PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis

Meral Gunay-Aygun, Maya Tuchman, Esperanza Font-Montgomery, Linda Lukose, Hailey Edwards, Angelica Garcia, Surasawadee Ausavarat, Shira G. Ziegler, Katie Piwnica-Worms, Joy Bryant, Isa Bernardini, Roxanne Fischer, Marjan Huizing, Lisa Guay-Woodford, William A. Gahl

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/congenital hepatic fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified.

Original languageEnglish (US)
Pages (from-to)160-173
Number of pages14
JournalMolecular genetics and metabolism
Volume99
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

Keywords

  • Autosomal recessive polycystic kidney disease
  • Congenital hepatic fibrosis
  • DNA sequencing
  • Missense variant
  • PKHD1
  • Pathogenicity prediction

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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