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

The Evolving Science of Genetic Carrier Screening

Several professional societies have published guidelines for preconception and prenatal carrier screening.1,2,3 These recommendations are based on ancestry and personal history. This article discusses the limitations of current carrier screening guidelines and the evolving technologies of expanded genetic carrier screening, which can be offered regardless of race or ethnicity. 

Limitations of Current Carrier Screening Guidelines

Condition-directed carrier screening focuses on the risk assessment of individual conditions.4 The American College of Obstetrics and Gynecology (ACOG) provides recommendations for carrier screening of genetic diseases including cystic fibrosis, spinal muscular atrophy, hemoglobinopathies (including sickle cell disease, α- and β-thalassemias), fragile X, and Tay-Sachs disease.1 ACOG recommends pan-ethnic carrier screening only for cystic fibrosis and spinal muscular atrophy.1 For other genetic conditions, ACOG recommends an approach based on personal or family history, as well as ethnic origin.

There are limitations associated with condition-directed carrier screening, including that it relies on accurate ascertainment of the patient’s family history and ancestry.4 Some of these limitations include:
  1. Patients may have inaccurate knowledge of ancestry. Among 99 anonymously surveyed participants, approximately 9% did not know their biological parents’ heritage, and 40% did not know the heritage of all 4 grandparents.5 In another study, only 30% of patients of Mediterranean origin correctly self-reported their ancestry without a family history consultation.6 For this reason, patient knowledge of their own ancestry can be a barrier in implementing condition-directed carrier screening which relies on knowledge of one’s ancestry.
  2. The effects of an increased multiethnic society. Increasing inter-ethnic marriages will eventually result in an increased prevalence of heterozygous states and a wider population.7,8 It is also difficult to categorize a patient’s ethnic origin into a specific group.9 In one study, patients that self-identified as having African ancestry had an average of 12.4% European ancestry and 79.3% African ancestry.6 The variability was even higher in patients who self-reported as having Latin American ancestry. These patients had an average of 12.0% African, 24.4% Native American, and 52.1% European ancestry.6 The unreliability of ethnicity classification can be avoided if screening is offered to all women.9 In fact, ACOG recommended in 2005 that all patients should be offered cystic fibrosis carrier screening because of the “increasing difficulty in assigning a single ethnicity to individuals.”1
  3. Genetic conditions do not solely exist in specific ethnic groups.4 Although certain ethnic groups have higher rates of heterozygous states of a specific genetic condition and have a higher risk of being affected by the disease, individuals from other ethnic groups may also be carriers, albeit, at a lower frequency. 
  4. At risk individuals left without screening because of condition-based screening that relies on accurate disclosures of family history and carrier status. Disclosure among family members may be incomplete. In a study examining family history and carrier status disclosure patterns of cystic fibrosis, carriers with a family history of cystic fibrosis informed only 84% of their living parents, 56% of their siblings, and even fewer informed their second- and third-degree relatives.10
  5. Conflicting recommendations and guidelines on condition-based genetic screening from both ACOG and the American College of Medical Genetics and Genomics (ACMG). The ACMG recommended screening panel differs from the minimum required tests suggested by ACOG for individuals of Ashkenazi Jewish descent.1,3
  6. Limited patient knowledge. Screening for a restricted number of specific genetic conditions restrains patient knowledge and the amount of genetic information available to the patient.4 Expanded screening would avoid missing cases of rare disorders for which morbidity and mortality may be reduced by early intervention.11

Expanded Carrier Screening

Evolving developments in laboratory technologies have resulted in commercially available expanded carrier screening panels.11 In expanded carrier screening, all patients are screened for a large number of conditions regardless of one’s race or ethnicity.4 Although expanded carrier screening panels typically include all of the genetic conditions recommended by current guidelines, they may include hundreds of other conditions, many of which are rare.4

