Yield of Exome Sequencing for Mendelian Disorders Screening in Asymptomatic Fetuses Undergoing Prenatal Diagnosis: A Retrospective Analysis of 1766 Cases.

Objective: We aimed to evaluate the yield of exome sequencing (ES) as a routine screening test for Mendelian disorders in asymptomatic fetuses undergoing prenatal diagnosis, with a focus on identifying gene variants associated with moderate to severe diseases.

Methods: A total of 2593 fetuses underwent prenatal ES (pES) testing at the Third Affiliated Hospital of Sun Yat-Sen University between 2021 and 2022. Out of these, we excluded 827 pES datasets from fetuses with abnormal ultrasound findings, as well as those with a confirmed/suspected family history of Mendelian disorders. Consequently, a cohort of 1766 singleton ES datasets from asymptomatic fetuses was included in this study and subsequently subjected to retrospective analysis.

Results: We identified 25 cases with 30 variants in 23 genes that may present with moderate to severe diseases, giving a yield of 1.42% (25/1766). Among these genes, 73.91% were associated with autosomal dominant (AD) inheritance, 21.74% with autosomal recessive (AR) inheritance, and 4.35% with X-linked recessive (XLR) inheritance. Of the 30 identified variants, 23.33% were classified as pathogenic, 73.33% as likely pathogenic, and 3.33% as variants of uncertain significance. The types of variants included missense (23.33%), nonsense (33.33%), frameshift deletion (26.67%), splicing region (13.33%), and inframe deletion (3.33%). Clinically, 40% (10/25) of the cases were at risk of severe diseases, and 60% (15/25) of the cases were at risk of moderate diseases. Of the positive cases, 92% (23/25) were liveborn, and 73.91% (17/23) were effectively followed up to the age of three. Among these 17 cases, two exhibited clinical presentations that highly met the criteria for ES findings, while two exhibited clinical presentations that partially met the criteria.

Conclusion: The findings of this study suggest that application of ES as a routine test in asymptomatic fetuses undergoing prenatal diagnosis could enhance the detection of Mendelian disorders, thereby providing information to parents about the health of their fetus, providing them with reproductive options, as well as providing the potential for medical interventions prenatally or postnatally. However, challenges may arise in variant interpretation in the absence of phenotype, along with the risk of uncertain outcomes for positive cases.