Advancing the Current Understanding of Female Reproductive Failure: Genetic Causes and Personalized Care for Molar Pregnancies
Dr. Rima Slim, Principal Investigator at the Research
Institute of the McGill University Health Centre.
“Our work is advancing the current understanding of female reproductive failure and promoting the use of precision medicine in clinical practice to better diagnose this condition and tailor the management of the patients to their exact gene defects. The most rewarding aspect of my work is helping patients directly or indirectly by helping their physicians be up-to-date on the genetics of female reproductive failure.”
Reproductive failure affects 10-15% of couples worldwide, manifesting as infertility, repeated miscarriages, and molar pregnancies (pregnancies with no embryos). The genetic causes of these conditions are not well understood because they are complex and vary from case to case.
A molar pregnancy, also called a hydatidiform mole, happens when the embryo stops developing after fertilization, but the tissue that normally forms the placenta hyperproliferates. The sporadic form of hydatidiform moles happens in about 1 in every 600 pregnancies in Western countries. Hydatidiform mole is the most common gestational tumour, but most of them are benign, and in up to 15% of the cases, the patients may require chemotherapy. In rare cases, they can become malignant, requiring more aggressive treatments. If not treated, malignant moles may lead to serious health problems and death.
There are two types of molar pregnancies: complete and partial. Complete molar pregnancies do not have genetic material from the mother and result from the fertilization by one or two sperm. Until recently, it was not known when and how the egg loses its chromosomes. In a partial molar pregnancy, an egg with 23 chromosomes is fertilized by two sperm, creating an embryo with too many chromosomes (69 chromosomes or triploid).
Research shows that people who have had one hydatidiform mole have a 1-4% chance of having another one. Recurrent diploid biparental (two sets of chromosomes, one from each parent) moles are often linked to single gene defects. Identifying the defective gene causing recurrent molar pregnancy is important for managing the condition, predicting the chances of it happening again, guiding genetic counselling, and tailoring assisted reproductive technologies to each patient's needs.
Professor Rima Slim, a principal investigator at the Research Institute of the McGill University Health Centre, leads research focused on identifying the genes and mechanisms behind different forms of female reproductive failure, including recurrent hydatidiform mole, recurrent miscarriage, and infertility. Her team has identified the first maternal-effect gene, NLRP7, responsible for recurrent diploid biparental moles. They discovered that the severity of the defects in this gene in the patients correlates negatively with the differentiation of embryonic tissues in the conception and positively with the excessive growth of the placenta. In collaboration with Professor Jacek Majewski, an expert in high throughput genomic analyses, Dr. Slim's team also found three other genes – MEI1, TOP6BL, and REC114 – linked to recurrent androgenetic (with no maternal chromosomes) moles. With the collaboration of Professor Teruko Taketo, an expert in mouse oogenesis, they modelled the mechanism of this disease in a mouse model for one of these genes, Mei1, and visualized how the oocytes lose all their chromosomes by extruding them with the spindles into the first polar bodies.
The goal of Dr. Slim's research group is to improve the understanding of the genetics behind female reproductive failure and use this knowledge to create new DNA tests that can help diagnose these conditions. This can lead to more personalized care for patients based on their genetic profiles. Because of Dr. Slim's research, patients, in Canada and everywhere, are now tested for mutations in NLRP7, MEI1, TOP6BL, and REC114, genes to get more personalized care. For patients with two defective copies of these genes, the chances of having children with their own eggs are very low, and assisted reproductive technologies with their own eggs are unlikely to help. However, patients with two defective NLRP7 copies may still have children using donated eggs.
Dr. Slim's team collaborates closely with patients, clinicians, and genetic counsellors at all stages of their research. They are currently recruiting patients with at least two molar pregnancies (all types), at least five miscarriages without a live birth, or at least five years of infertility without a live birth. Their goal is to find more genes linked to all forms of reproductive failure.
Contact information for patients interested in the study: rrw@muhc.mcgill.ca.
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