PurposeThe 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 noncarriers, 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.MethodsCarrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and were evaluated for panels satisfying various criteria. Condition-specific clinical detection rates were estimated via simulation.ResultsDifferent 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 the clinical detection rate remains >84% for conditions with carrier rates as low as 1 in 1000.ConclusionThe 1-in-100 criterion limits at-risk couple detection and should be reconsidered.
PurposeMedical society guidelines recommend offering genotyping-based cystic fibrosis (CF) carrier screening to pregnant women or women considering pregnancy. We assessed the performance of sequencing-based CF screening relative to genotyping, in terms of analytical validity, clinical validity, clinical impact, and clinical utility.MethodsAnalytical validity was assessed using orthogonal confirmation and reference samples. Clinical validity was evaluated using the CFTR2 database. Clinical impact was assessed using ~100,000 screened patients. Three screening strategies were compared: genotyping 23 guideline-recommended variants (“CF23”), sequencing all coding bases in CFTR (“NGS”), and sequencing with large copy-number variant (CNV) identification (“NGS + CNV”). Clinical utility was determined via self-reported actions of at-risk couples (ARCs).ResultsAnalytical accuracy of NGS + CNV was 100% for SNVs, indels, and CNVs; interpretive clinical specificity relative to CFTR2 was 99.5%. NGS + CNV detected 58 ARCs, 18 of whom would have gone undetected with CF23 alone. Most ARCs (89% screened preconceptionally, 56% prenatally) altered pregnancy management, and no significant differences were observed between ARCs with or without at least one non-CF23 variant.ConclusionModern NGS and variant interpretation enable accurate sequencing-based CF screening. Limiting screening to 23 variants does not improve analytical validity, clinical validity, or clinical utility, but does fail to detect approximately 30% (18/58) of ARCs.
Next-generation sequencing (NGS) technology has led to the ability to test for multiple cancer susceptibility genes simultaneously without significantly increasing cost or turnaround time. With growing usage of multigene testing for inherited cancer, ongoing education for nurses and other health-care providers about hereditary cancer screening is imperative to ensure appropriate testing candidate identification, test selection, and posttest management. The purpose of this review article is to (1) provide an overview of how NGS works to detect germline mutations, (2) summarize the benefits and limitations of multigene panel testing, (3) describe risk categories of cancer susceptibility genes, and (4) highlight the counseling considerations for patients pursuing multigene testing.
Carrier screening, a nearly half-century old practice, aims to provide individuals and couples with information about their risk of having children with serious genetic conditions. Traditionally, the conditions for which individuals were offered screening depended on their self-reported race or ethnicity and which conditions were seen commonly in that population. This process has led to disparities and inequities in care as the multi-racial population in the U.S. has grown exponentially, yet databases used to determine clinical practice guidelines are made up of primarily White cohorts. Technological advancements now allow for pan-ethnic expanded carrier screening (ECS), which screens for many conditions regardless of self-reported race or ethnicity. ECS presents a unique opportunity to promote equitable genetic testing practices in reproductive medicine. However, this goal can only be achieved if we acknowledge and appreciate the innumerable inequities evidenced in reproductive medicine and other socio-legal practices in the United States, and if we intentionally work in concert with healthcare providers, policy makers, advocates, and community health champions to reduce current and future reproductive health disparities. Herein, we provide a brief review of the way that US medical racism and genetic discrimination has shaped the current landscape of carrier screening.
OBJECTIVE: To investigate the underlying etiology of three variable phenotypic congenital heart defects (CHD) in a set of identical triplets. STUDY DESIGN: The initial diagnosis of fetal CHD was made during an anatomy scan performed at 20 weeks and 2 days of gestation. Further analysis of the triplet hearts were performed via interval echocardiograms throughout the pregnancy. Post-natal evaluations included neonatal echocardiograms and familial microarray comparative genomic hybridization (aCGH) assays and next generation sequencing (NGS) gene panels. RESULTS: Final diagnoses of cardiac status of infant A: patent foramen ovale; infant B: bicuspid pulmonary valve, pulmonary stenosis,
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.