Shaheen Ranad, Al Hashem Amal, Alghamdi Mohammed H, Seidahmad Mohammed Zain, Wakil Salma M, Dagriri Khalid, Keavney Bernard, Goodship Judith, Alyousif Saad, Al-Habshan Fahad M, Alhussein Khalid, Almoisheer Agaadir, Ibrahim Niema, Alkuraya Fowzan S
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
J Med Genet. 2015 May;52(5):322-9. doi: 10.1136/jmedgenet-2015-102992. Epub 2015 Feb 23.
Truncus arteriosus (TA) is characterised by failure of septation of the outflow tract into aortic and pulmonary trunks and is associated with high morbidity and mortality. Although ranked among the least common congenital heart defects, TA provides an excellent model for the role of individual genes in cardiac morphogenesis as exemplified by TBX1 deficiency caused by point mutations or, more commonly, hemizygosity as part of the 22q11.2 deletion syndrome. The latter genetic lesion, however, is only observed in a proportion of patients with TA, which suggests the presence of additional disease genes.
To identify novel genes that cause Mendelian forms of TA.
We exploited the occurrence of monogenic forms of TA in the Saudi population, which is characterised by high consanguinity, a feature conducive to the occurrence of Mendelian phenocopies of complex phenotypes as we and others have shown. Indeed, we demonstrate in two multiplex consanguineous families that we are able to map TA to regions of autozygosity in which whole-exome sequencing revealed homozygous truncating mutations in PRKD1 (encoding a kinase derepressor of MAF2) and NRP1 (encoding a coreceptor of vascular endothelial growth factor (VEGFA)). Previous work has demonstrated that Prkd1(-/-) is embryonic lethal and that its tissue-specific deletion results in abnormal heart remodelling, whereas Nrp1(-/-) develops TA. Surprisingly, molecular karyotyping to exclude 22q11.2 deletion syndrome in the replication cohort of 17 simplex TA cases revealed a de novo hemizygous deletion that encompasses PRDM1, deficiency of which also results in TA phenotype in mouse.
Our results expand the repertoire of molecular lesions in chromatin remodelling and transcription factors that are implicated in the pathogenesis of congenital heart disease in humans and attest to the power of monogenic forms of congenital heart diseases as a complementary approach to dissect the genetics of these complex phenotypes.
共同动脉干（TA）的特征是流出道未能分隔成主动脉和肺动脉干，且与高发病率和死亡率相关。尽管TA位列最不常见的先天性心脏缺陷之一，但它为单个基因在心脏形态发生中的作用提供了一个极佳模型，例如由点突变导致的TBX1缺陷，或更常见的作为22q11.2缺失综合征一部分的半合子状态。然而，后一种基因病变仅在一部分TA患者中观察到，这表明存在其他致病基因。
鉴定导致孟德尔式TA的新基因。
我们利用沙特人群中TA单基因形式的出现情况，该人群以高度近亲结婚为特征，正如我们和其他人所表明的，这一特征有利于复杂表型的孟德尔拟表型的出现。事实上，我们在两个多重近亲家庭中证明，我们能够将TA定位到纯合子区域，全外显子测序在这些区域揭示了PRKD1（编码MAF2的激酶去阻遏物）和NRP1（编码血管内皮生长因子（VEGFA）的共受体）中的纯合截短突变。先前的研究表明，Prkd1基因敲除小鼠胚胎致死，其组织特异性缺失会导致心脏重塑异常，而Nrp1基因敲除小鼠会发生TA。令人惊讶的是，在17例散发性TA病例的复制队列中，用于排除22q11.2缺失综合征的分子核型分析发现了一个新生的半合子缺失，该缺失包含PRDM1，其缺陷在小鼠中也会导致TA表型。
我们的结果扩展了与人类先天性心脏病发病机制相关的染色质重塑和转录因子中的分子病变谱，并证明先天性心脏病的单基因形式作为剖析这些复杂表型遗传学的一种补充方法的作用。
