Genetics of Congenital Anomalies of the Kidneys and Urinary Tract

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

“…1,2 CAKUT can present as an isolated renal condition or as part of a clinical syndrome. [3][4][5][6][7] Despite large differences in clinical manifestation, these conditions likely share a pathogenic origin in dysregulation of renal morphogenesis. 8,9 We hypothesized that human CAKUT may be caused by mutations in distinct single monogenic genes.…”

Novel Insights into the Pathogenesis of Monogenic Congenital Anomalies of the Kidney and Urinary Tract

“…4,8,9 CAKUT may occur either as an isolated condition or along with extrarenal manifestations as part of a syndromic disorder. [10][11][12][13] To date, .200 clinical syndromes have been described that comprise features of CAKUT as part of their distinct phenotype. 14 The term CAKUT summarizes a large variety of diverse congenital malformations that range from conditions of the upper urinary tract (e.g., renal agenesis and renal hypodysplasia) to phenotypes primarily affecting the lower urinary tract, such as vesicoureteral reflux (VUR), ureterovesical junction obstruction (UVJO), and posterior urethral valves (PUVs).…”

“…It is important to note that, although different manifestations from within the CAKUT spectrum may coexist in the same individual, 3,15 unilateral CAKUT (e.g., renal agenesis) can also exist in the presence of an entirely unblemished contralateral urinary system. 10 The diverse manifestations of CAKUT phenotypes are thought to result from disturbances at any point in renal morphogenesis ( Figure 1). 15,16 Most importantly, imbalances in the communication between the metanephric mesenchyme (MM) and the ureteric bud (UB) are believed to be central to the pathogenesis of CAKUT phenotypes (Figure 1, C-E).…”

“…10 Supporting evidence for a monogenic etiology in the case of CAKUT comes from (1) the familial occurrence of CAKUT phenotypes (approximately 10%-15% of patients with CAKUT cases are familial), (2) the existence of monogenic syndromes with a distinct syndromic phenotype that includes manifestations from within the CAKUT spectrum (.200 to date), (3) the existence of monogenic mouse models that exhibit CAKUT (.180 to date), and (4) the fact that the development of the kidney and urinary tract is governed by distinct developmental genes. 10,11,19,20 Approximately 40 different monogenic causes for human CAKUT (25 dominant and 15 recessive) have so far been identified (Table 1). 12,13, Many established CAKUT genes encode transcription factors and follow a dominant pattern of inheritance.…”

“…12,13, Many established CAKUT genes encode transcription factors and follow a dominant pattern of inheritance. 3,10 Some of the genes listed in Table 1, however, remain questionable in regard to their pathogenic effect and will require more support through functional studies in the future. 52,53 Currently, at most, up to 18% of CAKUT cases can be explained by these established monogenic causes (Table 1).…”