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

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.

Correlation of Kidney Function, Volume and Imaging Findings, and PKHD1 Mutations in 73 Patients with Autosomal Recessive Polycystic Kidney Disease

“…The diagnosis was confirmed in 73 patients by finding at least one PKHD1 variant judged likely to be pathogenic (22). Clinical and mutational data from these 73 patients are presented (Table 1).…”

“…DNA variant analyses were performed using Sequencher (GeneCodes, Ann Arbor, MI). The pathogenicity of missense variants was evaluated as described (22) using segregation analysis, general population frequencies, three computational prediction tools [Align GVGD (http://agvgd.iarc.fr/agvgd_ input.php); PolyPhen (http://coot.embl.de/PolyPhen); and SNAP (http://cubic.bioc.columbia.edu/services/SNAP)], and the splice variant interpretation software NetGene2 Server (http://www.cbs.dtu.dk/ services/NetGene2).…”

“…We identified potentially pathogenic PKHD1 variants on both alleles in 43 families and on one allele in 20; these mutations have been previously published (22). Twentyeight patients (25 families) had either one truncating mutation or a truncating mutation in combination with a missense variant.…”

Intrahepatic cholangiocarcinoma with congenital hepatic fibrosis

“…Studies on COACH syndrome have shown gene involvement in MKS3/TMEM67 genes [12,13]. Exome sequencing on patients with Caroli syndrome have shown association with WDR19 mutations [14,15]. While these genes currently do not play a significant role in diagnosing or treating this condition, there may be clinical utility in the future of these genetic studies.…”

Transcriptional Complexity in Autosomal Recessive Polycystic Kidney Disease

“…To date, .700 different PKHD1 mutations are known (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The longest open reading frame of PKHD1 comprises 66 exons and encodes a single-transmembrane protein, called polyductin/fibrocystin, which is mainly expressed in the kidney and liver/cholangiocytes (6,7,19).…”