Carrier Screening in Third Party Reproduction

A Round Table Discussion hosted by Fairfax EggBank 

What IS the ideal carrier screening panel to utilize in third-party reproduction? 

Fairfax EggBank hosted a roundtable discussion on this topic with several experts in the field. The points discussed examined the topic from multiple angles and covered several categories including: 

• Gene content and panel size 
• Clinical utility of carrier screening 
• Laboratory results reporting and detection rates 
• Lack of coverage by payors 
• Factors to consider in selecting a carrier screening laboratory 

Read on to learn more

Introduction

Carrier screening is an integral part of third-party reproduction as it facilitates the suitability matching between gamete donors and recipients.  Its primary purpose is to identify gamete sources who are at increased reproductive risk for certain monogenic conditions, mainly recessive and X-linked, in order to consider reproductive options. There is now a greater adoption by national professional societies for using pan-ethnic (formerly called “expanded”) screening panels due to higher equity in care compared to ethnicity-based panels^1,2,3.  

As a result of a wider adoption of pan-ethnic carrier screening panels, most gamete banks and IVF clinics are currently utilizing larger panels of a few hundred genes. However, there is an extreme variability of panel sizes and gene content in the market such that there remain large discrepancies even between two equally large panels. The continuous expansion of gene panels has several implications including: 

• Increasing the need for additional testing on either donors or recipients which can be expensive, delays the fertility treatment process, and reduces selection options. 
• Creating discrepancy in donor exclusion criteria based on carrier results with potential manifestation of symptoms, as some health risks may be more subjective in nature than others. 
• Decreasing consistency and standardization of what constitutes an appropriate yet comprehensive panel to use for gamete donors.  

As such, one might ask: what IS the ideal carrier screening panel to utilize in third-party reproduction? 

To help us discuss the topic, we invited a group of experts in the field for a roundtable discussion. Their expertise spanned several specialties including reproductive endocrinology, embryology, genetic counseling, gamete donation, clinical product management and medical affairs in an industry setting. Below is a summary of the major points discussed. 

Gene content and panel size 

The roundtable experts agree that there should not be a “shot gun approach” to carrier screening panels. Panel size is not the issue; the focus should be on its quality and the consistency in using the same/similar panel for all gamete donors to help clinics determine the best screening options for their patients.   

Kara Baldwin, MS, CGC, Senior Manager of Reproductive Genetics at California Cryobank explains: 

“From a gamete bank’s perspective, it’s incredibly hard to match a donor panel to a specific patient population because patients from around the world are typically using these gametes. That is why a lot of places have gone to bigger panels with the goal of capturing what could have been screened in various patient populations.” 

Even on the clinical side, there is a notion that bigger panels may be better as more screening is often thought of as leading to a healthier outcome.   

The 2021 ACMG Practice Resource on Carrier Screening³ proposes a tier-based system of carrier screening. It states that all individuals who are pregnant or planning a pregnancy should be offered a tier 3 (113 genes) panel inclusive of conditions with a carrier frequency ≥1/200 in any ethnic group with at least 1% representation in the United States. A tier 4 panel (includes tier 3 plus conditions with <1/200 carrier frequency) can be considered when there’s a consanguineous relationship or a warranted family/medical history. 

The roundtable experts agree that while it is a reasonable approach to include genes in a panel based on disease carrier frequency in the general population, there are limitations to this approach:  

• The literature and databases used to evaluate population carrier rates may be incomplete and/or based on a low number of published articles.  
• For some of the genes recommended by ACMG, like F8 associated with hemophilia and FXN, associated with Fredrich’s ataxia, there are technical challenges in testing which reduces detection rates. The risk-benefit of including them with a potential “false negative” result should be weighed.  

Another point was raised regarding the knowledge we currently have on variant interpretation when it comes to genes associated with rare conditions. Adding more and more rare conditions to a panel may seem like a favorable approach; however, the ability to classify variants as pathogenic depends on several lines of assessment including published cases in the literature. Oftentimes, the lack of reported cases for rare diseases may be a limiting factor for the accurate classification of a variant. 

