Grunert Marcel, Dorn Cornelia, Schueler Markus, Dunkel Ilona, Schlesinger Jenny, Mebus Siegrun, Alexi-Meskishvili Vladimir, Perrot Andreas, Wassilew Katharina, Timmermann Bernd, Hetzer Roland, Berger Felix, Sperling Silke R
Group of Cardiovascular Genetics, Department of Vertebrate Genomics and Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrück Center (MDC) for Molecular Medicine, Berlin 13125, Germany.
Group of Cardiovascular Genetics, Department of Vertebrate Genomics and Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrück Center (MDC) for Molecular Medicine, Berlin 13125, Germany Department of Biology, Chemistry and Pharmacy, Free University of Berlin, Berlin 14195, Germany.
Hum Mol Genet. 2014 Jun 15;23(12):3115-28. doi: 10.1093/hmg/ddu021. Epub 2014 Jan 23.
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Its genetic basis is demonstrated by an increased recurrence risk in siblings and familial cases. However, the majority of TOF are sporadic, isolated cases of undefined origin and it had been postulated that rare and private autosomal variations in concert define its genetic basis. To elucidate this hypothesis, we performed a multilevel study using targeted re-sequencing and whole-transcriptome profiling. We developed a novel concept based on a gene's mutation frequency to unravel the polygenic origin of TOF. We show that isolated TOF is caused by a combination of deleterious private and rare mutations in genes essential for apoptosis and cell growth, the assembly of the sarcomere as well as for the neural crest and secondary heart field, the cellular basis of the right ventricle and its outflow tract. Affected genes coincide in an interaction network with significant disturbances in expression shared by cases with a mutually affected TOF gene. The majority of genes show continuous expression during adulthood, which opens a new route to understand the diversity in the long-term clinical outcome of TOF cases. Our findings demonstrate that TOF has a polygenic origin and that understanding the genetic basis can lead to novel diagnostic and therapeutic routes. Moreover, the novel concept of the gene mutation frequency is a versatile measure and can be applied to other open genetic disorders.
法洛四联症（TOF）是最常见的青紫型先天性心脏病。其遗传基础表现为兄弟姐妹及家族性病例的复发风险增加。然而，大多数TOF是散发性的、病因不明的孤立病例，据推测，罕见的个体常染色体变异共同决定了其遗传基础。为了阐明这一假设，我们采用靶向重测序和全转录组分析进行了多层次研究。我们基于基因的突变频率提出了一个新的概念，以揭示TOF的多基因起源。我们发现，孤立性TOF是由凋亡和细胞生长、肌节组装以及神经嵴和第二心脏场（右心室及其流出道的细胞基础）所必需的基因中的有害个体和罕见突变共同导致的。受影响的基因在一个相互作用网络中重合，该网络在具有相互影响的TOF基因的病例中存在显著的表达紊乱。大多数基因在成年期持续表达，这为理解TOF病例长期临床结果的多样性开辟了一条新途径。我们的研究结果表明，TOF具有多基因起源，了解其遗传基础可带来新的诊断和治疗途径。此外，基因突变频率的新概念是一种通用的测量方法，可应用于其他开放性遗传疾病。
