Volpi Julia, Zhao Xiaonan, Owen Nichole, Evans Tia, Holder-Espinasse Muriel, Lahiri Nayana, Sherlock Eleanor, Poke Gemma, Breckpot Jeroen, Devriendt Koen, Cools Bjorn, Brusco Alfredo, Ferrero Giovanni Battista, Grosso Enrico, Vasudevan Pradeep, Loddo Sara, Novelli Antonio, Digilio Maria Cristina, Engwerda Aafke, Hitzert Marrit, Male Alison, Bownass Lucy, Newbury-Ecob Ruth, Miedzybrodzka Zosia, Armstrong Ruth, Lynch Sally Ann, Houge Gunnar, Xiong Shiyi, Lalani Seema R, Rosenfeld Jill A, Luna Pamela N, Shaw Chad A, Scott Daryl A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Baylor Genetics Laboratories, Houston, TX, 77030, USA.
Eur J Hum Genet. 2025 Aug 12. doi: 10.1038/s41431-025-01916-8.
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.
法洛四联症（TOF）是最常见的青紫型先天性心脏病（CHD）。TOF可能单独出现，也可能与一种或多种非心脏先天性异常或神经发育障碍同时出现（TOF+）。各种基因检测策略的疗效存在不确定性，且对TOF+的遗传原因了解不全面，可能导致在推荐基因检测时犹豫不决，尤其是临床外显子组测序（cES）。在此，我们分析了131例TOF+个体的cES数据。对31例个体做出了明确或可能的诊断，诊断率为23.6%（31/131）。1例个体获得了三种诊断。市售的CHD检测板仅能检测到cES做出的诊断的27.3%（9/33）至63.6%（21/33）。然后，我们使用机器学习方法确定了四个基因，有充分证据支持其表型扩展包括TOF：DVL3、MED13L、PUF60和MEIS2。由于据报道染色体微阵列分析（CMA）在TOF个体中的诊断效力为10 - 20%，我们得出结论，对于所有未通过CMA建立分子诊断的TOF+个体，应考虑进行cES检测。我们还得出结论，TOF代表一种低外显率表型，与由DVL3、MED13L、PUF60和MEIS2中的致病变异引起的遗传综合征相关。
