Expanded carrier screening for reproductive risk assessment: An evidence‐based practice guideline from the National Society of Genetic Counselors

Abstract

Expanded carrier screening (ECS) intends to broadly screen healthy individuals to determine their reproductive chance for autosomal recessive (AR) and X‐linked (XL) conditions with infantile or early‐childhood onset, which may impact reproductive management (Committee Opinion 690, Obstetrics and Gynecology, 2017, 129, e35). Compared to ethnicity‐based screening, which requires accurate knowledge of ancestry for optimal test selection and appropriate risk assessment, ECS panels consist of tens to hundreds of AR and XL conditions that may be individually rare in various ancestries but offer a comprehensive approach to inherited disease screening. As such, the term “equitable carrier screening” may be preferable. This practice guideline provides evidence‐based recommendations for ECS using the GRADE Evidence to Decision framework (Guyatt et al., BMJ, 2008, 336, 995; Guyatt et al., BMJ, 2008, 336, 924). We used evidence from a recent systematic evidence review (Ramdaney et al., Genetics in Medicine, 2022, 20, 374) and compiled data from peer‐reviewed literature, scientific meetings, and clinical experience. We defined and prioritized the outcomes of informed consent, change in reproductive plans, yield in identification of at‐risk carrier pairs/pregnancies, perceived barriers to ECS, amount of provider time spent, healthcare costs, frequency of severely/profoundly affected offspring, incidental findings, uncertain findings, patient satisfaction, and provider attitudes. Despite the recognized barriers to implementation and change in management strategies, this analysis supported implementation of ECS for these outcomes. Based upon the current level of evidence, we recommend ECS be made available for all individuals considering reproduction and all pregnant reproductive pairs, as ECS presents an ethnicity‐based carrier screening alternative which does not rely on race‐based medicine. The final decision to pursue carrier screening should be directed by shared decision‐making, which takes into account specific features of patients as well as their preferences and values. As a periconceptional reproductive risk assessment tool, ECS is superior compared to ethnicity‐based carrier screening in that it both identifies more carriers of AR and XL conditions as well as eliminates a single race‐based medical practice. ECS should be offered to all who are currently pregnant, considering pregnancy, or might otherwise biologically contribute to pregnancy. Barriers to the broad implementation of and access to ECS should be identified and addressed so that test performance for carrier screening will not depend on social constructs such as race.

Performance of single‐gene noninvasive prenatal testing for autosomal recessive conditions in a general population setting

“…Carrier screening with reflex to sgNIPT should be considered as a first-line approach in many circumstances, particularly when the patient is already pregnant and early detection of an at-risk fetus will maximize the patient's options as well as opportunities for in-utero treatment where applicable. While ECS is increasingly being incorporated into recommendations for reproductive carrier screening, 48,49 there are known limitations to this approach as have been discussed in this paper and in the literature. 2,4,5,10,30,50,51 Several studies have investigated the improvement of the detection of high-risk couples (and therefore fetuses with a 1 in 4 risk to be affected) by ECS.…”

Bridging the Gap: Animal Models in Next-Generation Reproductive Technologies for Male Fertility Preservation

“…Genetic screening is a diagnostic and therapeutic search to detect individuals whose offspring are susceptible or at risk for genetic disease [131]. Prenatal molecular diagnosis with FISH or PCR technology can identify severe genetic disorders, permitting prompt treatment or the selective termination of pregnancy [132].…”

Embryo and fetal gene editing: Technical challenges and progress toward clinical applications

“…Carrier screening plays an important role in identifying risk factors for birth defects, particularly in populations with high prevalence of certain genetic conditions (e.g., cystic fibrosis among Caucasian populations of Nordic ancestry, inborn errors of metabolism among Ashkenazi Jewish populations, hemoglobinopathies among South Asian populations). 11 Fertility planning in couples concordant for heritable pathological alleles includes early prenatal diagnosis following a spontaneous pregnancy and alternatives to child-bearing, including donor gametes and adoption. An increasingly precise, rapid, and acceptable approach to at-risk couples is preimplantation genetic testing (PGT) of embryos produced by in vitro fertilization (IVF) and selection of healthy mutation-free embryos for uterine transfer.…”

“…More diseases may be caused by de novo mutations, and some conditions may have genetic causes that are only identified upon detection of a fetal complication. 11 Unless this is performed before pregnancy, embryo screening and selection will not be available to at-risk couples. Additionally, the ethical and clinical boundaries regarding genetic manipulation of the germline and the associated concerns about, among other things, access inequalities, the rights of the future person’s autonomy and interests, and equitable access to healthcare for all affected generations must be specifically debated and widespread societal consensus reached.…”