Non-isolated tetralogy of fallot (TOF+): exome sequencing efficacy and phenotypic expansions

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD). TOF may present in isolation or in conjunction with one or more non-cardiac congenital anomalies or neurodevelopmental disorders (TOF+). Uncertainty regarding the efficacy of various genetic testing strategies, and an incomplete understanding of the genetic causes of TOF+, may lead to hesitancy in recommending genetic testing, particularly, clinical exome sequencing (cES). Here, we analyzed cES data from 131 individuals with TOF+. A definitive or probable diagnosis was made for 31 individuals, yielding a diagnostic rate of 23.6% (31/131). One individual received three diagnoses. Commercially available CHD panels would have detected only 27.3% (9/33) to 63.6% (21/33) of the diagnoses made by cES. We then used a machine learning approach to identify four genes for which there is sufficient evidence to support a phenotypic expansion including TOF: DVL3, MED13L, PUF60, and MEIS2. Since chromosomal microarray analysis (CMA) has been reported to have a diagnostic efficacy of 10-20% in individuals with TOF, we conclude that cES should be considered for all individuals with TOF+ for whom a molecular diagnosis has not been established by CMA. We also conclude that TOF represents a low penetrance phenotype associated with genetic syndromes caused by pathogenic variants in DVL3, MED13L, PUF60, and MEIS2.

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Publication Details

Journal
European Journal of Human Genetics
Published
2025-08-12
DOI
https://doi.org/10.1038/s41431-025-01916-8
Citations
2
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
1.61

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article

Non-isolated tetralogy of fallot (TOF+): exome sequencing efficacy and phenotypic expansions

Björn Cools, Giovanni Battista Ferrero, Tom Evans, Zosia Miedzybrodzka et al.
2 citations
European Journal of Human Genetics
Congenital heart defects research
1.61
article

Non-isolated tetralogy of fallot (TOF+): exome sequencing efficacy and phenotypic expansions

Björn Cools, Giovanni Battista Ferrero, Tom Evans, Zosia Miedzybrodzka, Antonio Novelli, Pradeep Vasudevan, Aafke Engwerda, Jeroen Breckpot, Gemma Poke, Seema R. Lalani, Nichole Owen, Sara Loddo, Enrico Grosso, Muriel Holder‐Espinasse, Jill Anne Rosenfeld, Lucy Bownass, Alfredo Brusco, Chad A. Shaw, Koenraad Devriendt, Shiyi Xiong, Nayana Lahiri, Gunnar Houge, Julia Volpi, Ruth Newbury‐Ecob, Sally Ann Lynch, Daryl A. Scott, Alison Male, Pamela N. Luna, Xiaonan Zhao, Maria Cristina Digilio, Marrit M. Hitzert, Ruth Armstrong, Eleanor Sherlock
article en
2 citations

Abstract

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD). TOF may present in isolation or in conjunction with one or more non-cardiac congenital anomalies or neurodevelopmental disorders (TOF+). Uncertainty regarding the efficacy of various genetic testing strategies, and an incomplete understanding of the genetic causes of TOF+, may lead to hesitancy in recommending genetic testing, particularly, clinical exome sequencing (cES). Here, we analyzed cES data from 131 individuals with TOF+. A definitive or probable diagnosis was made for 31 individuals, yielding a diagnostic rate of 23.6% (31/131). One individual received three diagnoses. Commercially available CHD panels would have detected only 27.3% (9/33) to 63.6% (21/33) of the diagnoses made by cES. We then used a machine learning approach to identify four genes for which there is sufficient evidence to support a phenotypic expansion including TOF: DVL3, MED13L, PUF60, and MEIS2. Since chromosomal microarray analysis (CMA) has been reported to have a diagnostic efficacy of 10-20% in individuals with TOF, we conclude that cES should be considered for all individuals with TOF+ for whom a molecular diagnosis has not been established by CMA. We also conclude that TOF represents a low penetrance phenotype associated with genetic syndromes caused by pathogenic variants in DVL3, MED13L, PUF60, and MEIS2.

European Journal of Human GeneticsVol. 34(3)
Guy's Hospital (GB), University Medical Center Groningen (NL), St George's, University of London (GB), University of Groningen (NL), Baylor College of Medicine (US), University of Aberdeen (GB), Leicester Royal Infirmary (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Haukeland University Hospital (NO), St George’s University Hospitals NHS Foundation Trust (GB), Society for Maternal-Fetal Medicine (US), University Hospitals of Leicester NHS Trust (GB), Cambridge University Hospitals NHS Foundation Trust (GB), Children's Health Ireland at Crumlin (IE), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), NHS Grampian (GB), Bambino Gesù Children's Hospital (IT), St Michael's Hospital (GB), Genomics England (GB), Shanghai First Maternity and Infant Hospital (CN), Baylor Genetics (US), St Michaels Hospital (GB), University of Turin (IT), KU Leuven (BE)
Wellcome Trust, European Bioinformatics Institute, National Institutes of Health, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Openalex Percentile: Top 15%
Congenital heart defects research
1.61
DOIOpen Access PDFOpenAlex
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