title: Challenges in establishing genotype-phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pediatrics, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Ebner
authors.affiliation: Department of Pediatrics, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.|Department II of Internal Medicine and Center for Molecular Medicine Cologne University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dafinger
authors.affiliation: Institute of Human Genetics, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Nadina
authors.initials: N
authors.lastname: Ortiz-Bruechle
authors.affiliation: Pediatric Radiology, Institute of Diagnostic and Interventional Radiology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Koerber
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine Cologne University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine Cologne University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.affiliation: Department of Pediatrics, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Dötsch
authors.affiliation: Institute of Human Genetics, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.affiliation: Department of Pediatrics, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors.forename: Lutz Thorsten
authors.initials: LT
authors.lastname: Weber
authors.affiliation: Institute of Human Genetics and Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Bodo B
authors.initials: BB
authors.lastname: Beck
authors.affiliation: Department of Pediatrics, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany. max.liebau@uk-koeln.de.|Department II of Internal Medicine and Center for Molecular Medicine Cologne University of Cologne, Cologne, Germany. max.liebau@uk-koeln.de.|Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany. max.liebau@uk-koeln.de.
authors.forename: Max Christoph
authors.initials: MC
authors.lastname: Liebau
mesh_terms: D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006529:Hepatomegaly / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D006965:Hyperplasia; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D007438:Introns / Q000235:genetics; D007668:Kidney / Q000000981:diagnostic imaging / Q000473:pathology*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D009154:Mutation; D010641:Phenotype; D017354:Point Mutation; D017044:Polycystic Kidney, Autosomal Recessive / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface
keywords: Autosomal recessive polycystic kidney disease; Congenital hepatic fibrosis; Fibrocystin; PKHD1; Polycystic kidney disease