Clinical validity of expanded carrier screening: Evaluating the gene‐disease relationship in more than 200 conditions

Balzotti, Marie; Meng, Linyan; Muzzey, Dale; Taber, Katherine Johansen; Beauchamp, Kyle A.; Team, Myriad Genetics Curation; Team, Baylor Genetics Curation; Mar‐Heyming, Rebecca; Buckley, Bethany A.; Moyer, Krista

doi:10.1002/humu.24033

Cited by 9 publications

(7 citation statements)

References 24 publications

(36 reference statements)

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“…Ben‐Shachar et al and Guo and Gregg concluded that a panel meeting the “carrier frequency of 1 in 100 or greater” criterion would include approximately 40 conditions when that threshold is applied to any ethnicity 19,22 . Balzotti et al examined the “well‐defined phenotype” criterion by applying the ClinGen framework for gene‐disease association evidence 23 to more than 200 genes commonly included on commercial ECS panels, and found that the vast majority had the highest level gene‐disease association evidence 24 . These studies, taken together with ours, provide evidence‐based interpretations of ACOG panel design criteria and act as guidance for laboratories in the design of ECS offerings.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…8 We therefore used ACMG's recommended quantification and threshold for evaluating genotype-phenotype relationship. Of the 176 conditions examined here, 175 (99.4%) met the moderate or higher gene-disease association threshold 22 (Figure 1B). This 175-condition panel would capture 99.8% of carriers and >99.9% of ARCs compared with a 176-condition panel (Supplemental Table 6).…”

Section: Genotype-phenotype Relationship As a Criterion For Panel Inclusionmentioning

confidence: 92%

“…Criterion 1 was defined by carrier frequency thresholds described in ACOG and ACMG criteria and evaluated using carrier rates from 460,608 individuals across 11 races/ethnicities (as seen further on). 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).…”

Section: Methodsmentioning

confidence: 99%

“…Criterion 2 addresses ACOG and ACMG genotypephenotype relationship criteria (Table 1). 4,8 Although ACOG does not define how to quantify this relationship, ACMG recommends evaluating evidence for gene-disease association using the ClinGen framework that categorizes the strength of such evidence, 22,28 recommending a threshold of at least moderate gene-disease association for panel inclusion. 8 We therefore used ACMG's recommended quantification and threshold for evaluating genotype-phenotype relationship.…”

Section: Genotype-phenotype Relationship As a Criterion For Panel Inclusionmentioning

confidence: 99%

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

Taber

Ben‐Shachar

Torres

et al. 2022

Genetics in Medicine

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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.

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“…This framework has been applied to many monogenic conditions, including those commonly included on ECS panels, with classifications published on the ClinGen website. [43][44][45][46][47][48] This provides a valuable resource for considering which conditions are appropriate for inclusion on ECS panels.…”

Section: Genotype-phenotype Associationmentioning

confidence: 99%

Expanded carrier screening: What conditions should we screen for?

2023

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Carrier screening tests reproductive couples for their risk of having children affected by serious monogenic conditions. Carrier screening has historically been offered for certain conditions in high‐risk populations. However, more recent evidence has shown that offering carrier screening to all patients, regardless of their ethnicity, more effectively and equitably identifies at‐risk couples. Coupled with technology that enables screening for a nearly unlimited number of conditions, this expanded carrier screening (ECS) approach is now supported by professional society guidelines. Despite recent recommendations by the American College of Medical Genetics and Genomics to screen all patients who are pregnant or considering pregnancy for 113 conditions, questions remain about what conditions should be included on a core ECS panel. Here, we briefly review the history of carrier screening and guidelines on criteria for panel design. We then suggest which of these criteria are most critical, as well as thresholds to identify which conditions meet these criteria. Based on these interpretations, we recommend a core panel of 64 conditions that would identify the vast majority of at‐risk couples. Widespread adoption of a core panel such as this would result in a marked improvement in the number of patients currently receiving comprehensive carrier screening.

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Clinical validity of expanded carrier screening: Evaluating the gene‐disease relationship in more than 200 conditions

Cited by 9 publications

References 24 publications

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

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

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

Expanded carrier screening: What conditions should we screen for?

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