Related Experiment Video
Updated: Sep 11, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Non-isolated tetralogy of fallot (TOF+): exome sequencing efficacy and phenotypic expansions
Julia Volpi1, Xiaonan Zhao1,2, Nichole Owen1,2
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Insights
Clinical exome sequencing (cES) is effective for diagnosing Tetralogy of Fallot plus (TOF+) conditions, identifying more genetic causes than standard panels. This study highlights cES as a valuable tool for TOF+ genetic diagnosis.
Area of Science:
- Genetics
- Cardiology
- Developmental Biology
Background:
- Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD).
- TOF can occur with other congenital anomalies or neurodevelopmental disorders (TOF+).
- Genetic testing for TOF+ has uncertainties, potentially limiting the use of clinical exome sequencing (cES).
Purpose of the Study:
- To evaluate the diagnostic yield of cES in individuals with TOF+.
- To compare cES with CHD panels and chromosomal microarray analysis (CMA).
- To identify novel genes associated with TOF phenotypes.
Main Methods:
- Analysis of cES data from 131 individuals with TOF+.
- Comparison of diagnoses from cES with those from CHD gene panels.
- Machine learning approach to identify candidate genes for TOF.
- Review of CMA diagnostic efficacy in TOF.
Main Results:
- cES achieved a 23.6% diagnostic rate (31/131) in individuals with TOF+.
- cES identified significantly more diagnoses than CHD panels (27.3%-63.6% detection rate).
- Four genes (DVL3, MED13L, PUF60, MEIS2) were identified with phenotypic expansion including TOF.
Conclusions:
- cES should be considered for TOF+ when CMA is non-diagnostic.
- TOF can be a low penetrance phenotype of genetic syndromes involving DVL3, MED13L, PUF60, and MEIS2.
- cES offers a higher diagnostic yield for complex TOF cases.
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.
