Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot
Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot
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DOI：
10.1136/jmg.2009.070391
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发表时间：
2010-05-01
影响因子：
4
通讯作者：
Rauch, Anita
中科院分区：
文献类型：
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作者：
Rauch, Ralf;Hofbeck, Michael;Rauch, Anita
法洛四联症（Tetralogy of Fallot，ToF）是最常见的紫绀型先天性心脏病，与心内和心外表型有关。为了进一步了解基因型与表型的相关性，对230例ToF患者进行了全面的研究，方法和结果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测序，以及在选定的患者中进行分子核型分析。在42例患者（18%）中发现致病性遗传畸变，其中22q11.2缺失是最常见的诊断（7.4%），其次是21三体（5.2%）和其他染色体畸变或亚显微拷贝数变化（3%）。在3名Alagille综合征患者中检测到JAG1突变（1.3%），而在2名非综合征ToF患者中观察到NKX2.5突变（0.9%）。1例患者表现出TBX1内的反复多聚丙氨酸拉伸延伸，这代表了一个真正的突变，导致转录活性的丧失，由于胞质蛋白aggregation.Conclusion这项研究表明，22q11.2缺失是ToF最常见的已知原因，相关的心脏表型是不同的阻塞近端肺动脉，中央肺动脉发育不全和锁骨下动脉异常。合并ToF的房室间隔缺损非常提示21三体综合征，几乎排除22q11.2缺失。我们报告了另一个TBX1内反复出现多聚丙氨酸拉伸延伸的患者，并首次将TBX1细胞质蛋白聚集与先天性心脏病联系起来。
Background 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.Methods and results 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.Conclusion 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.