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.

Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)

“…64 All conditions were at least moderately severe. 5,65 OMIM Online Mendelian Inheritance in Man. 55 allele frequency in gnomAD.…”

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

“…Criterion 2 was defined as gene-disease association and evaluated by applying the ClinGen clinical validity framework, which quantifies gene-disease association by assessing the strength of available evidence, 22 as recommended by ACMG. Criteria 3 to 5 were defined as factors of severity and were evaluated by mapping criteria to disease traits reported in Arjunan et al 23 Criterion 6 was evaluated using published age of onset data (Supplemental Table 2). Consistent with professional society consensus, 3 "early in life" was defined as infancy or childhood (birth to age 2 years or age 2 to 12 years, respectively).…”

Evaluating the efficacy of three carrier screening workflows designed to identify at‐risk carrier couples

“…The panel prioritizes prevalent diseases that are profound and severe as described in Beauchamp et al 9 . and Arjunan et al 10 . Patients and couples considered to be “at risk” were those with variants that were interpreted as being likely pathogenic or pathogenic via the American College of Medical Genetics and Genomics Criteria 11 .…”

“…We retrospectively analyzed deidentified data from samples tested using the Foresight® Carrier Screen (Myriad Women's Health), which included up to 176 genes, 5,9 over a 25-month period. The methodology of the Foresight Carrier Screen has been previously described in Hogan et al 5 The panel prioritizes prevalent diseases that are profound and severe as described in Beauchamp et al 9 and Arjunan et al 10 Patients and couples considered to be "at risk" were those with variants that were interpreted as being likely pathogenic or pathogenic via the American College of Medical Genetics and Genomics Criteria. 11 The at-risk calculations accounted for known disease-specific variant combinations that influence pathogenicity (e.g., a couple in which both partners were silent carriers for alpha thalassemia and therefore not at risk of an affected child were not counted as an ARC).…”

“…and a reduction in turnaround time could reduce such anxiety, though additional research may be needed to test this hypothesis.Pan-ethnic carrier screening has traditionally been limited to CF and, more recently, SMA. However, ECS identifies ARCs for many conditions that are equally as or more severe than CF and SMA 10,16,17. An additional consideration is the time commitment required for provider follow-up for both partner testing and results disclosure, particularly for ECS panels that may result in a higher number of positive results than screening for only CF or SMA.…”