A 2025 study of women with repeated IVF failure and unexplained infertility found that about 13% had mutations affecting egg or embryo development, mostly in the TUBB8 and PATL2 genes, suggesting that many “unexplained” cases may have underlying genetic causes.
Repeated IVF failure can result from problems with the egg, sperm, or embryo.
Previous research has identified genetic factors that contribute to these issues, such as mutations in genes like TUBB8, which disrupts how the egg’s chromosomes are organized and divided during maturation, or in PADI6, which causes embryos to arrest shortly after fertilization.
A new multicenter study by Chen et al. (2025) analyzed 3,627 patients with unexplained infertility and recurrent IVF failure using whole-exome sequencing (WES) to map genetic causes of egg and embryo defects. The researchers categorized patients into three main groups:
- Oocyte defects (eg. immature eggs or abnormalities in the zona pellucida, 1554 patients)
- Abnormal fertilization (eg. no pronuclei or multiple pronuclei after fertilization, 248 patients)
- Embryonic arrest (eg. embryos that stopped developing before reaching the blastocyst stage, 1825 patients)
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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About 13% of patients had identifiable genetic causes
The researchers screened the 3,627 women with recurrent IVF failure for mutations in 37 known genes linked to oocyte and embryo defects. They identified mutations in 479 patients (13.2%), with several genes explaining most of the cases.
- TUBB8 (225 patients, 47%) – the most common, linked to oocyte maturation arrest, embryonic arrest, and abnormal fertilization.
- PATL2 (45 patients, 9.4%) – associated with oocyte maturation arrest and early embryonic arrest.
- PADI6 (16 patients, 3%) – associated with early embryonic arrest or implantation failure.
- NLRP5 (10 patients, ~2%) – involved in early embryonic arrest and low fertilization.
- ZP1 (9 patients, ~2%) – associated with empty follicle syndrome or abnormal zona formation.
- CDC20 (8 patients, ~2%) – linked to maturation arrest and low fertilization rates.
- WEE2 (7 patients, ~1.5%) – linked to total fertilization failure.
- Rare variants were also found in other genes, including TLE6, NLRP2, NLRP7, TRIP13, MEI1, MEI4, BTG4, ZP2, ZP3, LHX8, TBPL2, PANX1, COX15, and KPNA7, each tied to specific phenotypes such as zygote arrest, zona abnormalities, or oocyte degeneration.
In this group of 3,627 patients, genetic causes were identified in 17.5% of those with oocyte defects, 15.3% of those with abnormal fertilization, and 9.3% of those with embryonic arrest. TUBB8 and PATL2 together accounted for most oocyte defect cases, WEE2 and TUBB8 were the main contributors to abnormal fertilization, and TUBB8 and PADI6 were most frequently linked to embryonic arrest.
So what do these genes do?
- TUBB8 helps the egg divide properly by forming the spindle that separates chromosomes. When this process goes wrong, eggs can’t mature or embryos stop developing.
- PATL2 manages the egg’s stored instructions (maternal mRNA) that guide early development before the embryo’s own genes switch on.
- WEE2 acts as the “start signal” for the egg to finish maturing and activate after fertilization, so mutations here cause fertilization failure.
- PADI6 helps the early embryo divide by stabilizing a supportive structure inside the egg, and when it doesn’t work, embryos often arrest before reaching the blastocyst stage.
Five new genes found linked to egg and embryo defects
In addition to these 37 genes, the researchers also uncovered 123 novel candidate genes that may be involved in egg or embryo defects. This expands the picture of how many different genetic pathways can influence egg and embryo development.
They confirmed five of these (CNTD2, SPDYC, DDOST, INCENP, and MLH3) by testing them in mouse eggs. These genes are involved in key processes like cell division, protein function, and DNA repair. When their activity was disrupted, the eggs couldn’t mature or the embryos stopped developing, suggesting that these genes play important roles in fertility.
Conclusion
This study found that about 13% of women with repeated IVF or ICSI failure and unexplained infertility had genetic mutations affecting their eggs or embryos, most often in the TUBB8 and PATL2 genes. The researchers also identified over 100 new candidate genes for further study, including five that were shown to disrupt egg development in mice.
Still, most cases did not have a clear cause, possibly due to non-genetic factors, limits in current testing that miss some genetic or epigenetic changes, and the fact that male genetics were not analyzed.
While sperm also plays a role in embryo development, the egg is especially important early on because it provides everything the embryo needs before its own genes turn on (“embryonic genome activation”). During this stage, the embryo depends completely on the egg’s stored RNA and proteins, so mutations in the egg can more easily disrupt embryo development. You can read more about embryonic genome activation in my post on Embryo arrest.
Still, research shows that sperm matters too: DNA damage, abnormal methylation, and rare gene mutations can affect embryo quality and increase miscarriage risk. Understanding both egg and sperm genetics will help explain more cases of failed fertilization and early embryo loss.
These results suggest that many cases of “unexplained” IVF failure may actually have genetic causes. Testing and counseling can help identify these issues, giving patients clearer answers and helping doctors plan the next steps.
Want to read more about genetics and its link to infertility?
Even when embryos are euploid and pass PGT-A, miscarriage can still happen. A new 2025 study suggests that genetic mutations too small to be seen by standard PGT-A may explain some of these losses. Read more.
Researchers in a 2023 study discovered 6 genes associated with recurrent miscarriage of euploid embryos, which were found to impair reproductive ability in mouse models. Read more.
Researchers in a 2021 review examined how sperm and eggs can sometimes be genetically incompatible, based on a group of proteins called human leukocyte antigens (HLA), which may lead to implantation failure or embryo arrest when they're mismatched. Read more.
Researchers in 2023 provide evidence-based guidelines for managing patients with unexplained infertility, as prepared by ESHRE. Read more.
Related studies
These additional studies were referenced by the authors of the paper and haven’t been covered on Remembryo. They may be helpful if you’re exploring this topic further. This section is available for paid subscribers.
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
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