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

Gunay-Aygun, Meral; Tuchman, Maya; Font-Montgomery, Esperanza; Lukose, Linda; Edwards, Hailey; Garcia, Angelica; Ausavarat, Surasawadee; Ziegler, Shira G; Piwnica-Worms, Katie; Bryant, Joy; Bernardini, Isa; Fischer, Roxanne; Huizing, Marjan; Guay-Woodford, Lisa; Gahl, William A
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.
PMID: 19914852
ISSN: 1096-7206
CID: 3980262

Outcomes of uncertain dementia [Meeting Abstract]

Roe, Catherine M.; Piwnica-Worms, Katherine; Galuin, James; Storandt, Martha; Morris, John
ISSN: 0028-3878
CID: 3980242