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<p>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: <i>DVL3, MED13L, PUF60</i>, and <i>MEIS2</i>. 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 <i>DVL3, MED13L, PUF60</i>, and <i>MEIS2</i>.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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

摘要

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.