The American College of Obstetricians and Gynecologists (ACOG) define carrier screening as ‚Äúgenetic testing performed on an asymptomatic individual to determine whether that person has a mutation or abnormal allele within a gene that is associated with a particular disorder.‚ÄĚ Historically, ethnicity-based carrier screening has been recommended by professional societies. This approach means only screening for conditions that are common in a specific ethnicity. For example, hemoglobinopathies in patients with African or Asian ethnicity; or Tay-Sachs for individuals with Ashkenazi Jewish ancestry. However, ACOG recognizes two issues with this strategy:

  • ‚ÄúIn today‚Äôs multi-racial civilization, it may be problematic for patients to know their exact ethnicity or heritage.‚ÄĚ
  • ‚ÄúRacial admixture of reproductive partners lowers the probability that a specific condition will be confined to a single ethnic group.‚ÄĚ

Accordingly, carrier screening has moved from ethnicity-based screening to pan-ethnic screening. This involves offering the same screening to all patients, regardless of their ethnicity.  Also, within a relatively short about of time, pan-ethnic screening has been replaced, in some cases, with expanded carrier screening (ECS) protocols because of cost and efficiency, among other reasons.

ECS was introduced clinically in 2009, and has become widely adopted since then. The advent of next-generation sequencing (NGS) lowered the cost of carrier screening tremendously.  This technology has historically allowed clinicians to screen for hundreds of conditions for the cost of testing for a single condition. There are a multitude of ECS panels available by many commercial laboratories. These are laboratory developed tests (LDTs) and do not require FDA approval. While many labs report that their tests are developed within guidelines of professional societies, panels should be reviewed by the ordering clinician to ensure they will assist in caring for their patients. ACOG states that ethnicity-based, pan-ethnic, and ECS are all acceptable forms of carrier screening. Therefore, clinicians are responsible for implementing a screening protocol as they see fit. While no specific test has been endorsed by professional guidelines, the application of such strategies should fall within certain recommendations.

Regardless of what test is offered, all patients should be offered the same test. Minimizing health disparities is critical. Carrier screening is optional and patients may opt-in or opt-out. Pre- and post-test genetic counseling by a qualified healthcare provider is crucial for informed consent. This will also assist patients in making informed decisions. If a patient is a carrier of a disease-causing mutation, testing for the reproductive partner should be offered. Testing may be performed concurrently when there are time constraints in a current pregnancy. Ideally, carrier screening should be performed preconceptually.

One important question regarding carrier screening is, ‚ÄúHow do I select the appropriate test?‚ÄĚ Studies have shown that, the larger the testing panel, the more positives will be detected. One study, which had a panel of over 700 conditions, estimated it took an average of about an hour for a clinician to follow up with a patient who tested positive. It is extremely important providers consider clinical¬†and¬†logistical issues when choosing a carrier screening protocol. The ECS panel of over 700 conditions had an astounding 78% positivity rate in the study population. This may place a large workflow burden on the clinical staff when using such a large panel.

Providers must not only select the size of panel, but should review the panel’s technology. Genotyping detects well-defined pathogenic mutations. Sequencing looks at larger coding regions of a particular gene. Sequencing may have higher detection rates compared to genotyping.  It may identify at-risk couples who would have been missed by genotyping and can even find some patients who are affected with a milder phenotype of a specific disease.  However, sequencing may produce results that are difficult to interpret, such as a variant of uncertain significance (VUS), which may provide less clarity to the patient.

Another method of vetting conditions that may be included in a panel is to characterize them by severity of symptoms. Interestingly, a study that performed ECS on 133 patients found little variation in uptake depending on disease severity. They grouped conditions into five categories: significantly shortened lifespan (100% accepted), serious conditions (98% accepted), mild conditions (97% accepted), conditions with unpredictable outcomes (95% accepted), adult-onset conditions (96% accepted), secondary findings that are medically actionable (99% accepted). While this was a small single-center study, it demonstrates that choosing diseases based on phenotype may not always be important to the patient.

Expanded carrier screening is more better

A recent study by a group of genetic counselors proposed modified guidelines for selecting or excluding conditions for ECS. These criteria expand upon already established professional society recommendations:

  • Carrier frequency should be 1 in 100 or greater in one or more well-defined populations.
  • Conditions with incomplete penetrance or mild phenotypes should not be included.
  • Adult-onset conditions should not be included on reproductive screening panels.
  • Detection rate and carrier prevalence should be known within at least one well-defined population.
  • Screening sensitivity should be 70% or greater within at least one well-defined population.

Finally, it is important to consider how these tests may be reimbursed by payers. Clinical utility should be demonstrated.  Clinical utility (which differs from personal utility) may be measured differently by certain groups:

  • Use of the test causes a change in physician management decision.
  • Ability to bring ‚Äúvalue‚ÄĚ to the healthcare system (i.e. reducing cost).
  • Use of the test improves health outcomes.

Unfortunately, there is a lack of evidence in the literature to indicate that carrier screening shows clinical utility. Specific studies should be published regarding this topic.

It is clear there is more than one path available for clinicians to take on in their carrier screening journeys. Some have the opinion to screen for many diseases to detect the largest number of at-risk couples as possible. Other physicians may not have the logistical resources in place to follow up with their positive patients, so they may choose a smaller panel. Providers must also consider that lack of clear evidence demonstrating clinical utility may be a barrier for payer reimbursement.


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