Genomic profiling in bilateral renal agenesis, the most severe end of the CAKUT spectrum

术语CAKUT（先天性肾脏和泌尿道异常）通常用于总结一组临床和遗传异质性疾病，这些疾病构成儿童和年轻成人慢性肾脏疾病（CKD）和终末期肾脏疾病（ESRD）的最常见原因，约占所有病例的40- 50%。CAKUT包括广泛的肾脏和泌尿/泌尿生殖道畸形，范围从潜在的轻度疾病（如膀胱输尿管反流）到严重的肾脏发育不全或肾脏发育不全/发育不全。到目前为止，已知有50多个单基因CAKUT相关基因，大多数以常染色体显性遗传，但也有常染色体隐性遗传。到目前为止，只有不到20%的CAKUT病例可以用这些基因的致病性变异来解释。从基因敲除小鼠模型和CAKUT的家族聚集性判断，有强有力的证据表明CAKUT存在进一步的单基因形式。通过全面测序，未来将发现更多的致病基因，进一步揭示肾脏发育的复杂过程。肾发育不良和肾发育不全是CAKUT谱中最严重的一类，属于围产期致死性肾脏疾病，包括双侧肾发育不全、单侧肾发育不全伴对侧发育不良和严重梗阻性尿路病。通常，具有这些表型的患者在子宫内或围产期死亡。有文献记载，一些受影响的个体表现为双侧肾发育不全，而另一些表现为单侧肾发育不全、肾发育不全或单侧肾发育不全伴单侧肾发育不全，这表明这些疾病可能属于致病连续体或表型谱。如上所述，对于绝大多数患者，潜在的肾发育缺陷尚不清楚，特别是对于预后极差的最严重的CAKUT型双侧肾发育不全。确定与双侧肾发育不全相关的遗传原因将为双侧肾发育不全的胚胎肾发育机制提供宝贵的见解。因此，计划研究的目的是在30例散发性和家族性双侧肾发育不全索引患者的联合队列中进行全基因组测序（在所有索引病例中，核型分析、染色体微阵列和基因组诊断不明显）。在10名没有致病变异的患者中，应进行新的Tell-SeqTM测序技术以识别结构变化。本研究将进一步阐明双侧肾发育不全及其相关症状（CAKUT）的病理机制。

The term CAKUT (congenital anomalies of the kidney and urinary tract) is commonly used to summarize a clinically and genetically heterogenous group of disorders that constitute the most frequent cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in children and young adults, accounting for approximately 40-50 % of all cases. CAKUT comprises a broad spectrum of malformations of the kidney and urinary/urogenital tract ranging from potentially mild conditions like vesicoureteral reflux to the severe end of the spectrum with renal hypodysplasia or renal agenesis/aplasia. So far, more than 50 monogenic CAKUT-associated genes are known, mostly inherited in an autosomal dominant but also autosomal recessive fashion. Less than 20 % of CAKUT cases can be explained by pathogenic variants in these genes so far. Judging from knockout mouse models and familial clustering of CAKUT, there is strong evidence for further monogenic forms of CAKUT. By means of comprehensive sequencing more disease-causing genes will be described in the future, further unraveling the complex process of kidney development.Renal hypodysplasia and renal aplasia fall at the most severe end of the CAKUT spectrum and belong to a group of perinatally lethal renal diseases, including bilateral renal aplasia, unilateral renal agenesis with contralateral dysplasia, and severe obstructive uropathy. Usually, patients with these phenotypes suffer from death in utero or in the perinatal period. Families have been documented in which some affected individuals presented with bilateral renal aplasia whereas others showed unilateral renal aplasia, renal dysplasia, or unilateral renal aplasia with unilateral renal dysplasia, suggesting that these conditions may belong to a pathogenic continuum or phenotypic spectrum.As mentioned above, for the vast majority of patients the underlying renal developmental defects remain unclear, especially for the most severe CAKUT type of bilateral renal aplasia which has a very poor prognosis. The identification of genetic causes associated with bilateral renal agenesis will provide invaluable insight into mechanisms of embryonic kidney development in bilateral renal agenesis. Therefore, the aim of the planned study is to perform whole genome sequencing in a joint cohort of 30 index patients with sporadic and familial form of bilateral renal aplasia (in all index cases karyotyping, chromosomal microarray and gene panel diagnostics were inconspicuous). In 10 patients without disease-causing variants the new Tell-SeqTM sequencing technique should be performed to identify structural changes. This study will give further insight into the pathomechanism of bilateral renal aplasia and its related symptoms (CAKUT).