A joint statement from ACMG, ACOG, the National Society of Genetic Counselors (NSGC), Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine recognized that expanded carrier screening, rather than condition-based screening, can be a reasonable approach for patients.4 The ACOG Committee on Genetics also published a separate committee opinion stating that ethnic-specific, pan-ethnic, and expanded carrier screening are all acceptable approaches for preconception and prenatal genetic carrier screening.12

There are diverse offerings in commercially available expanded carrier screening panels with varying panel sizes (Table 1)13-17 and assay technologies.18 Even 2 seemingly identical expanded carrier screening panels with similar technology that test the same number of genes may have different sensitivities. The differences in sensitivities may be caused by the number of interrogated positions in each gene and how detected variants are interpreted.18 The service providers, names of expanded carrier panels, and the mutation components covered are evolving rapidly. Thus, when considering use of expanded carrier screening technology, it is important to consider the finer elements of their make-up and design, particularly given the extent to which screening results can affect the lives of those screened.

Assay Technologies

One approach used to detect mutations in expanded carrier screening panels is a “full-exon sequencing strategy.”18 With this approach, next-generation sequencing (NGS) is used to assess bases across protein-coding regions known as exons, along with other noncoding regions which have acknowledged contributions to disease pathogenesis.18 This sequencing method can probe thousands of bases per gene and can identify all common variants in addition to rare novel variants. Because full-exon sequencing may uncover novel variants, this strategy requires novel-variant curation, a process used to interpret the clinical impact of observed variants.18

Some strategies bypass the need for novel-variant curation by restricting interrogation to a set of known and predefined pathogenic variants, usually only between 1 to 50 variants per gene. This strategy is called “targeted genotyping.”18 Polymerase chain reaction, microarrays, and NGS can be used in targeted genotyping.18 The smaller assayed regions and lack of novel variant interpretation requirements make targeted genotyping relatively inexpensive. However, it has lower detection rates than full-exon sequencing.18 These lower detection rates may eventually lead to an increase in overall healthcare spending because of the cost of care for unknown affected pregnancies.18,19 Given the challenges of achieving both high sensitivity and high specificity in a low-labor process, careful selection of variants is essential.

Framework for Evaluating and Designing Expanded Screening Panels

The Centers for Disease Control and Prevention established the ACCE framework as a process to evaluate genetic testing.20 ACCE derives its name from the 4 criteria for assessing a genetic test:
  1. Analytic validity
  2. Clinical validity
  3. Clinical utility
  4. Associated ethical, legal, and social implications
To optimize these 4 criteria, experts have proposed that expanded carrier screening panels should be designed with the following considerations:18
  1. Candidate diseases being evaluated should be clinically “desirable.” Included diseases should be considered “severe” or “profound.”
  2. Aggregate panel sensitivity should be maximized. One way to maximize aggregate panel sensitivity is to select high-incidence diseases.
  3. Per-disease sensitivity and negative predictive value should be maximized. High confidence in test results for both carrier and noncarrier status can be achieved for each genetic condition.
  4. Specificity should be maximized to near 100% by using carefully designed assay and variant curation methods.
Sensitivity, specificity, and predictive values are important determinants of analytical and clinical validity.

Analytical Validity

Analytical validity means that a test can predict the presence or absence of a genetic mutant.22

ACMG and the College of American Pathologists have published recommendations on the necessary performance parameters of genetic testing using NGS technology. In particular, these organizations recommend measuring analytical sensitivity, specificity, accuracy, precision, and reproducibility of an NGS-based test.23,24 Expanded carrier screening panels with greater than 99.99% analytical sensitivity, specificity, and accuracy and greater than 99.9% inter- and intra-assay reproducibility are commercially available.25

Clinical validity. Clinical validity refers to the ability of a test and to accurately identify couples at risks of passing on serious genetic diseases to their offspring.26 Clinical validity depends on several factors, such as high clinical sensitivity (a positive test when the genetic disorder is present), and specificity (a negative test when the genetic disorder is absent).27 Another factor is an established relationship between genotype and condition phenotype. To establish clinical validity, the genetic testing should be applied in populations where the test may be present.27

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