Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract
Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract
复制标题
DOI：
10.1681/asn.2015080962
复制
发表时间：
2017-01-01
影响因子：
13.6
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Vivante, Asaf;Hwang, Daw-Yang;Hildebrandt, Friedhelm
先天性肾脏和泌尿道异常（CAKUT）是儿童CKD的主要原因，具有各种各样的畸形。在大约12%的患者中可以检测到单基因原因。然而，CAKUT的形态学临床表型常常不能指示要检查的特定基因。为了确定通过全外显子组测序（WES）检测致病性隐性突变的可能性，我们分析了来自33个不同血缘家庭的CAKUT个体。使用纯合性定位和WES，我们确定了致病突变的33个家庭中的9个（27%）。我们在9个已知的致病基因中检测到隐性突变：ZBTB24、WFS1、HPSE2、ATRX、ASPH、AGXT、AQP2、CTNS和PKHD1。值得注意的是，当突变时，这些基因引起多器官综合征，其可能包括CAKUT作为特征（综合征性CAKUT）或引起可能表现为CAKUT表型的肾脏疾病。在本研究之前，临床上没有怀疑上述单基因致病基因。这些患者的随访临床特征使我们能够在更合适的发病背景下修改和检测相关的新临床特征。因此，将WES应用于CAKUT的诊断方法为准确和早期基于病因学的诊断和改善临床管理提供了机会。
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the leading cause of CKD in children, featuring a broad variety of malformations. A monogenic cause can be detected in around 12% of patients. However, the morphologic clinical phenotype of CAKUT frequently does not indicate specific genes to be examined. To determine the likelihood of detecting causative recessive mutations by whole-exome sequencing (WES), we analyzed individuals with CAKUT from 33 different consanguineous families. Using homozygosity mapping and WES, we identified the causative mutations in nine of the 33 families studied (27%). We detected recessive mutations in nine known disease-causing genes: ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, and PKHD1. Notably, when mutated, these genes cause multiorgan syndromes that may include CAKUT as a feature (syndromic CAKUT) or cause renal diseases that may manifest as phenocopies of CAKUT. None of the above monogenic disease-causing genes were suspected on clinical grounds before this study. Follow-up clinical characterization of those patients allowed us to revise and detect relevant new clinical features in a more appropriate pathogenetic context. Thus, applying WES to the diagnostic approach in CAKUT provides opportunities for an accurate and early etiology-based diagnosis and improved clinical management.