Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus
Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus
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DOI：
10.1136/jmedgenet-2015-102992
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发表时间：
2015-05-01
影响因子：
4
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
--
作者：
Shaheen, Ranad;Al Hashem, Amal;Alkuraya, Fowzan S.
背景动脉干（TA）的特征是流出道分隔失败，进入主动脉和肺动脉干，并与高发病率和死亡率相关。虽然TA是最不常见的先天性心脏病之一，但它为单个基因在心脏形态发生中的作用提供了一个很好的模型，例如由点突变引起的TBX 1缺陷，或者更常见的是作为22q11.2缺失综合征一部分的半合子。然而，后者的遗传病变，只观察到在一个比例的患者与TA，这表明存在额外的疾病genes. ObjectiveTo确定新的基因，导致孟德尔形式的tag.Methods和结果我们利用发生单基因形式的TA在沙特人口，这是其特点是高血缘，正如我们和其他人所展示的，这一特征有利于复杂表型的孟德尔表型复制的发生。事实上，我们证明，在两个多重的血缘家庭，我们能够映射TA的区域的自合性，其中全外显子组测序显示纯合截断突变PRKD 1（编码激酶解阻遏物的MAF 2）和NRP 1（编码血管内皮生长因子（VEGFA）的辅助受体）。先前的工作已经证明Prkd 1（-/-）是胚胎致死的，并且其组织特异性缺失导致异常心脏重塑，而Nrp 1（-/-）发展TA。令人惊讶的是，在17例单纯性TA病例的复制队列中排除22q11.2缺失综合征的分子核型分析揭示了包括PRDM 1的从头半合子缺失，结论我们的研究结果扩展了与人类先天性心脏病发病机制有关的染色质重塑和转录因子的分子损伤谱，并证明了单基因形式的先天性心脏病的力量作为一种补充方法来剖析这些复杂表型的遗传学。
Background 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.Objective To identify novel genes that cause Mendelian forms of TA.Methods and results 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.Conclusions 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.