Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract

Abstract

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the leading cause of CKD in children, featuring a broad variety of malformations. A monogenic cause can be detected in around 12% of patients. However, the morphologic clinical phenotype of CAKUT frequently does not indicate specific genes to be examined. To determine the likelihood of detecting causative recessive mutations by whole-exome sequencing (WES), we analyzed individuals with CAKUT from 33 different consanguineous families. Using homozygosity mapping and WES, we identified the causative mutations in nine of the 33 families studied (27%). We detected recessive mutations in nine known disease-causing genes: ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, and PKHD1 Notably, when mutated, these genes cause multiorgan syndromes that may include CAKUT as a feature (syndromic CAKUT) or cause renal diseases that may manifest as phenocopies of CAKUT. None of the above monogenic disease-causing genes were suspected on clinical grounds before this study. Follow-up clinical characterization of those patients allowed us to revise and detect relevant new clinical features in a more appropriate pathogenetic context. Thus, applying WES to the diagnostic approach in CAKUT provides opportunities for an accurate and early etiology-based diagnosis and improved clinical management.

Keywords: CAKUT; WES; monogenic disease.

Figure 1.

Renal imaging and clinical findings in selected patients with disease-causing mutations. (A and B) Photographs of an affected girl (B268) with the HPSE2 mutation show characteristic grimace on smiling. (C) Dimercaptosuccinic acid scan at different views of the patient (B268) with the HPSE2 mutation shows differential renal function. Left kidney, 30%; right kidney, 70%. (D) Voiding cystourethrogram imaging of patient B407 with the ATRX mutation shows bilateral grade 3 VUR (black asterisks). (E and F) Abdominal computed tomography scans of patient A3772 with the PKHD1 mutation show gallbladder stones (white arrow) and dilated segmental intrahepatic biliary radicles (white arrowheads).