Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease

Young Hwan Hwang, John Conklin, Winnie Chan, Nicole M. Roslin, Jannel Liu, Ning He, Kairong Wang, Jamie L. Sundsbak, Christina M. Heyer, Masoom Haider, Andrew D. Paterson, Peter C Harris, York Pei

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1861-1868
Number of pages8
JournalJournal of the American Society of Nephrology
Volume27
Issue number6
DOIs
StatePublished - Jun 1 2016

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Autosomal Dominant Polycystic Kidney
Genetic Association Studies
Kidney
Mutation
Genotype
Chronic Kidney Failure
Creatinine
Odds Ratio
Confidence Intervals
Survival
Serum
Genes

ASJC Scopus subject areas

  • Nephrology

Cite this

Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease. / Hwang, Young Hwan; Conklin, John; Chan, Winnie; Roslin, Nicole M.; Liu, Jannel; He, Ning; Wang, Kairong; Sundsbak, Jamie L.; Heyer, Christina M.; Haider, Masoom; Paterson, Andrew D.; Harris, Peter C; Pei, York.

In: Journal of the American Society of Nephrology, Vol. 27, No. 6, 01.06.2016, p. 1861-1868.

Research output: Contribution to journalArticle

Hwang, YH, Conklin, J, Chan, W, Roslin, NM, Liu, J, He, N, Wang, K, Sundsbak, JL, Heyer, CM, Haider, M, Paterson, AD, Harris, PC & Pei, Y 2016, 'Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease', Journal of the American Society of Nephrology, vol. 27, no. 6, pp. 1861-1868. https://doi.org/10.1681/ASN.2015060648
Hwang, Young Hwan ; Conklin, John ; Chan, Winnie ; Roslin, Nicole M. ; Liu, Jannel ; He, Ning ; Wang, Kairong ; Sundsbak, Jamie L. ; Heyer, Christina M. ; Haider, Masoom ; Paterson, Andrew D. ; Harris, Peter C ; Pei, York. / Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 6. pp. 1861-1868.
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abstract = "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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AU - He, Ning

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AU - Sundsbak, Jamie L.

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