Analysis Of Mutations In Six Chinese Families With Autosomal Dominant Polycystic Kidney Disease

Background:Autosomal dominant polycystic kidney disease（ADPKD）is the most common hereditary kidney disease with a prevalence of 1/400-1/1000.As the 4^thetiology for end-stage renal disease,ADPKD can cause irreversible damage to renal structure and function and eventually lead to end-stage renal failure.It is established that ADPKD is mainly triggered by mutations in genes PKD1 and PKD2.Methods:The clinical data and genetic features of 6 Chinese families with ADPKD patients were analyzed.Next generation sequencing（NGS）and multiplex ligation-dependent probe amplification（MLPA）were used for DNA analysis.Bioinformatics analysis was performed to analyze the target genes PKD1 and PKD2 of the probands of the families with ADPKD.Thereafter,the suspicious responsible mutation sites of family members were subjected to Sanger sequencing and genetic linkage analysis,and protein function of the mutations were predicted using SIFT and Polyphe software.Results:For the proband（II5）with polycystic kidney,hypertension,left ventricular hypertrophy and valvular heart disease in family A,a heterozygous nonsense mutation c.5086C>T（p.Gln1696Ter）was found in the coding region of the PKD1 gene（NM＿001009944）,which terminated the protein-coding sequence in advance,induced production of truncated proteins or gene degradation.For the proband（II3）with polycystic kidney,polycystic liver,hypertension,hypertrophy of left ventricle and septum,valvular heart disease,stage 5 chronic kidney disease（CKD）,bilateral renal calculi and right inguinal hernia in family B,a heterozygous missense mutation c.6695T>C（p.Phe2232Ser）was seen in the coding region of the PKD1 gene.For the proband（III1）with polycystic kidney,polycystic liver,seminal vesicle cyst,hypertension,stage 3 CKD,hypertrophy of left ventricle and septum and valvular heart disease in family C,a heterozygous nonsense mutation c.662T>G（p.Leu221Ter）was detected in the coding region of the PKD2 gene（NM＿000297）,which terminated the protein-coding amino acid in advance and induced production of truncated proteins.For the proband（III3）with polycystic kidney,hypertension and stage 5 CKD in family D,a heterozygous missense mutation c.8311G>A（p.Glu2771Lys）was detected in the coding region of the PKD1 gene.For the proband（II1）with polycystic kidney,polycystic liver,hypertension and stage 5 CKD in family E,a heterozygous deletion mutation exon15-22 was found in the PKD1 gene coding region.For the proband（II2）with polycystic kidney,polycystic liver,stage 3 CKD,hypertension,thickened interventricular septum and valvular heart disease in family F,a heterozygous missense mutation c.1649A>G（p.His550Arg）was found in the coding region of the PKD2 gene.The above mutations were all considered responsible mutation sites through Sanger sequencing and family phenotype-genetic cross-linkage analysis.Conclusion:There are various mutations in the ADPKD families with no mutational hotspots and the clinical phenotypes are different.The two genes PKD1 and PKD2 are not markedly correlated.Four novel responsible mutation sites are discovered in this study.