title: Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease.
abstract: Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus (PKD1 versus PKD2). Recent studies identified nontruncating PKD1 mutations in approximately 30% of patients who underwent comprehensive mutation screening, but the clinical significance of these mutations is not well defined. We examined the genotype-renal function correlation in a prospective cohort of 220 unrelated ADPKD families ascertained through probands with serum creatinine ≤1.4 mg/dl at recruitment. We screened these families for PKD1 and PKD2 mutations and reviewed the clinical outcomes of the probands and affected family members. Height-adjusted total kidney volume (htTKV) was obtained in 161 affected subjects. Multivariate Cox proportional hazard modeling for renal and patient survival was performed in 707 affected probands and family members. Overall, we identified pathogenic mutations in 84.5% of our families, in which the prevalence of PKD1 truncating, PKD1 in-frame insertion/deletion, PKD1 nontruncating, and PKD2 mutations was 38.3%, 4.3%, 27.1%, and 30.3%, respectively. Compared with patients with PKD1 truncating mutations, patients with PKD1 in-frame insertion/deletion, PKD1 nontruncating, or PKD2 mutations have smaller htTKV and reduced risks (hazard ratio [95% confidence interval]) of ESRD (0.35 [0.14 to 0.91], 0.10 [0.05 to 0.18], and 0.03 [0.01 to 0.05], respectively) and death (0.31 [0.11 to 0.87], 0.20 [0.11 to 0.38], and 0.18 [0.11 to 0.31], respectively). Refined genotype-renal disease correlation coupled with targeted next generation sequencing of PKD1 and PKD2 may provide useful clinical prognostication for ADPKD.
authors.affiliation: Department of Medicine, Eulji General Hospital, Seoul, South Korea; Division of Nephrology and.
authors.forename: Young-Hwan
authors.initials: YH
authors.lastname: Hwang
authors.affiliation: Department of Medical Imaging, University Health Network and University of Toronto, Toronto, Ontario, Canada;
authors.forename: John
authors.initials: J
authors.lastname: Conklin
authors.affiliation: Division of Nephrology and.
authors.forename: Winnie
authors.initials: W
authors.lastname: Chan
authors.affiliation: Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada; and.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Roslin
authors.affiliation: Division of Nephrology and.
authors.forename: Jannel
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Nephrology and.
authors.forename: Ning
authors.initials: N
authors.lastname: He
authors.affiliation: Division of Nephrology and.
authors.forename: Kairong
authors.initials: K
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Sundsbak
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Heyer
authors.affiliation: Department of Medical Imaging, University Health Network and University of Toronto, Toronto, Ontario, Canada;
authors.forename: Masoom
authors.initials: M
authors.lastname: Haider
authors.affiliation: Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada; and.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: Division of Nephrology and york.pei@uhn.ca.
authors.forename: York
authors.initials: Y
authors.lastname: Pei
mesh_terms: D000328:Adult; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000503:physiopathology; D011446:Prospective Studies
keywords: ADPKD; genetic renal disease; genetics and development