Gabriel Lazarin, MS, CGC, Vice President of Medical Affairs at Myriad Genetics explains: 

“As gene panels get bigger, there is less that we know about the genes which inhibits our ability to give patients a clear answer. A patient could potentially be given a negative result for a rare condition because we don’t know much about the variants detected and can at best label them as variants of uncertain significance.” 

Clinical utility of carrier screening 

The most important aspect of carrier screening is its clinical utility, which is its ability to provide reproductive options that are proven to reduce the risk of disease. In third party reproduction, a panel’s major clinical utility is facilitating a suitability match between a recipient and donor. Other reproductive options may include pre-implantation genetic testing for monogenic conditions (PGT-M), prenatal testing, postnatal testing, and the option of declining all testing options. 

The more genes are added, the higher the complexity of results including manifesting carriers (e.g. Gaucher disease, GBA), mild and manageable conditions (e.g. Mild hemochromatosis, HFE), and complex results involving pseudogenes and unknown phasing of variants (e.g. Congenital adrenal hyperplasia, CYP21A2-related). Who decides when additional testing on a mild condition for a donor/recipient is indicated? Who aids in the interpretation of complex results? Who decides the appropriate panel to consider for a donor-recipient matching process? 

Dr. Brian Levine, MD, Practice Director at CCRM, New York, describes how it is not necessarily a perfect process and that knowing the clinic’s transfer policies in advance helps: 

“Identification of shared ‘mild diseases’ has the unfortunate result of reducing the number of available embryos for patients.  While it might be covered by their insurance or employer-based benefit, it adds a layer of complexity to treating patients.  Many clinics have firm policies that ‘affected’ embryos can only be transferred after a waiver is signed, thereby adding significant stress to an already stressful process.” 

It is generally agreed that pre- and post-genetic counseling is crucial for patient-centered care. Experts agree that IVF clinics would greatly benefit from hiring in-house genetic counselors (GCs). While several labs offer complimentary genetic counseling services, attention must be paid to the scope of practice of various GCs in the field and what they can and cannot access or discuss⁴. Clinic-based GCs are aware of all clinical aspects of a case and are positioned to make clinical judgements and facilitate decision making of the patient. Laboratory GCs are focused on discussing their laboratory’s own technology and results reporting and may be conservative/neutral in their recommendations. As such, a combination of these services may be ideal depending on the case. However, laboratory-based GCs should not be utilized in lieu of clinic-based GCs. 

Lusine Aghajanova, MD, Reproductive Endocrinologist at Stanford adds: 

“We are lucky to have our own genetic counselor. I do believe a lot of facilitation of decisions on PGT-M comes from the approach of [clinical] genetic counselors. For example, for mild biotinidase deficiency variants, our genetic counselor may not recommend PGT-M as an option, and more unity on that front from various genetic counselors would be helpful to reproductive endocrinologists.”

Although there are complimentary, third-party GC options offered through carrier screening companies, there is typically a preference not to make a clinical judgement on behalf of the referring clinic. As such, more PGT-M may be recommended when third-party GC services are used than when an in-house genetic counselor is incorporated into fertility care. A recently published ASRM Committee Opinion on PGT-M Indications and Management provides additional direction on this matter⁵. 

Another important aspect of the clinical utility of carrier screening is that it is field-of-practice dependent. For example, in prenatal settings, there are certain conditions that do not have prenatal diagnosis available as an option. As such, including these genes in a prenatally offered carrier screening panel may not be the most clinically useful. However, in a third-party reproduction setting, this may allow recipients to choose a suitable donor. 

Laboratory results reporting and detection rates 

Carrier screening laboratories are independent in the way they classify variants and report results. For example, the c.686G>A (p.R229Q) variant in NPHS2, associated with Congenital Nephrotic Syndrome, can be reported as a carrier status, not reported at all, or reported several pages into a report under special results to note. In each case, the consequence and recommendations could be different based on the lab used. In addition, labs differ in their reported detections rates and population carrier rates for tested conditions.  

The roundtable experts agree that laboratories should be responsible for clarifying limitations and the clinical utility of results. There should be an effort towards consistency in reporting. The onus should not fall on the clinical teams and gamete banks to expertly interpret the information included in the reports. Utilization of genetic counseling services also helps in the interpretation of results. 

