A guidelines-consistent carrier screening panel that supports equity across diverse populations

Abstract

The American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) suggest carrier screening panel design criteria intended to ensure meaningful results. This study used a data-driven approach to interpret the criteria to identify guidelines-consistent panels. Methods: Carrier frequencies in >460,000 individuals across 11 races/ethnicities were used to assess carrier frequency. Other criteria were interpreted on the basis of published data. A total of 176 conditions were then evaluated. Stringency thresholds were set as suggested by ACOG and/or ACMG or by evaluating conditions already recommended by ACOG and ACMG. Results: Forty and 75 conditions had carrier frequencies of ≥1 in 100 and ≥1 in 200, respectively; 175 had a well-defined phenotype; and 165 met at least 1 severity criterion and had an onset early in life. Thirty-seven conditions met conservative thresholds, including a carrier frequency of ≥1 in 100, and 74 conditions met permissive thresholds, including a carrier frequency of ≥1 in 200; thus, both were identified as guidelines-consistent panels. Conclusion: Clear panel design criteria are needed to ensure quality and consistency among carrier screening panels. Evidence-based analyses of criteria resulted in the identification of guidelines-consistent panels of 37 and 74 conditions.

A robust pipeline for ranking carrier frequencies of autosomal recessive and X-linked Mendelian disorders

“…2022 study, ref. 6 ). AFR African or African-American, ASJ Ashkenazi Jewish, MWH Mixed or Other White, FCA French Canadian or Cajun, EAS East Asian, FIN Finnish, AMR Hispanic (corresponding to the Latino/Admixed American population in gnomAD), MEA Middle Eastern, NEU Northern European, SAS South Asian, SEA Southeast Asian, SEU Southern European.…”

“…We further compared our rankings in the gnomAD cohort to actually observed carrier frequencies from a retrospective NGS based ECS study 6 . This ECS study evaluated carrier frequencies of 176 conditions in >460,000 individuals across 11 self-defined ethnicities.…”

“…Additionally, we compared GCRs of two representative genes, CFTR and ABCA4 , to previously studies (Supplementary Dataset 7 ) 6 , 7 , 9 , 10 . We observed similar carrier frequency values for CFTR compared to several published results; while for ABCA4 , our GCRs are comparable yet slightly higher.…”

“…more than 100 genes included) were primarily estimated based on genome-wide sequencing data of unaffected individuals 9 – 11 . Limited reports were available for carrier frequencies of large gene panels in individuals actually subjected to genetic testing 5 , 6 . Note that both estimation and actual observation of population-specific carrier frequencies were mostly on individuals resided in the United States (US) with self-report ethnicities.…”

Expanded carrier screening in the United States: A systematic evidence review exploring client and provider experiences

“…It should be noted that many of the studies included in these provider‐based outcomes were administered several years ago, notably before newer guidelines regarding ECS were published and NGS became more widespread As some of the criteria for panel inclusion by professional societies have been non‐specific, Johansen Taber et al combined the thresholds for ACOG and ACMG criteria and applied it to 176 conditions to determine the composition of a panel consistent with both society guidelines. Thirty‐seven conditions were identified to meet conservative thresholds, including a carrier frequency of greater or equal to 1 in 100, while 74 conditions met more broad thresholds, including a carrier frequency of greater or equal to 1 in 200 (K. Johansen Taber et al., 2022). As the numbers of conditions available vary by laboratory, additional interpretation of the guidelines and evidence‐driven data will be needed.…”