Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing

Sandro Rossetti, Katharina Hopp, Robert A. Sikkink, Jamie L. Sundsbak, Yean Kit Lee, Vickie Kubly, Bruce W. Eckloff, Christopher J. Ward, Christopher G. Winearls, Vicente E. Torres, Peter C. Harris

Research output: Contribution to journalArticlepeer-review

107 Scopus citations


Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1-32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing barcoded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from allele dropout, andwe characterized the pattern of deep intronic variation for both genes. In summary, this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations.

Original languageEnglish (US)
Pages (from-to)915-933
Number of pages19
JournalJournal of the American Society of Nephrology
Issue number5
StatePublished - May 2012

ASJC Scopus subject areas

  • General Medicine


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