Research Profile - Miscarriage at the molecular level
Dr. Evica Rajcan-Separovic
For some infertile couples, the problem isn't getting pregnant, it's staying pregnant. Unexplained repeated miscarriages can leave many couples not knowing where to turn.
As many as 15% of recognized pregnancies end in miscarriage. The routine clinical practice in these cases is to carry out a chromosomal analysis of the embryo to find out what went wrong. The problem is, this analysis only detects large problems, at the chromosome level. When nothing is revealed, a woman has no explanation for why she miscarried – and no assurances about whether it will happen again.
Evica Rajcan-Separovic thinks she might be able to help. She suspects that a genetic mutation that causes changes in the number of genes that are present (known as copy-number variation, or CNV) may be responsible for at least some of these miscarriages. These variations don't show up in standard chromosomal testing under a microscope, so she is using powerful whole genome array screening (an advanced technology that allows a research to search all the genes in the human genome), or array CGH screening, as it's also known, to look for small changes in DNA that might cause miscarriages. The technology is relatively new, she says, and can be applied in any case where genetic changes are suspected. She is the first person in Canada, and one of the very few in the world, to apply the technology to reproduction.
At a Glance:
Who: Dr. Evica Rajcan-Separovic, Associate Professor, Department of Pathology and Laboratory Medicine, University of British Columbia; Scientist Level 2 at the Child & Family Research Institute
Issue: Many women experience recurrent miscarriages, but don't know why. Existing analyses only uncover large-scale problems at the chromosomal level.
Approach: Dr. Rajcan-Separovic is using whole-genome scanning to determine whether smaller-scale genetic variations are responsible for these miscarriages.
Impact: The research may help identify women for whom recurrent miscarriage is a risk and allow them to make choices that reduce that risk.
Dr. Rajcan-Separovic's early research has found small DNA copy number variations in about 30% of embryos from miscarriages that show no cause when they are subjected to traditional analysis of their chromosomes under a microscope. It's a bit of an "a-ha!" moment – or so it appears. The reality is, she says, that this is only the first step of many.
"First, we have to prove the hypothesis," she says, referring to the need to collect more evidence to clearly demonstrate that the variations are tied to miscarriage. To further understand the potential linkage, Dr. Rajcan-Separovic will study the function of each of the genes contained in CNVs found in miscarried embryos – there can be many genes – to determine which ones are important for embryo development.
She will also be testing to see whether the parents have the same genetic mutation. If the variation occurs just in the embryo, then it is likely a problem unique to that particular fetus and that has nothing to do with the parents, so there's a good chance it won't happen again. If, however, one of the parents shares the mutation, it becomes more complex, because the likelihood of future miscarriages is increased. But, she says, it's also potentially more rewarding, because that's where the third step comes in: actually assisting parents.
"It's the most clinically beneficial thing," she says. "Down the road, we'll be able to counsel parents about ways to improve the likelihood of carrying a pregnancy to term."
One of the ways to reduce the risk of miscarriage, Dr. Rajcan-Separovic says, is to produce multiple embryos through in vitro fertilization (IVF), and then select those embryos that don't have the genetic mutation.
"From discovery to the clinic takes time," she says. "We're still far from clinical application, but we've opened up a new field."
What is a chromosome?
A chromosome is a “package” of DNA containing genes and proteins. Humans have 46 chromosomes, 23 that they inherit from their fathers and 23 that they inherit from their mothers.
Chromosomal abnormalities are responsible for at least half of first-trimester miscarriages.
"We can be thankful for the development of this new technology."
The study
Finding out why a miscarriage happens is vital to helping to prevent future miscarriages, but existing technologies cannot find a cause in 30-50% of all cases. Dr. Evica Rajcan-Separovic is using genomic array technology to detect tiny chromosomal changes that may represent predisposing genetic factors in recurrent miscarriages. Working with colleagues in Austria (Dr. Tom Philipp), Chicago (Dr. Mary Stephenson) and Vancouver (Drs. Wendy Robinson and Peter Leung), Dr. Rajcan-Separovic is examining both miscarried embryos and parents who have experienced multiple miscarriages to identify the genetic causes of recurrent miscarriages. She is also determining the function of the affected genes to understand their role in reproduction and embryo/placenta development. Her work will result in a better understanding of the genetic factors that contribute to miscarriage and pave the way for future prevention, as well as optimal care for families wishing to experience a successful pregnancy.