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Background: Congenital Anomalies of Kidney and Urinary Tract (CAKUT) are the most common cause of pediatric end stage renal disease (ESRD). The discovery of underlying genetic etiologies would not only improve diagnostic precision for non-syndromic forms, optimize management of affected patients, prevent disease recurrence by PGD (preimplantation genetic diagnosis), but also aid prenatal diagnosis in forms that result in early-onset ESRD. In this report, we show the utility of whole exome sequencing (WES) in a clinical diagnostic setting and in the genomic research of CAKUT.
Methods: We completed research WES in 65 families with CAKUT. Approximately 25% of the cases were familial and 10% were syndromic. Phenotypes of the patients were collected as part of the patient intake. We used the ACMG (American College of Medical Genetics and Genomics) standards to classify genetic variants. We focused on analysis of the cases with mutations in 20 genes that have been associated with or known to cause CAKUT and are central to development of the kidney and urinary tract.
Results: Mutational analysis was performed and the following deleterious or possibly deleterious mutations were identified: PAX2 (G24fs, S171P), HNF1B (Q378fs), RET (S401C), EYA1 (c.867+5G>A), SIX2 (P241L), and DSTYK (R592Q, D120N). No mutation was identified in GDNF, SIX1, SOX17, or GATA3. Benign variants or variants of unknown significance were identified in BMP7, CDC5L, CHD1L, SALL1, SIX5, ROBO2, UPK3A, BMP4, KAL1, and TNXB. The G24fs mutation occurs in a family with multiplex renal dysplasia and membranous nephropathy that has not been reported previously with PAX2 mutations. Q378fs is a novel mutation in HNF1B. Phenotypes of some of these families expand our current knowledge about the corresponding genes.
Conclusion: This is the first report utilizing WES for diagnosis in patients with CAKUT. At least 12% of individuals with CAKUT in this cohort have deleterious mutations in known genes that can be identified by WES. Therefore, WES should be considered as a diagnostic tool in such patients, especially in the families with complex medical histories. Identification of novel mutations and expansion of the phenotypes are additional important benefits of WES as a diagnostic tool.
 
Acknowledgement: Supported by: a-K12 DK0083014, the Multidisciplinary K12 Urologic Research (KURe) Career Development Program to DJL (MRB is a KURe Scholar). b- NHGRI Mendelian grant to JRL c- RAL is a Senior Scientific Investigator of Research to Prevent Blindness, New York, whose unrestricted funds supported part of these investigations.