TY - JOUR
T1 - The High Diagnostic Yield of Prenatal Exome Sequencing Followed by 3400 Gene Panel Analysis in 629 Ongoing Pregnancies With Ultrasound Anomalies
AU - Diderich, Karin E.M.
AU - Bruggenwirth, Hennie T.
AU - Joosten, Marieke
AU - Thurik, Florentine
AU - Mijalkovic, Jona
AU - Polak, Marike
AU - Kromosoeto, Joan
AU - Somers-Bolman, Galhana M.
AU - van den Born, Myrthe
AU - Drost, Mark
AU - Galjaard, Robert Jan H.
AU - Galjaard, Sander
AU - Hoefsloot, Lies H.
AU - Knapen, Maarten F.C.M.
AU - van Minkelen, Rick
AU - van der Schoot, Vyne
AU - van Slegtenhorst, Marjon A.
AU - Sleutels, Frank
AU - Stuurman, Kyra E.
AU - Weerts, Marjolein J.A.
AU - Go, Attie T.J.I.
AU - Wilke, Martina
AU - Srebniak, Malgorzata I.
N1 - Publisher Copyright:
© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.
PY - 2024/9/30
Y1 - 2024/9/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85205313939&partnerID=8YFLogxK
U2 - 10.1002/pd.6676
DO - 10.1002/pd.6676
M3 - Article
C2 - 39349395
AN - SCOPUS:85205313939
SN - 0197-3851
VL - 44
SP - 1444
EP - 1450
JO - Prenatal Diagnosis
JF - Prenatal Diagnosis
IS - 12
ER -