Challenges in providing residual risks in carrier testing

Abstract

The authors take responsibility for the presentation and publication of the commentary, have been fully involved at all stages of publication and presentation development, and are willing to take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the literature analysis and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors' personal interests, financial or non-financial, relating to this research and its publication have been disclosed.What's already known about this topic? What does this study add? There has been no published discussion of the methods and uncertainties involved in the calculation of residual risk that are discussed here. There has been much discussion of using ancestry in genetic testing but this review highlights the serious problems that arise in calculating and assigning ancestry-specific residual carrier risks at specific disease loci.  The review questions what has not been questioned before: Is there clinical utility to providing what are mostly imprecise residual carrier risks.

Expanded carrier screening: What conditions should we screen for?

“…gaps in global incidence information (due to differences in newborn screening programs in various populations), non-random mating patterns that undermine Hardy-Weinberg assumptions, inaccuracies of self-reported ethnicity, differences in carrier frequencies across ethnic groups, and the increasing number of individuals of admixed ethnicity. 53 While these factors make residual risk calculation Carrier frequencies listed represent the highest carrier frequency published among ethnicities with substantial representation in the US population. 30,33 A 1 in 10,000 carrier frequency for X-linked conditions is equivalent to a 1 in 100 carrier frequency for autosomal recessive conditions.…”

“…Residual risk is dependent on the prevalence of the disorder in question as well as the DR of the methodology used to screen. Some of the limitations in calculating a precise residual risk are the significant gaps in global incidence information (due to differences in newborn screening programs in various populations), non‐random mating patterns that undermine Hardy‐Weinberg assumptions, inaccuracies of self‐reported ethnicity, differences in carrier frequencies across ethnic groups, and the increasing number of individuals of admixed ethnicity 53 . While these factors make residual risk calculation difficult, they do not prohibit discussion of the concept of residual risk with patients, as residual risk is important in determining whether additional clinical intervention is warranted.…”

Reproductive Counseling and Care in Cystic Fibrosis: A Multidisciplinary Approach for a New Therapeutic Era

“…Individuals in the general population who receive a negative result have reduced, but not eliminated, their chance to be a CF carrier. Residual carrier risks are based upon the estimated test sensitivity and the baseline or the a priori chance of being a carrier and are typically less than half of one percent, meaning the risk is greatly reduced but greater than zero [65]. It is recommended that the labs offering CF carrier screenings assess a minimum panel of disease-causing CFTR variants; thus, when one member of a couple screens positive as a CF carrier or has CF, a limited genetic screening panel may be offered to the second partner, consistent with professional guidelines [30].…”