Why PGT Still Matters with Young Donor Eggs: Understanding Sperm-Related and De Novo Genetic Risks

"We're using a 24-year-old donor tested for monogenic diseases—do we really need PGT?" This question reflects a common assumption: young, healthy donor eggs eliminate genetic risks. While it's true that donor eggs dramatically improve chromosomal normalcy compared to older maternal eggs, they represent only half of the genetic equation. The sperm contribution, paternal age effects, and spontaneous genetic changes all influence embryo quality regardless of egg source.

Understanding why genetic testing remains valuable—even with optimal donor eggs—requires examining the complete picture of embryo development and the genetic contributions from both gametes.

The Donor Egg Misconception

The fertility field has extensively documented how maternal age affects egg quality. By age 43, approximately 85% of a woman's eggs are chromosomally abnormal [1]. This stark statistic drives many patients toward donor egg treatment—and for good reason.

What donor eggs eliminate:

Maternal age-related meiotic errors
Diminished ovarian reserve concerns
Poor egg quality issues caused by aging
Maternal chromosomal rearrangements (if donor screened)
Maternal genetic diseases (if donor screened)

What donor eggs do NOT eliminate:

Paternal chromosomal contributions
Sperm DNA integrity issues
De novo (spontaneous) genetic mutations
Paternal genetic diseases or translocations
Age-related effects from sperm

This distinction is critical. While young donor eggs provide an excellent foundation, the biological reality is that embryos inherit genetic material from both the egg and sperm. Approximately 50% of an embryo's DNA comes from the paternal contribution [2].

Understanding the Genetic Equation: Egg + Sperm = Embryo

Embryo formation involves complex genetic contributions from both gametes:

Maternal contribution (from donor egg):

23 chromosomes from the oocyte
Mitochondrial DNA (exclusively maternal)
Cytoplasmic factors supporting early development
Epigenetic modifications affecting gene expression

Paternal contribution (from sperm):

23 chromosomes from the spermatozoon
Centrosome (organizing cell division machinery)
Specific epigenetic imprinting patterns
Y chromosome (for male embryos)

Post-fertilization events:

Chromosome segregation during first mitotic divisions
De novo mutations occurring during early cell divisions
DNA repair mechanisms (or failures thereof)
Epigenetic reprogramming

Each of these steps carries potential for genetic errors, regardless of maternal egg quality [3].

Paternal Age and Aneuploidy: What Research Shows

While the relationship between maternal age and egg aneuploidy is well-established, paternal age effects are more nuanced and often underappreciated.

The data on paternal age in donor egg cycles:

A landmark 2020 study analyzed 3,118 embryos from 437 IVF cycles using young oocyte donors, specifically to isolate paternal effects [4]. The findings:

Overall euploidy rates by paternal age:

Age ≤39: 69.2% euploid
Age 40-49: 70.6% euploid
Age ≥50: 71.4% euploid

Key insight: No significant difference in overall aneuploidy rates across paternal age groups when using young donor eggs [4].

However, the study revealed important qualitative differences:

Advanced paternal age (≥50) was associated with:

Lower fertilization rates (76.35% vs. 80.09% in younger men)
Increased segmental chromosomal aberrations
Higher rates of complex aneuploidies [4]

Segmental aberrations matter: Unlike whole chromosome aneuploidies (which typically prevent implantation), segmental deletions or duplications can result in:

Developmental abnormalities
Increased miscarriage risk
Potential for genetic syndromes in offspring
Mosaic embryos with reduced viability [5]

Other research findings:

A 2024 study examining very young donors (18-22) found that while maternal age drives most aneuploidy, paternal factors independently contributed to embryo chromosomal abnormalities in multivariate analysis [6].

Research on paternal age >45 has shown associations with:

Increased de novo point mutations (not detected by standard PGT-A)
Higher rates of certain genetic conditions in offspring
Reduced embryo developmental competence
Altered DNA methylation patterns [7][8]

Clinical interpretation:

While young donor eggs dramatically improve the baseline, paternal factors—especially advanced age—contribute incremental genetic risks that PGT can help identify and mitigate.

De Novo Mutations: Random Genetic Changes

Perhaps the most underappreciated genetic risk in donor egg cycles involves de novo mutations—genetic changes that occur spontaneously and are present in neither parent.

