Purpose: The recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.Methods: Guided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.Results: Based on modeled fetal risks for "severe" and "profound" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome). Conclusion:The described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

Purpose: Carrier status associates strongly with genetic ancestry, yet current carrier screening guidelines recommend testing for a limited set of conditions based on a patient's self-reported ethnicity. Ethnicity, which can reflect both genetic ancestry and cultural factors (e.g., religion), may be imperfectly known or communicated by patients. We sought to quantitatively assess the efficacy and equity with which ethnicity-based carrier screening captures recessive disease risk. Methods: For 93,419 individuals undergoing a 96-gene expanded carrier screen (ECS), correspondence was assessed among carrier status, self-reported ethnicity, and a dual-component genetic ancestry (e.g., 75% African/25% European) calculated from sequencing data. Results: Self-reported ethnicity was an imperfect indicator of genetic ancestry, with 9% of individuals having >50% genetic ancestry from a lineage inconsistent with self-reported ethnicity. Limitations of self-reported ethnicity led to missed carriers in atrisk populations: for 10 ECS conditions, patients with intermediate genetic ancestry backgrounds-who did not self-report the associated ethnicity-had significantly elevated carrier risk. Finally, for 7 of the 16 conditions included in current screening guidelines, most carriers were not from the population the guideline aimed to serve. Conclusion: Substantial and disproportionate risk for recessive disease is not detected when carrier screening is based on ethnicity, leading to inequitable reproductive care.

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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.

PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.ResultsBased on modeled fetal risks for “severe” and “profound” diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen’s sensitivity is greatly impacted by two factors: (1) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping), and (2) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches allow principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

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.

Objective: To evaluate the efficacy of three different carrier screening workflows designed to identify couples at risk for having offspring with autosomal recessive conditions.Methods: Partner testing compliance, unnecessary testing, turnaround time, and ability to identify at-risk couples (ARCs) were measured across all three screening strategies (sequential, tandem, or tandem reflex).Results: A total of 314,100 individuals who underwent carrier screening were analyzed. Sequential, tandem, and tandem reflex screening yielded compliance frequencies of 25.8%, 100%, and 95.9%, respectively. Among 14,595 couples tested in tandem, 42.2% of females were screen-negative, resulting in unnecessary testing of the male partner. In contrast, less than 1% of tandem reflex couples included unnecessary male testing. The median turnaround times were 29.2 days (sequential), 8 days (tandem), and 13.3 days (tandem reflex). The proportion of ARCs detected per total number of individual screens were 0.5% for sequential testing and 1.3% for both tandem and tandem reflex testing. Conclusion:The tandem reflex strategy simplifies a potentially complex clinical scenario by providing a mechanism by which providers can maximize partner compliance and the detection of at-risk couples while minimizing workflow burden and unnecessary testing and is more efficacious than both sequential and tandem screening strategies. Highlights What's already known about this topic?� Studies have explored barriers to carrier screening and follow up partner testing to identify at-risk couples. However, to date, no one has explored the efficacy of different carrier screening workflows.Ben-Shachar and Johansen Taber are co-senior authors.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Background Pathogenic variants in HEXA that impair β‐hexosaminidase A (Hex A) enzyme activity cause Tay‐Sachs Disease (TSD), a severe autosomal‐recessive neurodegenerative disorder. Hex A enzyme analysis demonstrates near‐zero activity in patients affected with TSD and can also identify carriers, whose single functional copy of HEXA results in reduced enzyme activity relative to noncarriers. Although enzyme testing has been optimized and widely used for carrier screening in Ashkenazi Jewish (AJ) individuals, it has unproven sensitivity and specificity in a pan‐ethnic population. The ability to detect HEXA variants via DNA analysis has evolved from limited targeting of a few ethnicity‐specific variants to next‐generation sequencing (NGS) of the entire coding region coupled with interpretation of any discovered novel variants. Methods We combined results of enzyme testing, retrospective computational analysis, and variant reclassification to estimate the respective clinical performance of TSD screening via enzyme analysis and NGS. We maximized NGS accuracy by reclassifying variants of uncertain significance and compared to the maximum performance of enzyme analysis estimated by calculating ethnicity‐specific frequencies of variants known to yield false‐positive or false‐negative enzyme results (e.g., pseudodeficiency and B1 alleles). Results In both AJ and non‐AJ populations, the estimated clinical sensitivity, specificity, and positive predictive value were higher by NGS than by enzyme testing. The differences were significant for all comparisons except for AJ clinical sensitivity, where NGS exceeded enzyme testing, but not significantly. Conclusions Our results suggest that performance of an NGS‐based TSD carrier screen that interrogates the entire coding region and employs novel variant interpretation exceeds that of Hex A enzyme testing, warranting a reconsideration of existing guidelines.