Clinical validity and utility of preconception expanded carrier screening for the management of reproductive genetic risk in IVF and general population

Abstract

STUDY QUESTION What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents? SUMMARY ANSWER The high detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population. WHAT IS KNOWN ALREADY About 2–4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds the potential to significantly improve couple’s genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring. STUDY DESIGN, SIZE, DURATION A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples. PARTICIPANTS/MATERIALS, SETTING, METHODS A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making. MAIN RESULTS AND THE ROLE OF CHANCE A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby. LIMITATIONS, REASONS FOR CAUTION The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene–disease associations. WIDER IMPLICATIONS OF THE FINDINGS These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF. STUDY FUNDING/COMPETING INTEREST(S) No external funding was used for this study. A.C., M.F., S.C., M.P., L.G., and C.P. are employees of Igenomix Italy. C.S. is the head of the scientific board of Igenomix. TRIAL REGISTRATION NUMBER N/A.

Current Updates on Expanded Carrier Screening: New Insights in the Omics Era

“…In turn, the analysis of a high number of diseases in a high number of individuals will improve couples’ management, allowing a better evaluation of their reproductive options [ 9 ]. Of course, to maximize these advantages, ECS should be carried out on both partners for having a more accurate estimation of the couple’s risk to transmit an inherited disease to their newborns [ 10 ]. However, the debate on this point is still open.…”

ISPD 2021 debate ‐ All in vitro fertilization cycles should involve pre‐implantation genetic testing to improve fetal health and pregnancy outcomes

“…As noted in the introduction, PGT-M is already an established and robust technique to allow couples to avoid having a child with a monogenic disorder, such as cystic fibrosis or Huntington disease. 31 The use of PGT-M will expand further with the increased offer of expanded reproductive carrier screening for autosomal recessive and X-linked conditions, which is predicted to identify 2%-4% of all couples as being at high risk, 6,32 and therefore potentially benefited by PGT-M. PGT-SR is also well accepted for couples where one carries a chromosome rearrangement, most commonly a translocation, showing significant benefits in babies per transferred embryo.…”

Interest in Cancer Predisposition Testing and Carrier Screening Offered as Part of Routine Healthcare Among an Ethnically Diverse Sample of Young Women

“…While carrier screening is ideally offered prior to pregnancy, it is often not offered until a pregnancy when results could increase anxiety to a greater extent due to the high likelihood of carrier status for one or more conditions and time for partner results ( Grody, 2016 ). In considering population screening efforts for expanded carrier screening, therefore, some research has examined interest among women, as well as their reproductive partners, in receiving this genetic testing prior to pregnancy ( Capalbo et al, 2021 ). Wide variability in interest and uptake of expanded carrier screening has been observed across available studies ( van Steijvoort et al, 2020 ).…”