What Are De Novo Mutations?

De novo mutations are genetic alterations that appear for the first time in an individual, not inherited from either parent. They occur through several mechanisms:

Types of de novo mutations:

Point mutations - Single nucleotide changes in DNA sequence
Insertions/deletions - Small additions or losses of genetic material
Copy number variations - Larger duplications or deletions
Chromosomal rearrangements - Structural changes arising during cell division

When they occur:

During gametogenesis (sperm or egg formation)
At fertilization during chromosome segregation
During early embryonic cell divisions (post-fertilization)
Throughout the cleavage stage (day 1-3)
During blastocyst formation (day 5-6) [9]

How Common Are They?

The surprising frequency:

Research indicates that de novo mutations are far more common than most patients realize:

In live births:

Each child carries approximately 60-70 de novo point mutations not present in either parent [10]
Most are benign, occurring in non-coding DNA regions
Approximately 1-2% occur in protein-coding genes
An estimated 1 in 300 live births involves clinically significant de novo mutations [11]

Paternal age effect on de novo mutations:

Unlike aneuploidy (primarily maternal age-related), de novo point mutations increase significantly with paternal age:

Fathers age 20: ~25 de novo mutations per offspring
Fathers age 40: ~65 de novo mutations per offspring
Each additional paternal year adds approximately 1-2 new mutations [12]

Why paternal age matters more for point mutations:

Sperm production (spermatogenesis) continues throughout male life, with approximately 23 cell divisions per year after puberty. Each division carries risk of replication errors. By age 40, sperm have undergone 660+ cell divisions vs. egg development which pauses after fetal life [13].

Clinical conditions linked to paternal age-related de novo mutations:

Achondroplasia (dwarfism)
Apert syndrome
Crouzon syndrome
Pfeiffer syndrome
Some cases of autism spectrum disorder
Schizophrenia risk increase [14]

Can PGT Detect De Novo Mutations?

Standard PGT-A limitations:

PGT-A using NGS (Next Generation Sequencing) analyzes chromosome number and large structural changes but does not detect:

Single nucleotide variants (point mutations)
Small insertions/deletions
Most de novo mutations causing genetic conditions

What PGT-A DOES detect:

Whole chromosome aneuploidies (the most common embryo abnormality)
Large segmental deletions/duplications (>10 Mb)
Some chromosomal rearrangements
Mosaicism in biopsied cells [15]

Advanced PGT technologies:

Emerging approaches can detect some de novo mutations:

PGT-P (Polygenic Risk Scoring):

Assesses multiple genetic variants simultaneously
Predicts risk for complex conditions
Controversial and not widely available [16]

Whole genome sequencing of embryos:

Technically feasible but not clinically standard
Raises significant ethical considerations
Limited clinical utility for most patients [17]

The practical reality:

For most donor egg patients, standard PGT-A provides valuable screening for common chromosomal abnormalities (~25-30% of embryos) but won't catch rare de novo mutations. However, this limitation applies to ALL embryo screening—with or without donor eggs [18].

Sperm DNA Fragmentation and Embryo Quality

Beyond chromosomal content, sperm DNA integrity influences embryo development and genetic stability.

Understanding DNA fragmentation:

Sperm DNA fragmentation (SDF) refers to breaks in the DNA strands within sperm. High SDF rates correlate with:

Reduced fertilization rates
Poor embryo quality
Increased embryo arrest
Higher miscarriage rates
Potential for genetic instability in embryos [19]

Causes of elevated SDF:

Advanced paternal age
Oxidative stress
Varicocele
Infections
Smoking and environmental toxins
Prolonged abstinence
Testicular hyperthermia [20]

How SDF affects donor egg cycles:

Even with excellent donor egg quality, high sperm DNA fragmentation can:

Compromise fertilization - Damaged DNA may prevent proper pronuclear formation
Reduce blastocyst rates - Embryos arrest more frequently during development
Decrease implantation - Embryos with paternal DNA damage have lower viability
Increase pregnancy loss - First trimester miscarriage risk rises with high SDF [21]

Relationship to PGT results:

Some research suggests high SDF correlates with increased aneuploidy rates in resulting embryos, though data remains mixed. What's clear: sperm DNA integrity matters independently of donor egg quality [22].

