Expanded carrier screeningThe American College of Medical Genetics and Genomics (ACMG) recently embarked on a systematic evidence review culminating in published recommendations for extensive changes in reproductive carrier screening testing. Genetics specialists across all disciplines have recognized the need for evidence-based guidelines promulgated by professional societies in this complex and challenging clinical space, as much of the conversation to date has been led by diagnostic laboratories.


It is evident that the ACMG committee worked diligently to address current imperfections as well as concerns associated with inequitable access to carrier screening. InformedDNA applauds the ACMG for thoughtful categorization of the recommendations as a Practice Resource and not a Clinical Practice Guideline. Our comments in this blog are intended to spur additional research and dialogue needed to address several important remaining concerns regarding this complex topic. 


The ACMG appropriately highlights the limitations of relying on self-reported ancestry to guide carrier screening and focuses on the ability of today’s technological advances to offer rapid and inexpensive testing which paves the way for a “consistent and equitable approach for offering carrier screening to all individuals.” ACMG proposes that this can be accomplished by the use of a 113-gene panel based on carrier frequency thresholds for autosomal recessive conditions of ≥1/200 in at least one ethnic subpopulation that makes up at least 1% of the U.S. population, as well as X-linked conditions with a disease prevalence of at least 1/40,000. There are real questions about the assumptions underlying these recommendations and whether this testing approach could actually translate into a cost-effective population-based screening program.


The Extent of the Problem Being Addressed is Unknown


While acknowledging that self-reported ethnicity is not ideal, the extent of the potential problem with today’s current carrier screening approach is unknown. Addressing public health issues requires a broad and in-depth assessment of the root causes, as well as a realistic assessment of the costs and benefits of potential options to address them. One question to ask is whether undertesting is an issue and the extent to which current carrier testing based on self-reported ethnicity contributes to it. It is important to note that the current testing approach does not limit individuals to testing of the few conditions recommended for all; when testing is pursued, additional genes are included based on known or even suspected ethnic background.


On the other hand, what if a major underlying issue is that testing is often not pursued? Or pursued but not acted upon? Several known and unaddressed disparities contribute to the rates of unanticipated birth of children with rare diseases. Many people simply do not have access to carrier testing at all. Many more do not have access to certain interventions that are essential to realizing the clinical utility of carrier testing – interventions that can change outcomes but are costly, and for many individuals, are not covered benefits. The list includes IVF with donor egg/sperm, preimplantation genetic diagnosis, or termination of pregnancy, which is becoming increasingly inaccessible for many women.


In addition to these known disparities, evidence is lacking to demonstrate that patients or providers have called for such broad carrier screening in the general population as an aid in reproductive planning. Inquiries, appeals, and petitions for expanded coverage received by InformedDNA and partner health plans are almost exclusively from genetic testing laboratories that stand to benefit significantly from such a proposed expansion. Research addressing all of these potential issues is essential before sweeping changes, known to be associated with substantial costs but unproven impacts, are made.


An Underlying Premise for the Recommended Changes is that Expanded Testing Will Be Performed at Low Cost


No formal, unbiased health economic analyses have been performed and by definition, 99% of the U.S. population who would be tested for the proposed additional conditions is at extremely low risk for them.


  • Importantly, while technological costs have decreased, pricing for expanded carrier screening panels is highly variable, ranging into several thousands of dollars. Even CMS pricing of CPT code 81443, often used for broad carrier screening panels, is listed at over $2,000.
  • In attempting to define the population for testing – which is a foundational step to justify, guide, and develop DNA-based screening programs – ACMG acknowledged that the defined carrier frequency is unknown across the general population for most of the proposed conditions. This precludes the ability to generate precise residual risks. Additionally, applying the carrier frequency in a rare subpopulation to the entire general U.S. population artificially inflates both the projected impact and utility of testing.

The Extent of the Potential Benefit of the Proposed Changes is Unknown


Just as it is unknown to what extent testing based on self-reported ethnicity is a problem, the potential benefit of the proposal to test everyone with expanded panels is also unknown. ACMG has defined the clinical utility of carrier screening by “its ability to provide individuals an opportunity to discuss their risks and consider reproductive options available pre-pregnancy, during pregnancy or after birth”. Once again, the society is thoughtful in recognizing several key factors that may limit the clinical utility of broadening carrier screening, including: 


  • Studies of clinical utility are very limited and anecdotal (survey data).
  • Studies may not reflect the clinical utility in an ethnically diverse population such as the proposed general population. 
  • The availability of testing is limited by regional, cultural and socioeconomic factors.  

What is the impact of the proposed carrier screening panel on improving prenatal/neonatal medical management or parental preparation for the birth of a child with one of the screened conditions? The answer to this key question of potential benefit is unknown.  We concur with Katie Stoll and Robert Resta’s (2021) recent review of the ACMG Practice Resource in calling for additional research to address this question. We also support the Society’s call for additional “ethnically inclusive” studies to address these issues in the future, as it is striking that the cited studies were so decidedly inequitable, with underrepresentation of key groups. 


Where Do We Go From Here? 


The genetics community, professional societies, and health systems continually strive for greater excellence in clinical care by considering complex questions. ACMG has exemplified this desire with the development of this Practice Resource. However, recommending and implementing such massive changes that would impact the U.S. general population requires inclusion of the voices of many stakeholders, including groups that represent minority individuals and those with disabilities; unbiased health economics analyses; and evidence of clinical utility in the proposed testing population. More work is required before the carrier screening panel proposed by these expert opinions can be considered medically necessary with substantiated clinical utility in the general population. 


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