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. 2024 Nov;44(12):1444-1450.
doi: 10.1002/pd.6676. Epub 2024 Sep 30.

The High Diagnostic Yield of Prenatal Exome Sequencing Followed by 3400 Gene Panel Analysis in 629 Ongoing Pregnancies With Ultrasound Anomalies

Karin E M Diderich  1 , Hennie T Bruggenwirth  1 , Marieke Joosten  1 , Florentine Thurik  1 , Jona Mijalkovic  1 , Marike Polak  2 , Joan Kromosoeto  1 , Galhana M Somers-Bolman  1 , Myrthe van den Born  1 , Mark Drost  1 , Robert Jan H Galjaard  1 , Sander Galjaard  3 , Lies H Hoefsloot  1 , Maarten F C M Knapen  3 , Rick van Minkelen  1 , Vyne van der Schoot  1 , Marjon A van Slegtenhorst  1 , Frank Sleutels  1 , Kyra E Stuurman  1 , Marjolein J A Weerts  1 , Attie T J I Go  3 , Martina Wilke  1 , Malgorzata I Srebniak  1
Affiliations

The High Diagnostic Yield of Prenatal Exome Sequencing Followed by 3400 Gene Panel Analysis in 629 Ongoing Pregnancies With Ultrasound Anomalies

Karin E M Diderich et al. Prenat Diagn. 2024 Nov.

Abstract

Background: The aim of this study was to evaluate the diagnostic yield of routine exome sequencing (ES) in fetuses with ultrasound anomalies.

Methods: We performed a retrospective analysis of the ES results of 629 fetuses with isolated or multiple anomalies referred in 2019-2022. Variants in a gene panel consisting of approximately 3400 genes associated with multiple congenital anomalies and/or intellectual disability were analyzed. We used trio analysis and filtering for de novo variants, compound heterozygous variants, homozygous variants, X-linked variants, variants in imprinted genes, and known pathogenic variants.

Results: Pathogenic and likely pathogenic variants (class five and four, respectively) were identified in 14.0% (88/629, 95% CI 11.5%-16.9%) of cases. In the current cohort, the probability of detecting a monogenetic disorder was ∼1:7 (88/629, 95% CI 1:8.7-1:5.9), ranging from 1:9 (49/424) in cases with one major anomaly to 1:5 (32/147) in cases with multiple system anomalies.

Conclusions: Our results indicate that a notable number of fetuses (1:7) with ultrasound anomalies and a normal chromosomal microarray have a (likely) pathogenic variant that can be detected through prenatal ES. These results warrant implementation of exome sequencing in selected cases, including those with an isolated anomaly on prenatal ultrasound.

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References

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