The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta-analysis

K. Reilly, S. Sonner, N. McCay, D. L. Rolnik, F. Casey, A. N. Seale, C. J. Watson, A. Kan, T. H. T. Lai, B. H. Y. Chung, K. E. M. Diderich, M. I. Srebniak, E. Dempsey, S. Drury, J. Giordano, R. Wapner, M. D. Kilby, L. S. Chitty, F. Mone*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

ObjectivesTo determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification.MethodsA systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747.ResultsOverall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%).ConclusionThe likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.What is already known?Congenital heart abnormalities are the most commonly occurring congenital anomalies and can be associated with chromosomal or monogenic conditions. With the increasing use of fetal sequencing, there is a need to define the association between monogenic conditions and specific cardiac abnormalities, particularly when isolated to facilitate triaging for prenatal sequencing.What does this study add?The incremental yield of prenatal exome sequencing over and above chromosome microarray for congenital heart abnormalities is 9.3% in isolated lesions and 35.2% in the presence of complex lesions/heterotaxy. Clinicians should consider the clinical utility of offering prenatal exome sequencing in selected isolated cardiac lesions dependent on resources available.
Original languageEnglish
Pages (from-to)821-831
Number of pages11
JournalPrenatal Diagnosis
Volume44
Issue number6-7
Early online date6 May 2024
DOIs
Publication statusPublished - Jun 2024

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Publisher Copyright:
© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

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