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

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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).