Noninvasive prenatal exome sequencing diagnostic utility limited by sequencing depth and fetal fraction. (21st July 2021)

• Record Type: Journal Article
• Authors: Filer, Dayne L.; Mieczkowski, Piotr A.; Brandt, Alicia; Gilmore, Kelly L.; Powell, Bradford C.; Berg, Jonathan S.; Wilhelmsen, Kirk C.; Vora, Neeta L.
• Is Part Of: Prenatal diagnosis. Volume 42:Number 5(2022)
• Page Start: 567
• Page End: 573
• Publication Date: 2021-07-21
• Subjects: Prenatal diagnosis -- Periodicals; Fetus -- Diseases -- Diagnosis -- Periodicals; Electronic journals; 618.32075
• DOI: 10.1002/pd.6009
• Languages: English
• ISSNs: 0197-3851

Abstract

Abstract: Objective: Sequencing cell‐free DNA now allows detection of large chromosomal abnormalities and dominant Mendelian disorders in the prenatal period. Improving upon these methods would allow newborn screening programs to begin with prenatal genetics, ultimately improving the management of rare genetic disorders. Methods: As a pilot study, we performed exome sequencing on the cell‐free DNA from three mothers with singleton pregnancies to assess the viability of broad sequencing modalities in a noninvasive prenatal setting. Results: We found poor resolution of maternal and fetal genotypes due to both sampling and technical issues. Conclusion: We find broad sequencing modalities inefficient for noninvasive prenatal applications. Alternatively, we suggest a more targeted path forward for noninvasive prenatal genotyping. Key points: What's already known about this topic? Sequencing‐based noninvasive testing detects large copy number abnormalities and some single‐gene disorders. Fetal exome sequencing (ES) provides 10%–20% diagnostic yield for structural abnormalities after normal karyotype and microarray. What does this study add? Cell‐free ES in three gravid patients with suspected genetic disease in the fetus. Discussion of probability theory underlying noninvasive fetal genotyping. We demonstrate broad sequencing approaches are limited by sampling and technical difficulties, concluding broad sequencing is currently inappropriate for noninvasive testing.