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Supplements Expanded Carrier Screening in Prenatal Care: Recent Advances and Key Considerations

The Evolving Science of Genetic Carrier Screening

Genomic assays demand careful curation processes to determine which genetic variants are clinically important and should be reported to clinicians and patients. The test’s sensitivity and specificity are directly affected through the process of variant interpretation.18 In these interpretive processes, there is a tradeoff among sensitivity, specificity, and labor. For instance, processes that rely only on computational methods in a low-labor workflow typically have low sensitivity and specificity.18

One way to achieve high-throughput variant curation is to use an automated process to collect evidence, like population frequency, computation protein structure information, etc. These pieces of evidence are then manually reviewed, along with functional studies and available clinical information to classify the variant.18 This process can be combined with a rule-based system to classify variants with no literature reports and those with high prevalence in unaffected populations.18 This method of variant curation achieves higher sensitivity and specificity than purely automated processes.18

Panel Constitution

Optimal sensitivity, specificity, negative predictive values, and positive predictive values are requisites for a clinically useful genetic test. Panel constitution is also equally important for a carrier screening panel.18

Several professional societies have published recommendations regarding the selection of conditions to be screened in expanded carrier screening panels.18 Instead of including as many disorders as possible, clear criteria should be established for panel constitution.28 According to ACOG and ACMG, genes being screened should have a well-defined relationship with a phenotype. Moreover, the condition should cause cognitive or physical impairment, have a detrimental effect on the quality of life, require medical or surgical intervention, or have an early onset.4,12 The European Society of Human Genetics also states that “an important screening criterion is that the natural course of the disease screened should be adequately understood, and that an acceptable and reliable test should be available with known sensitivity, specificity and predictive values.”29

Conditions to be included in an expanded carrier screening panel. Disease severity is an important criterion for a condition to be included in carrier screening. A severity classification algorithm was proposed and evaluated in a survey study of 192 healthcare professionals.30 In this algorithm, disease characteristics were classified as tier 1, 2, 3, and 4 (Table 2).30

Using disease characteristics, conditions can be classified as mild, moderate, severe, and profound based on the number of tier characteristics30:
  • Profound diseases have more than 1 tier 1 characteristic.
  • Severe diseases have at least 1 tier 1 characteristic or several tier 2 or 3 characteristics.
  • Moderate diseases are those with at least 1 tier 3 characteristic but no other characteristics from tiers 1 or 2.
  • Mild diseases are those without any tier 1, 2, or 3 characteristics.
Experts have proposed that expanded carrier screening should prioritize screening of “severe” and “profound conditions.”18 “Moderate” conditions may also be screened if results can provide an opportunity for early intervention.

Reproductive Decisions After Receipt of Expanded Carrier Screening Results

The utility of an expanded carrier screening panel can be illustrated by the likelihood that at-risk couples alter their reproductive decisions based on the results of the screening.31 Preliminary evidence suggests that couples do make reproductive choices based on expanded carrier screening results. In one study of individuals who underwent preconception or prenatal expanded carrier screening for up to 110 genes, 64 couples received preconception screening and were determined to be at risk.31 70% of these couples were not pregnant when receiving results, and of that percentage, the majority (62%) planned to use in vitro fertilization with preimplantation genetic diagnosis or prenatal diagnosis in future pregnancies.31 Only 29% did not plan to change their reproductive decisions after discovering the results.31 Importantly, disease severity was significantly associated with changes in reproductive decisions (P = .0001).31

Other studies also support the utility of expanded carrier screening. Out of 6643 individuals (3738 couples) in a study of infertile couples tested with expanded carrier screening, 1666 (25.1%) screened positive for at least one disorder.32 In 8 couples, both reproductive partners tested positive for the same genetic disorder, which placed them at risk for having an affected offspring.32 Three of these couples were both carriers for cystic fibrosis. Two of these couples carrying the mutation did not complete in vitro fertilization, and another couple became pregnant before her obstetric provider obtained chorionic villus sampling.32 Four couples were at risk for having a child with other recessive genetic conditions, including palmitoyltransferase II deficiency, Gaucher disease, GJB2-related DFNB-1 nonsyndromic hearing loss, and dihydrolipoamide dehydrogenase deficiency. These couples opted for preimplantation genetic testing to their embryos, and all patients delivered unaffected babies.32  

After discovering that they are genetic carriers for a serious condition, most couples altered their reproductive decisions to avoid having an affected child. Taken together, these studies support the use of expanded genetic screening in the preconception and prenatal period.

Comparison of Expanded Screening to Guideline-Based Screening

Expanded carrier screening has been compared to current guideline-based conventional screening. In the largest study to date among reproductive-aged individuals without any known indication for specific genetic testing (N = 346,790), expanded carrier screening increased the detection of carrier status for recessive conditions when compared to conventional screening.33 For example, even though the Ashkenazi Jewish population already represents the broadest ethnicity-specific panel according to ACOG and AMCG guidelines, 55% of fetuses (95% CI, 52%-59%) with severe or profound genetic conditions in this population would have been missed using a guideline-based screening panel.33 Of Middle Eastern couples, 91% of fetuses (95% CI, 87%-94%) would not have been identified by a guideline-based screening panel.33 Ethnicity-based panels were unable to detect many of the severe and profound genetic conditions in other ethnic groups (Table 3).33

The superiority of variant detection by expanded carrier screening panels has been corroborated by other studies. During a study of 506 individuals of Jewish descent, expanded screening identified a larger number of pathogenic genetic variants than traditional screening panels,34 and 27% of positive carriers would have been missed using traditional screening panels.34 In another study evaluating carrier screening in 27 sperm donors, expanded carrier screening panels identified 96 variants likely associated with severe disease variants among 81 genes.35 Just 6% of the variants were distinguished by traditional guideline-recommended panels.35


Condition-directed preconception and prenatal carrier screening focuses on risk assessment of individual conditions based on ancestry, as well as family and personal history.4 There are limitations associated with current guideline-based condition-directed carrier screening. Some of these limitations include the reliance on accurate ascertainment of the patient’s family history4 and the difficulties in implementing guideline-based recommendations in an increasingly multiethnic society.7,8

The emergence of NGS technology allows the possibility of expanded carrier screening. In expanded carrier screening, all individuals are offered screening for a set of conditions regardless of race or ethnicity.4 According to the ACCE framework, expanded carrier screening should have optimal analytic validity, clinical validity, clinical utility, and accepted ethical, legal, and social implications.20 Diseases included should typically be considered “severe” or “profound.” A severity classification algorithm was proposed and evaluated, and can serve as a framework for future expanded carrier screening panel design.30

Expanded carrier screening has been compared with current guideline-based carrier screening among reproductive-aged individuals. In the largest study to date, expanded carrier screening increased the detection rates of carrier status for recessive conditions and detected more severe or profound conditions that would have been missed by guideline-based screening panels.33 

Evolving technologies may overcome the limitations of guideline-based carrier screening. With the variety of available panels, it is important to consider the design, what it is testing for, and how useful the results of the panel are for individuals or couples. Expanded carrier screening panels with high analytical validity, clinical validity, and clinical utility are commercially available and have the potential to further enable couples to make reproductive choices according to their values.

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