Identification Of Pathogenic Mutations In Candidate Genes In Chinese Han Patients With Unilateral Renal Agenesis

Background:Few genetic studies have focused on unilateral renal agenesis(URA),which is a disorder with insidious clinical manifestations and a tendency to develop hypertension,proteinuria and even end stage renal disease in the long run.Objective:To detect pathogenic mutations in nephrogenesis-related genes that were identified by literature review in a large cohort of Chinese Han patients with URA.Methods:We determined our candidate genes by literature review and referring to gene/protein public databases.We enrolled Chinese Han URA patients dignozed by radiology methods in the nephrology department of Rujin hospital between January 2008 and January 2016.Patients with a solitary kidney due to nephrectomy or renal atrophy due to secondary factors were excluded.1 00 ethnically matched healthy controls were included as well.All coding exons and adj acent intron regions of the candidate genes were analyzed using next-generation sequencing and were validated by subsequent Sanger sequencing and in 100 controls.Results:We selected 25 candidate genes which all played crucial roles in nephrogenesis.Most of the genes interacted in a network.In addition,mutations of these genes could lead to renal agenesis or renal hypodysplasia in humans in accordance with autosomal dominant,autosomal recessive and X-linked inheritance.Eighty-six unrelated URA patients were included and the average age at diagnosis was 32 years.Nine(10.5%)patients had a family history of abnormal nephrogenesis.Fifteen(17.4%)patients had additional malformations of the urogenital system.Ten potential pathogenic mutations(9 missense mutations and 1 deletion mutation)were identified in SALL1,EYA1,RET,HNF1B,DSTYK,WNT4 and SIX5.All mutations were novel or rare(frequency<0.1%)in the public database(The Human Gene Mutation Database,1000 Genomes project,Exome Sequencing project,Exome Aggregation Consortium)and absent from the 100 healthy controls.According to the results of domain and conservation analysis,most of the identified mutant sites in these genes were highly conserved from primates to zebrafish,and some of them were located in functional domains.Moreover,some of the variants identified in our study were close to or in the same domain with those sites reported in previous studies as pathogenic mutations.Nine(10.5%)of the Chinese Han cases with URA could be explained by mutations in our candidate genes.Seven patients carried one single heterozygous mutation and two of them shared the same mutation DSTYK c.1532A>G.One patient carried compound heterozygous mutations in RET and another carried 2 single heterozygous mutations in HNF1B and EYA1 respectivelyConclusion:Ten potential pathogenic muations were identified in our candidate genes and 8 of them were novel mutations.The pathogenesis of 10.5%Chinese Han URA patients could be explained by these mutations.The mutation spectrum had a decentralized distribution without any hotspots mutations.