Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract

Abstract

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito‐urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%–20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.

Implication ofFOXD2dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT)

“…Interestingly, amongst upregulated genes in Foxd2 mutant versus control cells, top GO term hits were related to leucocyte migration, antigen presentation and chemotaxis followed by regulation of MAPK activity (GO:0043405, p = 2.96=10 -10 ; Table 3, Supplementary Figure 8A-B). Transcriptome analysis of Foxd2 mutant clone F7 compared to unedited control cells further suggested a significant upregulation of Nfia (log2Fc 7,27, adj p = 3.358=10 -7 ; Figure 6A and Supplementary Figure 9A).…”

“…Over 45 genes associated with isolated monogenic CAKUT and over 135 genes associate with syndromic CAKUT are known. 6, 7 Furthermore, copy number variants (CNV) play an important role in CAKUT. 4 Nevertheless, only about 10 % of CAKUT cases can be genetically solved and incomplete penetrance and variable expressivity are often observed.…”

Hedgehog-GLI mediated control of renal formation and malformation

“…To date, most investigations have focused on monogenic causes of CAKUT, with causative genes identified in both isolated and syndromic forms. However, monogenic CAKUT only accounts for 15-20% of all CAKUT cases, and poses a diagnostic challenge owing to incomplete penetrance and variable phenotypic expression (8)(9)(10)(11). Other genetic causes of CAKUT include copy number variations (CNVs), chromosomal abnormalities, and, less commonly, oligogenic or polygenic CAKUT (7,(12)(13)(14)(15)(16).…”

A novel homozygous missense variant in TBC1D31 in a consanguineous family with congenital anomalies of the kidney and urinary tract (CAKUT)

“…1,2 More than 180 genes have been identified to cause CAKUT when mutated. 3,4 Copy number variations (CNVs) have also been implicated in genetic mechanism of the condition. 5 Nevertheless, altogether these can explain only about 10% of CAKUT cases.…”

“…Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of chronic kidney disease (CKD) in the first three decades of life and comprises a broad spectrum of malformations of the kidney and urinary tract ranging from vesicoureteral reflux to renal agenesis 1,2 . More than 180 genes have been identified to cause CAKUT when mutated 3,4 . Copy number variations (CNVs) have also been implicated in genetic mechanism of the condition 5 .…”