Identification of two novel CAKUT-causing genes by massively parallel exon resequencing of candidate genes in patients with unilateral renal agenesis.

Congenital abnormalities of the kidney and urinary tract (CAKUT) are the most frequent cause of chronic kidney disease in children, accounting for about half of all cases. Although many forms of CAKUT are likely caused by single-gene defects, mutations in only a few genes have been identified. In order to detect new contributing genes we pooled DNA from 20 individuals to amplify all 313 exons of 30 CAKUT candidate genes by PCR analysis and massively parallel exon resequencing. Mutation carriers were identified by Sanger sequencing. We repeated the analysis with 20 new patients to give a total of 29 with unilateral renal agenesis and 11 with other CAKUT phenotypes. Five heterozygous missense mutations were detected in 2 candidate genes (4 mutations in FRAS1 and 1 in FREM2) not previously implicated in non-syndromic CAKUT in humans. All of these mutations were absent from 96 healthy control individuals and had a PolyPhen score over 1.4, predicting possible damaging effects of the mutation on protein function. Recessive truncating mutations in FRAS1 and FREM2 were known to cause Fraser syndrome in humans and mice; however, a phenotype in heterozygous carriers has not been described. Thus, heterozygous missense mutations in FRAS1 and FREM2 cause non-syndromic CAKUT in humans.