Challenges in establishing genotype-phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations

Pediatr Nephrol. 2017 Jul;32(7):1269-1273. doi: 10.1007/s00467-017-3648-x. Epub 2017 Mar 31.


Background: Autosomal recessive polycystic kidney disease (ARPKD) constitutes an important cause of pediatric end stage renal disease and is characterized by a broad phenotypic variability. The disease is caused by mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1), which encodes a large transmembrane protein of poorly understood function called fibrocystin. Based on current knowledge of genotype-phenotype correlations in ARPKD, two truncating mutations are considered to result in a severe phenotype with peri- or neonatal mortality. Infants surviving the neonatal period are expected to carry at least one missense mutation.

Case-diagnosis/treatment: We report on a female patient with two truncating PKHD1 mutations who survived the first 30 months of life without renal replacement therapy. Our patient carries not only a known stop mutation, c.8011C>T (p.Arg2671*), but also the previously reported c.51A>G PKHD1 sequence variant of unknown significance in exon 2. Using functional in vitro studies we have confirmed the pathogenic nature of c.51A>G, demonstrating activation of a new donor splice site in intron 2 that results in a frameshift mutation and generation of a premature stop codon.

Conclusions: This case illustrates the importance of functional mutation analyses and also raises questions regarding the current belief that the presence of at least one missense mutation is necessary for perinatal survival in ARPKD.

Keywords: Autosomal recessive polycystic kidney disease; Congenital hepatic fibrosis; Fibrocystin; PKHD1; Polycystic kidney disease.

Publication types

  • Case Reports

MeSH terms

  • Child, Preschool
  • DNA Mutational Analysis
  • Exons / genetics
  • Female
  • Genetic Testing / methods
  • Genotype
  • Hepatomegaly / diagnostic imaging
  • Hepatomegaly / genetics*
  • Humans
  • Hyperplasia
  • Infant, Low Birth Weight
  • Infant, Newborn
  • Infant, Premature
  • Introns / genetics
  • Kidney / diagnostic imaging
  • Kidney / pathology*
  • Kidney Failure, Chronic / etiology
  • Kidney Failure, Chronic / therapy*
  • Magnetic Resonance Imaging
  • Mutation
  • Phenotype
  • Point Mutation
  • Polycystic Kidney, Autosomal Recessive / complications
  • Polycystic Kidney, Autosomal Recessive / diagnostic imaging
  • Polycystic Kidney, Autosomal Recessive / genetics*
  • Receptors, Cell Surface / genetics*


  • PKHD1 protein, human
  • Receptors, Cell Surface