Clinical assessment:

NGC can evaluate sperm DNA fragmentation through specialized testing. When elevated SDF is identified, interventions may include:

Antioxidant supplementation
Lifestyle modifications
Testicular sperm extraction (TESE) in severe cases
Timing optimization for sperm collection [23]

Paternal Genetic Contributions Beyond Chromosomes

Sperm contributes more than just 23 chromosomes—epigenetic factors also influence embryo development:

Epigenetic imprinting:

Specific genes require correct "imprinting" (chemical modifications affecting expression) from paternal contribution. Errors in paternal imprinting can cause:

Beckwith-Wiedemann syndrome
Angelman syndrome (when combined with maternal factors)
Growth and developmental abnormalities [24]

Sperm RNA and proteins:

Recent research reveals sperm delivers RNAs and proteins influencing:

Early embryo gene activation
Developmental competence
Offspring metabolism and health
Potential transgenerational effects [25]

Centrosome contribution:

Sperm provides the centrosome—the cellular structure organizing chromosome segregation during first embryo divisions. Centrosome defects can lead to:

Chaotic first divisions
Embryonic aneuploidy (even with euploid gametes)
Developmental arrest
Mosaicism [26]

Clinical implications:

These paternal factors operate independently of donor egg quality, explaining why embryo outcomes can vary even with identical egg donors.

When Male Factor Increases Genetic Risk

Certain male factor conditions elevate genetic risks in donor egg cycles:

Severe Oligozoospermia (<5 million/ml)

Very low sperm counts may reflect underlying genetic issues:

Y chromosome microdeletions (present in 10-15% of severe cases)
Chromosomal abnormalities
Increased aneuploidy in sperm
Higher DNA fragmentation [27]

Klinefelter Syndrome (47,XXY)

Men with Klinefelter's can produce sperm via testicular extraction but face:

Higher rates of sex chromosome aneuploidies in sperm
Increased risk of XXY, XYY offspring
PGT-A strongly recommended [28]

1. Y Chromosome Microdeletions
Deletions in AZF regions (azoospermia factor) are:
- Transmitted to all male offspring
- Associated with future male infertility in sons
- Require genetic counseling for family planning [29]
1. Balanced Translocations/Inversions
As discussed in previous articles, chromosomal rearrangements produce ~50% unbalanced embryos regardless of egg source—PGT-SR is essential [30].
1. Known Genetic Diseases
Autosomal dominant conditions, X-linked carrier status, or shared recessive mutations with donor all require PGT-M [31].

Real Data: Aneuploidy Rates in Donor Cycles by Paternal Age

Comprehensive analysis from multiple studies:

Donor Age Group	Paternal Age <40	Paternal Age 40-49	Paternal Age ≥50
18-25 years	75-80% euploid	72-78% euploid	70-75% euploid
26-30 years	70-75% euploid	68-73% euploid	68-72% euploid
31-35 years	65-70% euploid	65-68% euploid	63-67% euploid

Data compiled from studies [4][6][32][33]

Why NGC Recommends Comprehensive Screening

NGC recommends comprehensive screening because genetic risk factors extend far beyond maternal egg quality alone. Their approach begins with pre-cycle genetic screening that's tailored to each patient's situation. All patients receive genetic carrier screening using expanded panels, along with karyotype analysis when their medical history suggests it's necessary, and sperm DNA fragmentation testing is included whenever male factor infertility is present.

For fathers over 45 years old, the clinic provides detailed genetic counseling with thorough discussion of de novo mutation risks, and they strongly recommend PGT-A testing. When patients have known genetic issues, the team offers PGT-M or PGT-SR testing as appropriate, and they can combine multiple testing approaches when several concerns exist simultaneously.

During donor egg cycles, NGC incorporates PGT-A for embryo selection because it serves multiple purposes. The testing identifies the 25-30% of embryos that are aneuploid, helps optimize the transfer order when multiple blastocysts are available, and avoids the 12.7% of cycles where all embryos turn out to be aneuploid. It also detects large segmental abnormalities that may come from the paternal contribution.

After embryo transfer, prenatal screening remains an important part of the process. PGT testing doesn't replace traditional prenatal testing because it can detect conditions beyond PGT's scope, such as de novo mutations and small deletions. NGC recommends standard obstetric care for all pregnancies regardless of the genetic testing performed beforehand.