Amber Gamma, MS, CGC, Lead Genetic Counselor at IVIRMA adds: 

“The clarification [of results] should fall on the testing laboratory because IVF clinics and gamete banks are not the only ones using these tests. Labs should think about the democratization of carrier screening tests and tailor the information towards their least fluent user. Otherwise, there is a risk for misinterpretation of the results which is a big injustice.”

There is currently a wider discussion in the field regarding the utility of residual reproductive risks and whether they are helpful to patients. Residual carrier risks are typically calculated based on population carrier rates for diseases as well as detection rates set by the labs. Given that labs differ in the values they use for pre-test carrier rates and detection rates, shifting away from calculating specific residual risks may be more appropriate. 

Lack of coverage by payors 

Several experts agree that as part of discussing an “ideal” carrier screening panel, one must also look at cost and coverage by payors. Despite the increasing popularity of expanded carrier screening and the wider adoption by national societies, there has been a lack of payor coverage. The CPT code 81443 has not been covered by most insurance plans, which has caused some labs to stack on CPT codes to get some reimbursement for their testing. As more insurance companies cracked down on these multi-code practices, more and more denials have become the reality, and labs became less profitable. This led to the recent closure of several labs. 

As Jamie Zdrodowski, MS, CGC, a Product Manager at Fulgent Genetics explains:  

“Until there is a clear adoption of universal carrier screening as an acceptable form of screening on a population level by the American College of Obstetrics and Gynecology (ACOG), payors will continue to deny coverage.”   

It remains the reality that labs must be paid for their services. Often, excluding certain methodologies comes down to cost. As such, what constitutes an ideal panel cannot be discussed on an academic level only; attention must be paid to the process used to render the product more affordable to the public. 

Factors to consider in selecting a carrier screening laboratory 

Clinics may choose to partner with various carrier screening labs to provide ideal options for their patients. It is important to learn the types of panels that gamete banks of interest are using for donors so that the appropriate panels can be ordered for recipients.  

Other than focusing on good customer support, great turn-around times, logistics, and electronic portal/IT services, paying attention to the laboratory’s financial stability and market shares is also important. The laboratory should show equity growth and a feasible road to profitability to reduce the chance for sudden interruption in service due to lab closure. 

In conclusion, it may not be feasible to find an “ideal” carrier screening panel that would be clinically useful to all. Care must be taken to note the patient population being served, the field of practice (e.g. third-party reproduction versus prenatal care), and the available services to facilitate patient-centered care. There is also a need for laboratories to standardize reporting practices, gene panel options, variant interpretation practices, and customizability to fit client needs. 

By Rawan Awwad, MS, CGC, Director of Genetic Counseling, Fairfax EggBank 

References

1. Practice Committee of the American Society for Reproductive Medicine and the Practice Committee for the Society for Assisted Reproductive Technology (2021). Guidance regarding gamete and embryo donation. Fertility and sterility, 115(6), 1395–1410.
2. Sagaser, K. G., Malinowski, J., Westerfield, L., Proffitt, J., Hicks, M. A., Toler, T. L., Blakemore, K. J., Stevens, B. K., & Oakes, L. M. (2023). Expanded carrier screening for reproductive risk assessment: An evidence-based practice guideline from the National Society of Genetic Counselors. Journal of genetic counseling, 32(3), 540–557.
3. Gregg, A. R., et. al. & ACMG Professional Practice and Guidelines Committee (2021). Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the ACMG). Genetics in medicine: 23(10), 1793–1806.
4. Snider, A. C., Isley, L. J., & Black, L. D. (2020). Scope of practice distinctions based on primary work setting for genetic counselors in assisted reproductive technologies. F&S reports, 2(1), 80–87.
5. Practice Committee and Genetic Counseling Professional Group of the American Society for Reproductive Medicine, American Society for Reproductive Medicine, Washington, D.C. (2023). Indications and management of preimplantation genetic testing for monogenic conditions: a committee opinion. Fertility and sterility, 120(1), 61–71.