagnosis over the last 10 years," said Dennis Lo, MD, PhD, study co-author and Li Ka Shing, professor of medicine at the Chinese University of Hong Kong. "Digital PCR technologies have enabled us to measure the minute imbalance of mutant and normal DNA sequences in maternal plasma. This has freed us from the past restriction for monogenic disease analysis where we could only look at the paternally-inherited mutations noninvasively. This research represents a significant paradigm shift in the way we approach plasma DNA-based diagnostics, and offers substantial promise for bringing noninvasive prenatal diagnosis of monogenic diseases closer to reality."
According to Sequenom, more than 10 million people in the U.S. are carriers of the CF mutated gene and in certain regions of the world, thalassemia affects anywhere from 3% to 16% of the population. The company says it holds exclusive rights to this technology representing a new approach that could potentially eliminate the need for paternal testing and significantly reduce the use of invasive tests.
"Sequenom is committed to developing the next-generation of prenatal diagnostic tools that will provide physicians with the capabilities they need to noninvasively diagnose genetic disorders early in a woman's pregnancy," Stylli said. "Dr. Lo and his team have made another important breakthrough in prenatal diagnostics with these findings. These unique, noninvasive digital technologies have the potential to dramatically impact the prenatal diagnostic market and we look forward to continuing to work with Dr. Lo and his team to advance these innovative approaches as part of our long-term strategy to expand our prenatal diagnostics franchise."
Everyone has two sets or copies of each gene called alleles; one copy on each chromosome pair. Recessive diseases are monogenic disorders that occur from an individual having inherited two defective copies or alleles. Dominant diseases are monogenic disorders that involve defects to only one gene copy.
The discovery of cell-free fetal DNA in maternal plasma offers noninvasive prenatal diagnostics that eliminate the risk to the fetus. For many monogenic diseases of medical interest, a different quantitative approach is needed, Sequenom said. For example, for monogenic recessive diseases such as cystic fibrosis and thalassemia, the fetus would need to have inherited two copies of the mutant gene to suffer from the disease.
The inheritance of only one mutant gene signifies a disease carrier while inheritance of no mutant gene indicates a healthy fetus. However, such a precise degree of mutation quantification for noninvasive prenatal diagnosis has not previously been possible due to the presence of a high background of maternal DNA interfering with the analysis of the small amount of circulating fetal DNA in maternal plasma, the company noted.
Sequenom's commercial opportunities in prenatal diagnostics are built upon its SEQureDx technologies and are enabled by the pioneering inventions and associated intellectual property rights that it has exclusively licensed from Isis Innovation, the technology transfer company of the University of Oxford (Oxford, UK), as well as the Chinese University of Hong Kong. Sequenom's portfolio of noninvasive prenatal diagnostic patent rights and patent applications is platform-independent, includes genetic-analysis methods using circulating cell-free fetal nucleic acids from maternal serum, plasma or whole blood, and also includes a portfolio of methylation and nucleic-acid markers.
Sequenom says its MassArray system is a high-performance (in speed, accuracy and cost efficiency) nucleic acid analysis platform that quantitatively and precisely measures genetic target material and variations. Sequenom has exclusively licensed intellectual property rights for the development and commercialization of noninvasive prenatal genetic tests for use with the MassArray system and other platforms.