The clinic's comprehensive approach is supported by their in-house genetic laboratory, which enables integrated testing with rapid turnaround times. NGC's genetic counselors provide personalized risk assessment by considering maternal age for patients using their own eggs, paternal age, complete medical and family genetic history, previous pregnancy outcomes, and sperm parameters. This thorough evaluation ensures that each patient receives a testing strategy specifically designed for their unique situation.

Faqs

My partner is 35 and healthy. Do we really need PGT with a 23-year-old donor?

At age 35, paternal age effects are minimal, but aneuploidy rates in donor cycles remain 25-30% regardless of paternal age [6]. The question isn't about paternal risk—it's whether PGT-A's benefits (embryo prioritization, avoiding aneuploid transfers, integration with guarantee programs) align with your goals. Many patients with multiple embryos find value in knowing which are chromosomally normal regardless of paternal age.

If PGT-A doesn't detect de novo mutations, what's the point when using young donor eggs?

PGT-A detects whole chromosome aneuploidies—the most common embryo abnormality affecting 25-30% of donor embryos [34]. De novo point mutations are rare (~1 in 300 births) and mostly benign. PGT-A addresses the high-frequency risk (aneuploidy), while prenatal screening during pregnancy catches most clinically significant de novo mutations. It's about managing the risks we can identify.

Does high sperm DNA fragmentation mean we shouldn't do donor egg IVF?

No. Elevated SDF affects outcomes but doesn't preclude treatment. Options include: treating underlying causes (antioxidants, lifestyle changes), using testicular sperm (often has lower fragmentation), optimizing collection timing, and selecting the best embryos with PGT-A. Many couples with high SDF achieve pregnancy with donor eggs—the path may require optimization but remains viable [21].

My partner is 52. Should we use a sperm donor instead of his sperm with our egg donor?

Not necessarily. While paternal age >50 shows increased segmental aberrations and de novo mutation risk [4][12], many men this age have excellent sperm parameters and successful outcomes. Key considerations: sperm DNA fragmentation testing, comprehensive genetic counseling about de novo risks, PGT-A to screen embryos, and your comfort level with slightly elevated (but still small) absolute risks. This is a personal decision best made with genetic counseling support.

If we do PGT and transfer a euploid embryo, do we still need prenatal testing?

Yes. PGT-A is highly accurate for what it tests (chromosome number, large structural changes) but doesn't detect: small deletions/duplications, single gene mutations, or de novo changes in non-biopsied cells. Standard prenatal screening (NIPT, ultrasound) and diagnostic testing options (CVS, amniocentesis if indicated) remain recommended. Think of PGT as an additional layer of screening, not a replacement for prenatal care [35].

Scientific References

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[2] American Society for Reproductive Medicine. (2024). Genetic contributions to embryo development. Fertility and Sterility, 122(3), 421-434.

[3] Greco, E., Litwicka, K., Minasi, M.G., et al. (2020). Preimplantation Genetic Testing: Where We Are Today. International Journal of Molecular Sciences, 21(12), 4381.

[4] Dviri, M., Madjunkova, S., Koziarz, A., et al. (2020). Is there a correlation between paternal age and aneuploidy rate? An analysis of 3,118 embryos derived from young egg donors. Fertility and Sterility, 114(2), 293-300.

[5] Munné, S., & Wells, D. (2017). Detection of mosaicism at blastocyst stage with the use of high-resolution next-generation sequencing. Fertility and Sterility, 107(5), 1085-1091.

[6] Albero, S., Moral, P., Castillo, J.C., et al. (2024). The impact of (very) young donor age on euploid rates: An analysis of 1831 trophectoderm biopsies. European Journal of Obstetrics & Gynecology and Reproductive Biology, 297, 59-64.

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[8] Sharma, R., Agarwal, A., Rohra, V.K., et al. (2015). Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reproductive Biology and Endocrinology, 13, 35.

[9] Silva Santos, L., Rodrigues, M., Barros, A., & Dinis, J. (2024). Preimplantation genetic testing: A narrative review. Porto Biomedical Journal, 9(2), e229.

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[13] Goriely, A., & Wilkie, A.O. (2012). Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. American Journal of Human Genetics, 90(2), 175-200.

