Recent research has uncovered six new genes linked to recurrent molar pregnancies, shedding light on their increased prevalence in women aged 35 and older. A molar pregnancy, or hydatidiform mole, is an abnormal pregnancy characterized by an absent embryo and excessive placental cell growth. This condition affects approximately one in every 600 pregnancies in Quebec, with androgenetic moles—containing only paternal chromosomes—occurring ten times more frequently in older mothers. Alarmingly, up to 15% of these cases can progress to placental cancer.
Scientists at the Research Institute of the McGill University Health Centre (RI-MUHC) have identified six previously unknown genes—FOXL2, MAJIN, KASH5, SYCP2, HFM1, and MEIOB—that, when mutated on both alleles, contribute to recurrent molar pregnancies, miscarriages, and infertility. Five of these genes play a crucial role in Meiosis I, the process responsible for egg and sperm cell development. Defects in these genes have also been linked to premature ovarian failure and male infertility, highlighting their critical function in reproductive health.
These groundbreaking findings, published in the Journal of Clinical Investigation, are expected to revolutionize the molecular diagnosis of recurrent molar pregnancies and infertility. “Our research suggests that recurrent androgenetic moles are a marker of ovarian aging. This will lead to significant changes in clinical practice, particularly in evaluating ovarian reserve in affected patients,” explained Prof. Rima Slim, the study’s co-senior author and a professor in McGill University’s Department of Human Genetics.
Expanding the Genetic Landscape of Molar Pregnancies
The six newly discovered genes build upon previous research by the same team, which identified four other genes responsible for recurrent molar pregnancies, including NLRP7 (discovered in 2006) and MEI1, TOP6BL, and REC114 (discovered in 2018).
To further investigate the genetic basis of molar pregnancies, researchers collaborated with McGill’s Prof. Jacek Majewski, conducting exome sequencing on 75 patients from around the world who had experienced at least two molar pregnancies but did not carry mutations in previously known genes. Additional analysis included 240 patients with other forms of reproductive failure, referred primarily from the MUHC Repeated Pregnancy Loss Clinic and the Réseau des Maladies Trophoblastiques du Québec. This broader study revealed that 14% to 28% of patients carried single mutated alleles in genes linked to Meiosis I and ovarian function, suggesting a genetic predisposition to reproductive failure.
“Our findings provide a genetic explanation for the increased frequency of androgenetic moles with advanced maternal age,” said Prof. Slim. “Patients with mutations in these genes can conceive and have healthy children, but they face a higher risk of infertility, premature ovarian insufficiency, and pregnancy loss compared to the general population.”
Breakthroughs in Disease Modeling and Future Implications
To further investigate the genetic mechanisms underlying molar pregnancies, researchers developed a mouse model deficient in the HFM1 gene. Using live-cell imaging, they observed chromosomal abnormalities during egg cell development, similar to those previously documented in another molar pregnancy-related gene, Mei1. “For the first time, we were able to visualize how eggs from Hfm1-deficient mice lose all their chromosomes,” explained Dr. Teruko Taketo, co-senior author of the study and a professor in McGill’s Department of Surgery.
The identification of a common mechanism in multiple mouse models strengthens the plausibility of these findings in humans, providing deeper insight into the origins of androgenetic moles. “Since these abnormal pregnancies were first described in 1977, we now have a much clearer understanding of their formation,” added Prof. Slim.
This research marks a major advancement in reproductive genetics, paving the way for improved diagnostic tools, targeted fertility treatments, and personalized patient care for individuals affected by recurrent molar pregnancies and infertility.
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