Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies
Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies
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DOI：
10.1038/ki.2013.450
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发表时间：
2014-04-01
影响因子：
19.6
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Gee, Heon Yung;Otto, Edgar A.;Hildebrandt, Friedhelm
罕见的单基因疾病导致慢性疾病。然而，6000种隐性单基因疾病中有一半的原因仍然未知。由于隐性疾病基因可以阐明，至少部分地阐明疾病的病理机制，因此它们的鉴定为改善临床管理和潜在治疗提供了直接机会。罕见疾病包括儿童慢性肾脏疾病（CKD）的大部分，但众所周知难以诊断。全外显子组重测序有助于隐性疾病基因的鉴定。然而，其效用受到检测到的大量遗传变异的阻碍。在这里，我们克服了这一限制相结合的纯合性映射与全外显子组重测序在10个同胞对与肾单位结核相关的纤毛病变，这是最常见的遗传原因CKD在前三十年的生活。在10个兄弟姐妹中有7个组织学或超声诊断为肾结石相关的纤毛病变，我们检测到致病基因。在六个兄弟姐妹中，我们发现了已知的肾单位结核相关纤毛病变基因的突变，而在另外两个兄弟姐妹中，我们发现了已知的CKD致病基因SLC4A1和AGXT的突变，作为肾单位结核相关纤毛病变的表型。因此，全外显子组重测序建立了一个有效的，非侵入性的方法，对罕见肾脏疾病的早期检测和病因为基础的诊断。这种方法可以扩展到其他罕见的隐性疾病，从而
Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby