EP344: Making the grade: How carrier screening panels score against the American College of Medical Genetics and Genomics “Tier 3” recommendations

Abstract

Laboratories take many considerations when curating expanded carrier screening panels. Criteria considered when choosing conditions to include on panels often consists of condition severity, carrier frequency, ability and accuracy of testing strategies, well-established genotype-phenotype correlations, and reproductive testing options. The American College of Medical Genetics and Genomics (ACMG) recently issued a practice resource entitled “Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics and Genomics (ACMG)”. Because their previous documents were published before the current advancements in gene sequencing technology, they have since updated their recommendations for carrier screening panel curation, and shifted their focus from ethnic based carrier screening to equity of care. ACMG’s new recommendation states that all preconception and pregnant patients be offered Tier 3 carrier screening. Conditions qualifying for Tier 3 are defined as autosomal recessive conditions with a carrier frequency of greater than or equal to 1 in 200. ACMG did not specify if the carrier frequency should apply to the global population or specific ethnic groups. However, they do acknowledge that many genetic conditions do not have a pan-ethnic carrier frequency of 1 in 200, but do meet this criteria in a subpopulation that is well-represented in the United States. In this study, we examined expanded carrier screening panels from five different laboratories to determine what percentage of each panel meets the Tier 3 recommendations based on both the pan-ethnic carrier frequency and subpopulation carrier frequency for those ethnic backgrounds that have at least 1% representation in the United States. A total of five expanded carrier screening (ECS) panels from differing genetic testing laboratories were reviewed. Information regarding the conditions included on the panel as well as carrier frequencies were obtained from each laboratory’s website. The largest panels offered by each lab were selected, excluding any optional add-ons. The panels which varied in size by the number of conditions screened for were as follows: 113 (NxGen MDx), 172, 274, 287 and 501 conditions, respectively. Data was analyzed to determine how the different ECS panels scored when compared to the Tier 3 recommendations set forward by the American College of Medical Genetics and Genomics. Scoring was first determined through a percentage basis of how many conditions included on the ECS had a pan-ethnic carrier frequency of 1 in 200 or greater. Each panel was then scored based on how many conditions included on the ECS had a carrier frequency of 1 in 200 or greater in subpopulations that have at least 1% representation in the United States. ACMG suggested that X-linked conditions be included on an ECS based on a prevalence of 1/40,000 or greater. The X-linked conditions included in the scoring for these panels are the specific conditions recommended by ACMG in the practice resource. When scoring based on pan-ethnic carrier frequency alone, the 172 condition panel received the highest score with a 39.0%. NxGen MDx’s 113 condition panel received the second highest score at 33.6%. The remaining scores were as follows: 27.5% for the 287 condition panel, 24.5% for the 274 condition panel, and 18.2% for the 501 condition panel. When scoring with the addition of subpopulations that have at least 1% representation in the United States, NxGen MDx’s 113 condition panel received the highest score of 64.6%. The 172 condition panel received the second highest score at 63.4%. The remaining scores were as follows: 44.9% for the 274 condition panel, 42.9% for the 287 condition panel and 34.9% for the 501 condition panel. Interestingly, among the panels reviewed, the score appears to decrease as the panel size is expanded. None of the ECS panels examined in this study had over 50% of the conditions included on their panel that meet ACMG’s Tier 3 criteria when going by pan-ethnic carrier frequency alone. However, when including other subpopulation carrier frequencies, the two smallest panels had over 50% of their conditions meet Tier 3 criteria. Our analysis highlights the incongruity between ECS panels routinely offered in clinical settings and current ACMG recommendations. Though Tier 3 criteria should be considered in panel curation, selecting conditions solely on pan-ethnic carrier frequency may not be sufficient in addressing patient needs, as certain ethnicities may have a higher carrier frequency for conditions that otherwise have over a 1/200 pan-ethnic carrier frequency. Including these specific conditions on ECS panels addresses any concerns regarding the shift away from using self-reported patient ancestry for panel selection. As ECS panel curation continues to evolve, it will be important to consider more robust panel criteria that acknowledge other factors pertinent to patient care.