Evaluation and classification of severity for 176 genes on an expanded carrier screening panel

Abstract

Background: Disease severity is important when considering genes for inclusion on reproductive expanded carrier screening (ECS) panels. We applied a validated and previously published algorithm that classifies diseases into four severity categories (mild, moderate, severe, and profound) to 176 genes screened by ECS. Disease traits defining severity categories in the algorithm were then mapped to four severity-related ECS panel design criteria cited by the American College of Obstetricians and Gynecologists (ACOG).

Methods: Eight genetic counselors (GCs) and four medical geneticists (MDs) applied the severity algorithm to subsets of 176 genes. MDs and GCs then determined by group consensus how each of these disease traits mapped to ACOG severity criteria, enabling determination of the number of ACOG severity criteria met by each gene.

Results: Upon consensus GC and MD application of the severity algorithm, 68 (39%) genes were classified as profound, 71 (40%) as severe, 36 (20%) as moderate, and one (1%) as mild. After mapping of disease traits to ACOG severity criteria, 170 out of 176 genes (96.6%) were found to meet at least one of the four criteria, 129 genes (73.3%) met at least two, 73 genes (41.5%) met at least three, and 17 genes (9.7%) met all four.

Conclusion: This study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of a trait-based algorithm. Further, it operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation.

FIGURE 1

Severity classification algorithm evaluating specified disease traits (published by Lazarin et al. ⁴ ). Each genetic counselor (GC) and medical geneticist (MD) used the algorithm to independently review and classify genes and their associated phenotype arising in at least 25% of individuals in the untreated state, as profound, severe, moderate, or mild [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Workflow of the severity classification process. Eight GCs were divided into four pairs; each pair was asked to review 44 genes. Once the GC pairs finished their initial review and resolved discordances, the classification process was then passed to the four MDs for review and final classification. Gene numbers in this figure correspond to the gene numbers in Table 1 [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Concordance after initial gene severity classification. Concordance of initial severity classifications within each GC pair and in total among all GCs A, and concordance of initial severity classification within each MD pair and in total among all MDs B. Levels of discordance are indicated by color (green: concordant, red: discordant by one level, blue: discordant by two levels, yellow: discordant by three levels, gray: not classified) [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Genes classified by disease trait and American College of Obstetricians and Gynecologists (ACOG) severity criteria. A, Genes classified by disease trait. B, Genes classified by number of ACOG severity criteria met [Colour figure can be viewed at wileyonlinelibrary.com]