[14] Crow, J.F. (2000). The origins, patterns and implications of human spontaneous mutation. Nature Reviews Genetics, 1(1), 40-47.

[15] American Society for Reproductive Medicine. (2024). The use of preimplantation genetic testing for aneuploidy: a committee opinion. Fertility and Sterility, 122(3), 421-434.

[16] Treff, N.R., Zimmerman, R., Bechor, E., et al. (2019). Validation of concurrent preimplantation genetic testing for polygenic and monogenic disorders, structural rearrangements, and whole and segmental chromosome aneuploidies. Journal of Assisted Reproduction and Genetics, 36(7), 1317-1329.

[17] Jalas, C., Gavrilova, R., Blakemore, J.K., et al. (2020). Ethical considerations in preimplantation genetic diagnosis. Fertility and Sterility, 113(6), 1132-1137.

[18] Greco, E., Litwicka, K., Minasi, M.G., et al. (2020). Preimplantation Genetic Testing: Where We Are Today. International Journal of Molecular Sciences, 21(12), 4381.

[19] Agarwal, A., Majzoub, A., Esteves, S.C., et al. (2016). Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Translational Andrology and Urology, 5(6), 935-950.

[20] Simon, L., Brunborg, G., Stevenson, M., et al. (2010). Clinical significance of sperm DNA damage in assisted reproduction outcome. Human Reproduction, 25(7), 1594-1608.

[21] Robinson, L., Gallos, I.D., Conner, S.J., et al. (2012). The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Human Reproduction, 27(10), 2908-2917.

[22] Meseguer, M., Santiso, R., Garrido, N., et al. (2011). Effect of sperm DNA fragmentation on pregnancy outcome depends on oocyte quality. Fertility and Sterility, 95(1), 124-128.

[23] Esteves, S.C., Zini, A., Coward, R.M., et al. (2021). Sperm DNA fragmentation testing: Summary evidence and clinical practice recommendations. Andrologia, 53(2), e13874.

[24] Marques, C.J., Carvalho, F., Sousa, M., & Barros, A. (2004). Genomic imprinting in disruptive spermatogenesis. Lancet, 363(9422), 1700-1702.

[25] Jodar, M., Selvaraju, S., Sendler, E., et al. (2013). The presence, role and clinical use of spermatozoal RNAs. Human Reproduction Update, 19(6), 604-624.

[26] Manandhar, G., Schatten, H., & Sutovsky, P. (2005). Centrosome reduction during gametogenesis and its significance. Biology of Reproduction, 72(1), 2-13.

[27] Krausz, C., & Riera-Escamilla, A. (2018). Genetics of male infertility. Nature Reviews Urology, 15(6), 369-384.

[28] Aksglaede, L., & Juul, A. (2013). Testicular function and fertility in men with Klinefelter syndrome. European Journal of Endocrinology, 168(4), R67-R76.

[29] Krausz, C., Hoefsloot, L., Simoni, M., & Tüttelmann, F. (2014). EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: state-of-the-art 2013. Andrology, 2(1), 5-19.

[30] CCRM Fertility. (2024). Preimplantation Genetic Testing for Structural Rearrangements. Retrieved from genetics program documentation.

[31] CCRM Fertility. (2024). Preimplantation Genetic Testing for Monogenic Disorders. Retrieved from program materials.

[32] Hoyos, L.R., Cheng, C.Y., Brennan, K., et al. (2020). Euploid rates among oocyte donors: is there an optimal age for donation? Journal of Assisted Reproduction and Genetics, 37(3), 589-594.

[33] Doyle, N., Gainty, M., Eubanks, A., et al. (2020). Donor oocyte recipients do not benefit from preimplantation genetic testing for aneuploidy to improve pregnancy outcomes. Human Reproduction, 35(11), 2548-2555.

[34] Doyle, N., Gainty, M., Eubanks, A., et al. (2020). Donor oocyte recipients do not benefit from preimplantation genetic testing for aneuploidy to improve pregnancy outcomes. Human Reproduction, 35(11), 2548-2555.

[35] American College of Obstetricians and Gynecologists. (2020). Prenatal genetic screening and diagnostic testing. ACOG Practice Bulletin, Number 226.

[36] NGC Clinic. (2024). Comprehensive genetic counseling services. Retrieved from https://ngc.clinic/en/about