The evolving landscape of expanded carrier screening: challenges and opportunities

Abstract

Carrier screening allows individuals to learn their chance of passing on an autosomal or X-linked condition to their offspring. Initially introduced as single-disease, ancestry-based screening, technological advances now allow for the possibility of multi-disease, pan-ethnic carrier screening, which we refer to as “expanded carrier screening.” There are numerous potential benefits to expanded carrier screening, including maximizing the opportunity for couples to make autonomous reproductive decisions, and efficiency and marginal additional costs of including more conditions if the test is already being offered. While numerous laboratories currently offer expanded carrier screening services, it is not yet commonly used in clinical practice, and there is a lack of consensus among experts about the service, including whether this should be offered to individuals and couples, whether this should be offered preconception or prenatally, and what conditions to include in screening programs. Challenges for expanded carrier screening programs include a lack of demand from the public, low prioritization by health systems, the potential for pressure to undergo screening, the possibility of disability-based discrimination, needed adaptations to pre- and post-test counseling, technical limitations, and the evolving technological and socio-political landscape.

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

“…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. 2 Further, although our estimation of clinical detection rate attempted to account for unobserved pathogenic variants, we made assumptions about the number and frequency of unknown variants, and future research is needed to refine these estimates.…”

“…1 Advances in genomic technology coupled with decreasing sequencing costs has led to the advent and adoption of expanded carrier screening (ECS) for tens to hundreds of recessive conditions simultaneously. 2 For AR conditions, a couple is at risk if both individuals are carriers of the same condition, with the conceptus having a 25% probability of being affected with the condition. For X-linked conditions, a couple is at risk if the female is a carrier: the probability of a male conceptus being affected with the condition can be up to 50%.…”

“…1,8 Because ECS is commonly performed sequentially (i.e., ECS on initial patient and single-gene screening as needed on the partner), inclusion of each additional condition on a panel poses a trade-off: identification of at-risk couples provides actionable information to guide pregnancy management, 9 while concomitant detection of carriers can increase patient anxiety, 2,10,11 require additional counseling, 2,10 and introduce logistical burden for the provider. 2,11,12 For many conditions, the benefit of identifying at-risk couples offsets these challenges, but it is unclear when a condition is too rare to warrant screening. To that end, ACOG 1 and a clinical assessment of ECS panel design 8 recommend a 1-in-100 carrier frequency threshold for condition inclusion.…”

AutoPVS1: An automatic classification tool for PVS1 interpretation of null variants

“…The decreasing cost of massively parallel next-generation sequencing (NGS) has made it widely used for clinical diagnosis of hereditary diseases in patients 1 and preconception/prenatal expanded carrier screening in healthy couples. 2 With hundreds and thousands of variants produced per individual by NGS-based tests, interpreting their clinical significance and associations with clinical observations presents a significant challenge. The range of difficulties includes coping with different isoforms of a transcript, 3 determining variant frequency thresholds, 4 appropriately interpreting the clinical context, 5 and incorporating with continually updated knowledge.…”

Preimplantation Genetic Testing for HLA-matching: An Overview of Clinical Application and Utility

“…Nowadays, due to the wider availability and uptake of preconception genetic testing for a large number of recessive and X-linked conditions, carrier-couples are often identified prior to initiating a family. Consequent to this, more than 75% of detected at-risk couples take one of the above actions to avoid having an affected child [5,6].…”