Clinical utility of expanded carrier screening: results-guided actionability and outcomes

Taber, Katherine Johansen; Beauchamp, Kyle A.; Lazarin, Gabriel A.; Muzzey, Dale; Arjunan, Aishwarya; Goldberg, James D.

doi:10.1038/s41436-018-0321-0

Cited by 69 publications

(56 citation statements)

References 26 publications

(34 reference statements)

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“…Clinical practitioners are urged to inform all potential patients of the wide spectrum of autosomal recessive/X‐linked diseases they may carry and include ECS as part of their infertility screening and preconception work up. Invariably, this effort will steer clinicians towards a more personalized treatment approach that includes genetic counseling, in order for patients to engender informed clinical‐management decisions consistent with their values …”

Section: Discussionmentioning

confidence: 99%

Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population

et al. 2020

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Objective: Genetic carrier screening has the potential to identify couples at risk of having a child affected with an autosomal recessive or X-linked disorder. However, the current prevalence of carrier status for these conditions in developing countries is not well defined. This study assesses the prevalence of carrier status of selected genetic conditions utilizing an expanded, pan-ethnic genetic carrier screening panel (ECS) in a large population of Mexican patients.Methods: Retrospective chart review of all patients tested with a single ECS panel at an international infertility center from 2012 to 2018 were included, and the prevalence of positive carrier status in a Mexican population was evaluated.Results: Eight hundred five individuals were analyzed with ECS testing for 283 genetic conditions. Three hundred fifty-two carriers (43.7%) were identified with 503 pathogenic variants in 145 different genes. Seventeen of the 391 participating couples (4.34%) were identified as being at-risk couples. The most prevalent alleles found were associated with alpha thalassemia, cystic fibrosis, GJB2 nonsyndromic hearing loss, biotinidase deficiency, and familial Mediterranean fever.Conclusion: Based on the prevalence and severity of Mendelian disorders, we recommend that couples who wish to conceive regardless of their ethnicity background explore carrier screening and genetic counseling prior to reproductive medical treatment.

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Section: Discussionmentioning

confidence: 99%

Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population

et al. 2020

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“…In particular, we performed an investigation of the concordance between our variant classifications and the combined classifications in ClinVar (see Section 4; Figure , bottom). Consistency of variant classifications across laboratories is important to verify because when both partners are carriers because of pathogenic variants in the same autosomal gene, they have a 25% risk of an affected child and often pursue alternative reproductive options …”

Section: Resultsmentioning

confidence: 99%

Inter‐lab concordance of variant classifications establishes clinical validity of expanded carrier screening

Kaseniit

Collins

et al. 2019

Clinical Genetics

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Expanded carrier screening (ECS) panels that use next‐generation sequencing aim to identify pathogenic variants in coding and clinically relevant non‐coding regions of hundreds of genes, each associated with a serious recessive condition. ECS has established analytical validity and clinical utility, meaning that variants are accurately identified and pathogenic variants tend to alter patients' clinical management, respectively. However, the clinical validity of ECS, that is, correct discernment of whether an identified variant is indeed pathogenic, has only been shown for single conditions, not for panels. Here, we evaluate the clinical validity of a >170‐condition ECS panel by assessing concordance between >12 000 variant interpretations classified with guideline‐based criteria to their corresponding per‐variant combined classifications in ClinVar. We observe 99% concordance at the level of unique variants. A more clinically relevant frequency‐weighted analysis reveals that fewer than 1 in 500 patients are expected to receive a report with a variant that has a discordant classification. Importantly, gene‐level concordance is not diminished for rare ECS conditions, suggesting that large panels do not balloon the panel‐wide false‐positive rate. Finally, because ECS is intended to serve all reproductive‐age couples, we show that classification of novel variants is feasible and scales predictably for a large population.

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“…A ll conditions on an ECS panel should have a high analytical detection rate and clinical detection rate that together minimize residual risk. 3,8 Since the analytical detection rate is >99.9% for most conditions, 13 However, we have recently demonstrated that disease severity, not rarity, is a driver of ECS clinical utility, 20 and that the high-throughput of NGS testing enables inclusion of additional conditions at a low cost. 21 Additional limitations include that we did not explicitly evaluate the increased clinical burden associated with screening rare conditions including partner testing, genetic counseling, and patient anxiety.…”

Section: Discussionmentioning

confidence: 99%

A Data-Driven Evaluation of the Size and Content of Expanded Carrier Screening Panels

Ben‐Shachar

Svenson

Goldberg

et al. 2018

Preprint

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Purpose: The American College of Obstetricians and Gynecologists (ACOG) proposed seven criteria for expanded carrier screening (ECS) panel design. To ensure that screening for a condition is sufficiently sensitive to identify carriers and reduce residual risk of non-carriers, one criterion requires a per-condition carrier rate greater than 1-in-100. However, it is unestablished whether this threshold corresponds with a loss in clinical detection. The impact of the proposed panel-design criteria on at-risk couple detection warrants data-driven evaluation. Methods:Carrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and evaluated for panels satisfying various criteria. Condition-specific clinical detection rate was estimated via simulation.Results: Different interpretations of the 1-in-100 criterion have variable impact: a compliant panel would include between 3 and 38 conditions, identify 11%-81% fewer at-risk couples, and detect 36%-79% fewer carriers than a 176-condition panel. If the carrier-rate threshold must be exceeded in all ethnicities, ECS panels would lack prevalent conditions like cystic fibrosis.Simulations suggest that clinical detection rate remains >84% for conditions with carrier rates as low as 1-in-1000. Conclusions:The 1-in-100 criterion limits at-risk couple detection and should be reconsidered.

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Clinical utility of expanded carrier screening: results-guided actionability and outcomes

Cited by 69 publications

References 26 publications

Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population

Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population

Inter‐lab concordance of variant classifications establishes clinical validity of expanded carrier screening

A Data-Driven Evaluation of the Size and Content of Expanded Carrier Screening Panels

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