Is There Potential Clinical Utility in Reporting Variants of Uncertain Significance From Prenatal Sequencing?

Area of Science:

• Medical Genetics
• Fetal Medicine
• Bioinformatics

Background:

• Prenatal genetic sequencing for fetuses with detected abnormalities is increasingly common.
• Reporting variants of uncertain significance (VUS) during prenatal diagnosis remains a debated topic.
• National guidelines are evolving, with some opposing prenatal VUS reporting.

Purpose of the Study:

• To evaluate the clinical utility of reporting VUS identified through prenatal sequencing.
• To assess the resolution rate of VUS through follow-up investigations.
• To analyze the outcomes of VUS reported by a major English prenatal sequencing laboratory.

Main Methods:

• Retrospective review of a laboratory database (01/10/2020–30/04/2025).
• Identification of all reported VUS in prenatal sequencing cases.
• Collection of pregnancy outcome data to determine VUS status resolution.

Main Results:

• Variants of uncertain significance were reported in 41 out of 881 fetuses.
• Follow-up data were available for 38 cases; 23 VUS were upgraded to likely pathogenic.
• Post-mortem or postnatal review was the most common reason for VUS upgrade (17/23).

Conclusions:

• Reporting VUS in prenatal sequencing, after multidisciplinary team (MDT) discussion, demonstrates clinical utility.
• While VUS reporting introduces parental uncertainty, follow-up resolves this in a majority of cases (79% re-examined).
• Post-mortem and postnatal reviews are crucial for resolving VUS findings.