Systematic Design and Comparison of Expanded Carrier Screening Panels

Abstract

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.

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

“…Based on the variant‐interpretation concordance analyses presented here and in several previous studies describing the genes selected for inclusion on the panel, we conclude that the ECS investigated here has sufficient clinical validity for widespread screening.…”

Expanded carrier screening for monogenic disorders: where are we now?

“…Although, in principle, carrier couples may still benefit from their carrier status information by emotionally and logistically preparing for the possibility of having an affected child, these benefits may be less prominent where the identified disorder is of a mild nature . However, categorizing recessive disorders by severity can also be complicated by the fact that some disorders are associated with multiple phenotypes that may vary in their clinical characteristics …”

“…In contrast, larger ECS panels typically aimed at maximizing the reliability of negative test results, employing more comprehensive targeted mutation panels and/or nontargeted sequencing. The principal advantage of more comprehensive ECS tests is that couples receiving a negative test result can be highly confident that they are definitely not at risk of having a child with one of the screened disorders . However, this approach may also lead to an increased proportion of false positive results, where some couples identified as carriers through the test will not be at risk of having an affected child.…”

“…These may be particularly common in individuals from geographically isolated areas or with ethnic backgrounds where genotype data are sparse. Therefore, when applied under rigorous laboratory protocols and manual curation of all novel potentially relevant pathogenic variants, nontargeted sequencing can reliably identify some additional carrier couples . Among the ECS providers analyzed in our study, we found that half of them (8/16) employed nontargeted sequencing, either as the primary or as a complementary strategy to identify carriers.…”

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

“…ECS panel design is a complicated endeavor that must take into account a number of factors 18‐21 . ACOG suggests several criteria other than those related to severity that should guide ECS panel design, including a carrier frequency of one in 100 or greater, a well‐defined phenotype, and the ability to diagnose the disease prenatally 2 .…”