P-508 Management of incidental findings after preconception expanded carrier screening: identifying genetic predispositions to cancer and metabolic conditions in 8010 screened ART patients
Authors: López G , Guillén J  J , Bellés López A , Sánchez Díaz A , Domingo-Gallego A , Armengol X , Segura-Puimedon M , Armengol-Dulcet L , Buscà R , Mataró D , Popovic M , Miguel-Escalada I , Rodriguez-Aranda A 
Published: July 2024

Study question

How do individuals and fertility clinics navigate incidental findings from Expanded Carrier Screening (ECS) in reproductive decision-making?

Summary answer

Incidental ECS findings prompted varied responses from patients and gamete donors, influencing diverse reproductive choices and underscoring the pivotal role of pre-test genetic counseling.

What is known already

ECS aims to assess reproductive risk in the general population for specific autosomal recessive and X-linked conditions. These manifest in infancy or early childhood and impact life expectancy or the quality of life. ECS results may guide interventions to avoid affected pregnancies, such as the implementation of preimplantation genetic testing of embryos (PGT-M). Additionally, ECS has the potential to uncover incidental findings with significant health implications, such as an elevated cancer risk or diagnosis. However, the lack of comprehensive reporting guidelines necessitates meticulous analysis to ensure effective clinical guidance for these individual findings.

Study design, size, duration

This retrospective descriptive study assessed the results of ECS tests performed in 5475 patients and 2535 oocyte and semen donors from four different fertility clinics between July 2017 and December 2023. ECS reports with incidental findings in the ATM, FH or LDLR genes were identified and further examined. We calculated individual and reproductive risks for affected individuals and recorded the subsequent clinical management pertaining to each case.

Participants/materials, setting, methods

Pre-test counselling was offered to both patients and gamete donors before consenting to ECS. Testing was outsourced to an external genetics laboratory using a panel of 309 genes analyzed through next generation sequencing and complementary molecular techniques. The laboratory reported pathogenic and likely pathogenic variants that were subsequently manually reviewed by an internal genetics committee. Personal and reproductive risks were assessed for each case and genetic counseling was provided in a subsequent meeting.

Main results and the role of chance

Genetic variants in ATM, FH, or LDLR genes were reported in 134 out of 8010 individuals undergoing ECS (1.67%). Among these, 108 variants were identified in patients: 53.7% (n = 58) in ATM, 19.4% in FH (n = 21), and 26.8% (n = 29) in LDLR. Out of the variants identified as incidental findings, 20/108 were actionable and eligible for PGT-M: 19 were associated with an increased risk for breast cancer and 1 for renal cancer. After being informed of the findings and their implications, 7/20 couples opted to revoke treatment as, according to internal policies, PGT-M was mandatory in such cases; 6/20 couples chose to undergo double gamete donation; 6/20 couples opted for PGT-M. Patients with pathogenic variants in LDLR linked to autosomal dominant inheritance for familial hypercholesterolemia (20/108, 18.5%), received follow-up guidelines and family genetic counseling. Pathogenic variants in ATM, FH, and LDLR were also identified in 26 gamete donors (24 oocyte donors and 2 sperm donors). Following internal review, 14 of these variants were considered incidental findings with an increased risk for breast cancer (13/14) or familial hypercholesterolemia (1/14), leading to the exclusion of these potential donors from the donation program.

Limitations, reasons for caution

The reproductive handling of incidental findings in our population relies on subjective decisions by the internal genetics committee, which may evolve with scientific advancements and recommendations from professional societies. Follow-up data on long-term reproductive outcomes are lacking.

Wider implications of the findings

This study reveals the diverse reproductive decisions made in response to incidental findings, underscoring the importance of pre-test genetic counseling. Our findings also highlight the subsequent impact on fertility programs, which may lead to the exclusion of gamete donors or patients choosing to revoke treatment.

Trial registration number

Not Applicable