title: Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD.
abstract: Autosomal dominant polycystic kidney disease (ADPKD), caused by mutation in PKD1 or PKD2, is usually an adult-onset disorder but can rarely manifest as a neonatal disease within a family characterized by otherwise typical ADPKD. Coinheritance of a hypomorphic PKD1 allele in trans with an inactivating PKD1 allele is one mechanism that can cause early onset ADPKD. Here, we describe two pedigrees without a history of cystic kidney disease that each contain two patients with onset of massive PKD in utero. The presentations were typical of autosomal recessive PKD (ARPKD) but they were not linked to the known ARPKD gene, PKHD1. Mutation analysis of the ADPKD genes provided strong evidence that both families inherited, in trans, two incompletely penetrant PKD1 alleles. These patients illustrate that PKD1 mutations can manifest as a phenocopy of ARPKD with respect to renal involvement and highlight the perils of linkage-based diagnostics in ARPKD without positive PKHD1 mutation data. Furthermore, the phenotypic overlap between ARPKD and these patients resulting from incomplete penetrant PKD1 alleles support a common pathogenesis for these diseases.
authors.affiliation: Departments of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Mihailo
authors.initials: M
authors.lastname: Vujic
authors.forename: Christina M
authors.initials: CM
authors.lastname: Heyer
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
authors.forename: Katharina
authors.initials: K
authors.lastname: Hopp
authors.forename: Arseni
authors.initials: A
authors.lastname: Markoff
authors.forename: Charlotte
authors.initials: C
authors.lastname: Orndal
authors.forename: Bengt
authors.initials: B
authors.lastname: Rudenhed
authors.forename: Samih H
authors.initials: SH
authors.lastname: Nasr
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: Roser
authors.initials: R
authors.lastname: Torra
authors.forename: Nadja
authors.initials: N
authors.lastname: Bogdanova
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007223:Infant; D007668:Kidney / Q000000981:diagnostic imaging / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017044:Polycystic Kidney, Autosomal Recessive / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics; D050396:TRPP Cation Channels / Q000235:genetics*; D014463:Ultrasonography
chemical_list: D011956:Receptors, Cell Surface; D050396:TRPP Cation Channels; C451750:PKHD1 protein, human