Prenatal Exome Diagnostic Yield, Syndromic Landscape and Secondary Findings

Exome sequencing (ES) has become increasingly more prevalent across maternal fetal medicine spaces when anomalies are visualized on ultrasound. As such, Prevention Genetics implemented secondary finding categories into their prenatal exome based on professional recommendations in June of 2021. This study aimed to determine the diagnostic yield and syndromic landscape of reported variants during that timeframe.

Prenatal ES cases from June 2021 to June 2023 were retrospectively reviewed for secondary finding opt-ins, overall result outcomes, variant nomenclature, and inheritance/segregation patterns. From this data, quantitative and descriptive statistical methods were used to determine the frequency of positive primary and secondary results, including cases in which multiple molecular diagnoses were detected.

Of 520 fetal samples included in the cohort, 131 (25.2%) had a positive molecular result consistent with the clinical indication for exome. Within those 131 cases, 81 (61.8%) were caused by a de novo variant. From the total 520-sample cohort, 260 (50%) cases opted into at least one SF category. Among the 222 fetuses tested in which ACMG guideline-recommended genes were opted into, 14 (6.3%) were found to carry a reportable variant in genes associated with cardiovascular, metabolic, pediatric tumor-predisposition, or connective-tissue disorders. Four fetuses in the COD opt-in cohort were discovered to carry a deleterious variant in two separate SF genes, constituting comorbid pediatric molecular diagnoses. Unlike the primary reporting category, the majority (N = 25/30, 83.3%) of COD SF variants were inherited from a carrier parent.

The aim of this study is to provide meaningful information that can aid in the exome consenting process as improvements in testing technologies and laboratory offerings evolve in response to developments in genetic understanding and professional guidelines. As such, it is crucial for healthcare teams to stay abreast of the increased scope of testing, potential test outcomes, and the phenotypic expansion of various genetic disorders.