title: Presence of de novo mutations in autosomal dominant polycystic kidney disease patients without family history.
abstract: BACKGROUND
  At the University of Colorado Health Sciences Center, on detailed questioning, approximately 10% of patients with autosomal dominant polycystic kidney disease (ADPKD) gave no family history of ADPKD. There are several explanations for this observation, including occurrence of a de novo pathogenic sequence variant or extreme phenotypic variability. To confirm de novo sequence variants, we have undertaken clinical and genetic screening of affected offspring and their parents.
  
  
  METHODS
  Case series.
  
  
  METHODS
  24 patients with a well-documented ADPKD phenotype and no family history of polycystic kidney disease (PKD) and both parents of each patient.
  
  
  RESULTS
  Presence or absence of PKD1 or PKD2 pathogenic sequence variants in parents of affected offspring.
  
  
  METHODS
  Abdominal ultrasound of affected offspring and their parents for ADPKD diagnosis. Parentage testing by genotyping. Complete screening of PKD1 and PKD2 genes by using genomic DNA from affected offspring; analysis of genomic DNA from both parents to confirm the absence or presence of all DNA variants found.
  
  
  RESULTS
  A positive diagnosis of ADPKD by means of ultrasound or genetic screening was made in 1 parent of 4 patients (17%). No PKD1 or PKD2 pathogenic sequence variants were identified in 10 patients (42%), whereas possible pathological DNA variants were identified in 4 patients (17%) and 1 of their respective parents. Parentage was confirmed in the remaining 6 patients (25%), and de novo sequence variants were documented.
  
  
  CONCLUSIONS
  Size of patient group. No direct examination of RNA.
  
  
  CONCLUSIONS
  Causes other than de novo pathogenic sequence variants may explain the negative family history of ADPKD in certain families.
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver and Health Sciences Center, Aurora, CO 80014, USA. berenice.gitomer@uchsc.edu
authors.forename: Berenice
authors.initials: B
authors.lastname: Reed
authors.forename: Kim
authors.initials: K
authors.lastname: McFann
authors.forename: William J
authors.initials: WJ
authors.lastname: Kimberling
authors.forename: York
authors.initials: Y
authors.lastname: Pei
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Gabow
authors.forename: Karen
authors.initials: K
authors.lastname: Christopher
authors.forename: Eric
authors.initials: E
authors.lastname: Petersen
authors.forename: Catherine
authors.initials: C
authors.lastname: Kelleher
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.forename: Ann
authors.initials: A
authors.lastname: Johnson
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schrier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D050396:TRPP Cation Channels / Q000235:genetics; D055815:Young Adult
chemical_list: D050396:TRPP Cation Channels