The copy number variation landscape of congenital anomalies of the kidney and urinary tract
The copy number variation landscape of congenital anomalies of the kidney and urinary tract
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DOI：
10.1038/s41588-018-0281-y
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发表时间：
2019-01-01
期刊：
影响因子：
30.8
通讯作者：
Sanna-Cherchi, Simone
中科院分区：
文献类型：
--
作者：
Verbitsky, Miguel;Westland, Rik;Sanna-Cherchi, Simone
先天性肾脏和泌尿道异常（CAKUT）是小儿肾衰竭的主要原因。我们对2,824例病例和21,498例对照进行了全基因组拷贝数变异（CNV）分析。受影响的个体携带了显著的罕见外显子（即影响编码区）CNV负担，并富集了已知的基因组疾病（GD）。肾脏异常（KA）病例中外显子CNV最丰富，包括GD-CNV和新的缺失;梗阻性尿路病（BPH）的CNV负担较低，GD-CNV的患病率居中;膀胱输尿管反流（VUR）的GD-CNV最少，但富含新的外显子CNV，特别是重复。6个基因座（1 q21、4p16.1-p16.3、16p11.2、16p13.11、17 q12和22q11.2）占GD-CNVs的65%。17 q12、4p16.1-p16.3和22q11.2位点的缺失是KA的特异性缺失; 16p11.2位点表现出广泛的多效性。使用多学科的方法，我们确定TBX 6作为驱动器的CAKUT亚表型在16p11.2微缺失综合征。
Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.