Clinical Utility of Expanded Carrier Screening: Reproductive Behaviors of At-Risk Couples

Abstract

Purpose:Expanded carrier screening (ECS) analyzes dozens or hundreds of recessive genes for determining reproductive risk. Data on clinical utility of screening conditions beyond professional guidelines is scarce. Methods:Individuals underwent ECS for up to 110 genes. 537 at-risk couples (ARC), those in which both partners carry the same recessive disease, were invited to a retrospective IRB-approved survey of their reproductive decision making after receiving ECS results. Results:64 eligible ARC completed the survey. Of 45 respondents screened preconceptionally, 62% (n=28) planned IVF with PGD or prenatal diagnosis (PNDx) in future pregnancies. 29% (n=13) were not planning to alter reproductive decisions. The remaining 9% (n=4) of responses were unclear.Of 19 pregnant respondents, 42% (n=8) elected PNDx, 11% (n=2) planned amniocentesis but miscarried, and 47% (n=9) considered the condition insufficiently severe to warrant invasive testing. Of the 8 pregnancies that underwent PNDx, 5 were unaffected and 3 were affected. 2 of 3 affected pregnancies were terminated.Disease severity was found to have significant association (p=0.000145) with changes in decision making, whereas guideline status of diseases, controlled for severity, was not (p=0.284). Conclusion:Most ARC altered reproductive planning, demonstrating the clinical utility of ECS. Severity of conditions factored into decision making.

Systematic Design and Comparison of Expanded Carrier Screening Panels

“…This phenotype-based scheme was shown to agree with severity classifications by health-care professionals 2 , suggesting its feasibility for efficient classification and comparison of hundreds of diseases. Underscoring the usefulness of such severity classifications, a separate survey of at-risk couples with "severe" or "profound" diseases found that among at-risk couples (those found to both be carriers for the same autosomal recessive condition), those at-risk for severe or profound conditions altered reproductive decisions at a significantly higher rate than those carrying moderate conditions 13 . In the present work, we propose that the first step in ECS disease selection is to enumerate and prioritize diseases considered "severe" or "profound" under this scheme.…”

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“…A retrospective modeling study of many thousands of carrier screens for 94 single gene disorders suggested that around 1/94 to 1/392 fetuses per 100 000 would be affected, raising the possibility of using extended prenatal carrier screening to identify risk. Subsequently, a small study of parental views showed that if offered preconceptually, over half would opt for PGD, IVF, or prenatal diagnosis in subsequent pregnancies . In 2017, there was an increase in the use of sequencing to determine the genetic etiology in fetuses with congenital anomalies, with a shift from publications reporting small series of highly selected cases in which the diagnostic yield was as high as 80% to reports of larger numbers of unselected cases with much lower diagnostic yields of around 6% to 7% .…”

“…Subsequently, a small study of parental views showed that if offered preconceptually, over half would opt for PGD, IVF, or prenatal diagnosis in subsequent pregnancies. 22 In 2017, there was an increase in the use of sequencing to determine the genetic etiology in fetuses with congenital anomalies, with a shift from publications reporting small series of highly selected cases in which the diagnostic yield was as high as 80% to reports of larger numbers of unselected cases with much lower diagnostic yields of around 6% to 7%. 23 Many of us have counseled couples who have had pregnancies complicated by serious, and often fatal, fetal, or neonatal abnormalities in which there is no remaining biosample available to analyze.…”

Clinical Utility of Expanded Carrier Screening: Results-Guided Actionability and Outcomes

“…In a study of 64 at-risk couples (ARCs; defined as a reproductive couple in which both individuals carry pathogenic variants in the same gene, or a female carries an X-linked pathogenic variant) identified through ECS, 76% of those at-risk for severe or profound conditions took or planned to take action to reduce the risk of an affected birth, including IVF with PGT-M and PNDx. 16 In a separate study conducted among couples undergoing IVF, all ARCs in the sample (8/8) underwent or planned to undergo PGT-M to avert an affected birth. 17 Though conducted on cohorts with relatively few ARCs, these studies suggest that ECS enables reproductive decision-making that reduces the risk of having affected offspring, potentially leading to reduced incidence for a broad range of screened conditions and in diverse populations.…”