This is the first study that reports the long-term outcome of ARPKD patients with defined PKHD1 mutations. The 1- and 10-year survival rates were 85% and 82%, respectively. Chronic renal failure was first detected at a mean age of 4 years. Actuarial renal survival rates [end point defined as start of dialysis/renal transplantation (RTX) or by death due to end-stage renal disease (ESRD)] were 86% at 5 years, 71% at 10 years, and 42% at 20 years. All but six patients (92%) had a kidney length above or on the 97th centile for age. About 75% of the study population developed systemic hypertension. Sequelae of congenital hepatic fibrosis and portal hypertension developed in 44% of patients and were related with age. Positive correlations could further be demonstrated between renal and hepatobiliary-related morbidity suggesting uniform disease progression rather than organ-specific patterns. PKHD1 mutation analysis revealed 193 mutations (70 novel ones; 77% nonconservative missense mutations). No patient carried two truncating mutations corroborating that one missense mutation is indispensable for survival of newborns. We attempted to set up genotype-phenotype correlations and to categorize missense mutations. In 96% of families we identified at least one mutated PKHD1 allele (overall detection rate 76.6%) indicating that PKHD1 mutation screening is a powerful diagnostic tool in patients suspected with ARPKD.

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality. The clinical spectrum is widely variable. About 30 to 50% of affected individuals die in the neonatal period, while others survive into adulthood. ARPKD is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene on chromosome 6p12, which is among the largest human genes, with a minimum of 86 exons assembled into a variety of alternatively spliced transcripts. The longest continuous open reading frame is predicted to yield a 4,074-aa (447-kDa) multidomain integral membrane protein (fibrocystin/polyductin) of unknown function. This update compiles all known PKHD1 mutations and polymorphisms/sequence variants. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. Most PKHD1 mutations are unique to single families ("private mutations") hampering genotype-phenotype correlations. Correlations have been drawn for the type of mutation rather than for the site of individual mutations. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise, while patients surviving the neonatal period bear at least one missense mutation. However, some missense changes are obviously as devastating as truncating mutations. The present article intends 1) to provide an overview of PKHD1 mutations and polymorphisms/sequence variants identified so far, 2) to discuss potential genotype-phenotype correlations, and 3) to review them in the context of their clinical implications. A constantly updated list of mutations is available online (www.humgen.rwth-aachen.de) and investigators are invited to submit their novel data to this PKHD1 mutation database.