PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis.
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.
Gunay-Aygun
Meral
M
Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA. mgaygun@mail.nih.gov
Tuchman
Maya
M
Font-Montgomery
Esperanza
E
Lukose
Linda
L
Edwards
Hailey
H
Garcia
Angelica
A
Ausavarat
Surasawadee
S
Ziegler
Shira G
SG
Piwnica-Worms
Katie
K
Bryant
Joy
J
Bernardini
Isa
I
Fischer
Roxanne
R
Huizing
Marjan
M
Guay-Woodford
Lisa
L
Gahl
William A
WA
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008103:Liver Cirrhosis / Q000150:complications / Q000151:congenital* / Q000235:genetics*; D008297:Male; D017044:Polycystic Kidney, Autosomal Recessive / Q000150:complications* / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*
C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface