TY - JOUR
T1 - Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease
AU - Hwang, Young Hwan
AU - Conklin, John
AU - Chan, Winnie
AU - Roslin, Nicole M.
AU - Liu, Jannel
AU - He, Ning
AU - Wang, Kairong
AU - Sundsbak, Jamie L.
AU - Heyer, Christina M.
AU - Haider, Masoom
AU - Paterson, Andrew D.
AU - Harris, Peter C.
AU - Pei, York
N1 - Publisher Copyright:
Copyright © 2016 by the American Society of Nephrology .
PY - 2016/6
Y1 - 2016/6
N2 - Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus (PKD1versusPKD2). Recent studies identified nontruncatingPKD1 mutations in approximately 30% of patients who underwent comprehensivemutation screening, but the clinical significance of thesemutations 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.
AB - Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus (PKD1versusPKD2). Recent studies identified nontruncatingPKD1 mutations in approximately 30% of patients who underwent comprehensivemutation screening, but the clinical significance of thesemutations 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.
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U2 - 10.1681/ASN.2015060648
DO - 10.1681/ASN.2015060648
M3 - Article
C2 - 26453610
AN - SCOPUS:84992461943
SN - 1046-6673
VL - 27
SP - 1861
EP - 1868
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 6
ER -