TY - JOUR
T1 - PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis
AU - Gunay-Aygun, Meral
AU - Tuchman, Maya
AU - Font-Montgomery, Esperanza
AU - Lukose, Linda
AU - Edwards, Hailey
AU - Garcia, Angelica
AU - Ausavarat, Surasawadee
AU - Ziegler, Shira G.
AU - Piwnica-Worms, Katie
AU - Bryant, Joy
AU - Bernardini, Isa
AU - Fischer, Roxanne
AU - Huizing, Marjan
AU - Guay-Woodford, Lisa
AU - Gahl, William A.
N1 - Funding Information:
We thank the ARPKD/CHF Alliance for their extensive support of this protocol and the patients and their families who generously participated in this investigation. Supported by the Intramural Research Programs of the National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases and the NIH Clinical Center.
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - Autosomal recessive polycystic kidney disease
KW - Congenital hepatic fibrosis
KW - DNA sequencing
KW - Missense variant
KW - PKHD1
KW - Pathogenicity prediction
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U2 - 10.1016/j.ymgme.2009.10.010
DO - 10.1016/j.ymgme.2009.10.010
M3 - Article
C2 - 19914852
AN - SCOPUS:73749087490
SN - 1096-7192
VL - 99
SP - 160
EP - 173
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 2
ER -