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. 2022 Jun;42(7):822-830.
doi: 10.1002/pd.6108. Epub 2022 Feb 1.

Diagnostic yield of genome sequencing for prenatal diagnosis of fetal structural anomalies

Yiming Wang  1   2 , Elena Greenfeld  3   4 , Nicholas Watkins  4 , Peter Belesiotis  5 , Syed H Zaidi  5 , Christian Marshall  3   5 , Bhooma Thiruvahindrapuram  6 , Patrick Shannon  3   4 , Maian Roifman  1   7 , Karen Chong  7 , David Chitayat  1   7 , Dimitri James Stavropoulos  3   5 , Abdul Noor  3   4
Affiliations

Diagnostic yield of genome sequencing for prenatal diagnosis of fetal structural anomalies

Yiming Wang et al. Prenat Diagn. 2022 Jun.

Abstract

Objective: Genome sequencing (GS >30x) is beginning to be adopted as a comprehensive genome-wide test for the diagnosis of rare disease in the post-natal setting. Recent studies demonstrated the utility of exome sequencing (ES) in prenatal diagnosis, we investigate the potential benefits for GS to act as a comprehensive prenatal test for diagnosis of fetal abnormalities.

Methods: We performed GS on a prospective cohort of 37 singleton fetuses with ultrasound-identified structural abnormalities undergoing invasive prenatal testing. GS was performed in parallel with standard diagnostic testing, and the prioritized variants were classified according to ACMG guidelines and reviewed by a panel of board-certified laboratory and clinical geneticists.

Results: Diagnostic sequence variants were identified in 5 fetuses (14%), with pathogenic variants found in NIPBL, FOXF1, RERE, AMMECR1, and FLT4. A further 7 fetuses (19%) had variants of uncertain significance (VUS) that may explain the phenotypes. Importantly, GS also identified all pathogenic variants reported by clinical microarray (2 CNVs, 5%).

Conclusion: Prenatal GS offered diagnoses (sequence variants and CNVs) in 19% of fetuses with structural anomalies. GS has the potential of replacing multiple consecutive tests, including microarray, gene panels, and WES, to provide the most comprehensive analysis in a timely manner necessary for prenatal diagnosis.

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References

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