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

Journal: European journal of human genetics : EJHG
Published Date: Aug 12, 2025

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.

Authors

  • Julia Volpi
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Xiaonan Zhao
    Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA.
  • Nichole Owen
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Tia Evans
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Muriel Holder-Espinasse
    Clinical Genetics Department Guy's Hospital, London, SE1 9RT, United Kingdom.
  • Nayana Lahiri
    St George's University Hospital NHS Foundation Trust, London, United Kingdom.
  • Eleanor Sherlock
    St George's University Hospital NHS Foundation Trust, London, United Kingdom.
  • Gemma Poke
    Genetic Health Service New Zealand, Wellington, New Zealand.
  • Jeroen Breckpot
    Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
  • Koen Devriendt
    Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
  • Bjorn Cools
    Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
  • Alfredo Brusco
    Department of Neurosciences Rita Levi-Montalcini, University of Turin, Turin, 10126, Italy.
  • Giovanni Battista Ferrero
    Department of Clinical and Biological Sciences, University of Turin, 10049, Orbassano, TO, Italy.
  • Enrico Grosso
  • Pradeep Vasudevan
    University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, LE1 5WW, United Kingdom.
  • Sara Loddo
    Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Antonio Novelli
    Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Maria Cristina Digilio
    Medical Genetics Unit, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Aafke Engwerda
    Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Marrit Hitzert
    Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Alison Male
    North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
  • Lucy Bownass
    St Michael's Hospital, Southwell St, Bristol, BS2 8EG, United Kingdom.
  • Ruth Newbury-Ecob
    St Michael's Hospital, Southwell St, Bristol, BS2 8EG, United Kingdom.
  • Zosia Miedzybrodzka
    School of Medicine, Medical Sciences, Nutrition and Dentistry, University of Aberdeen, Aberdeen, United Kingdom.
  • Ruth Armstrong
    Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, United Kingdom.
  • Sally Ann Lynch
    Children's Health Ireland at Crumlin, Crumlin, Dublin 12, Republic of Ireland.
  • Gunnar Houge
    Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
  • Shiyi Xiong
    Prenatal Diagnosis Center & Fetal Medicine Unit, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai, 200092, China.
  • Seema R Lalani
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Jill A Rosenfeld
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Pamela N Luna
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Chad A Shaw
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Daryl A Scott
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. dscott@bcm.edu.

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