Prenatal Exome Diagnostic Yield, Syndromic Landscape and Secondary Findings

Area of Science:

• Medical Genetics
• Prenatal Diagnostics
• Genomic Medicine

Background:

• Exome sequencing (ES) is increasingly used in maternal fetal medicine for ultrasound-detected anomalies.
• Secondary finding (SF) categories were implemented in prenatal exome testing in June 2021.
• Understanding the diagnostic yield and syndromic landscape of these SFs is crucial.

Purpose of the Study:

• To determine the diagnostic yield of secondary findings in prenatal exome sequencing.
• To analyze the syndromic landscape of reported variants.
• To inform the exome consenting process amidst evolving genetic testing.

Main Methods:

• Retrospective review of prenatal ES cases (June 2021-June 2023).
• Analysis of secondary finding opt-ins, outcomes, variant nomenclature, and inheritance patterns.
• Quantitative and descriptive statistics to determine the frequency of primary and secondary results.

Main Results:

• 131 out of 520 (25.2%) fetal samples had positive molecular results; 61.8% were de novo.
• 50% of cases opted into at least one SF category.
• 14 out of 222 (6.3%) fetuses with ACMG gene opt-in had reportable SF variants; 4 had comorbid diagnoses. 83.3% of SF variants were inherited.

Conclusions:

• Prenatal exome sequencing offers significant diagnostic yield for both primary and secondary findings.
• Healthcare teams must stay updated on expanded testing scope and potential outcomes.
• This data aids in refining the exome consenting process for expectant parents.