Institute of Medical Genetics, Schorenstrasse 16, CH-8603 Zurich-Schwerzenbach, Switzerland.
J Med Genet. 2010 May;47(5):321-31. doi: 10.1136/jmg.2009.070391. Epub 2009 Nov 30.
Tetralogy of Fallot (ToF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra- and extracardiac phenotypes. In order to get further insight into genotype-phenotype correlation, a large cohort of 230 unselected patients with ToF was comprehensively investigated.
230 patients with ToF were studied by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. Pathogenic genetic aberrations were found in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic ToF (0.9%). One patient showed a recurrent polyalanine stretch elongation within TBX1 which represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation.
This study shows that 22q11.2 deletion represents the most common known cause of ToF, and that the associated cardiac phenotype is distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with ToF is very suggestive of trisomy 21 and almost excludes 22q11.2 deletion. We report a further patient with a recurrent polyalanine stretch elongation within TBX1 and for the first time link TBX1 cytoplasmatic protein aggregation to congenital heart defects.
法洛四联症（ToF）是最常见的发绀型先天性心脏病，与广泛的心脏内外表型相关。为了深入了解基因型-表型相关性，对 230 例未经选择的 ToF 患者进行了大型队列研究。
对 230 例 ToF 患者进行了核型分析、全面的 22q11.2 缺失检测和 TBX1、NKX2.5 和 JAG1 的测序，以及在选定患者中进行分子核型分析。在 42 例患者（18%）中发现了致病性遗传异常，最常见的诊断是 22q11.2 缺失（7.4%），其次是 21 三体（5.2%）和其他染色体异常或亚微拷贝数变化（3%）。3 例 Alagille 综合征患者检测到 JAG1 突变，2 例非综合征型 ToF 患者检测到 NKX2.5 突变（0.9%）。1 例患者在 TBX1 内发现了一个重复的多丙氨酸延伸，这是一个真正的突变，由于细胞质蛋白聚集导致转录活性丧失。
本研究表明，22q11.2 缺失是 ToF 最常见的已知原因，相关的心脏表型特征是近端肺动脉阻塞、中央肺动脉发育不良和锁骨下动脉异常。与 ToF 相关的房室间隔缺损非常提示 21 三体，几乎排除 22q11.2 缺失。我们报告了另一名 TBX1 内重复多丙氨酸延伸的患者，并首次将 TBX1 细胞质蛋白聚集与先天性心脏病联系起来。
