title: Clinical and genetic characterization of a founder PKHD1 mutation in Afrikaners with ARPKD.
abstract: BACKGROUND
  Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) occurs in 1:20,000 live births. Disease expression is widely variable, with approximately 30 % of affected neonates dying perinatally, while others survive to adulthood. Mutations at the PKHD1 locus are responsible for all typical presentations. The objectives of this study were to define the clinical and genetic characteristics in a cohort of South African patients of Afrikaner origin, a population with a high prevalence of ARPKD.
  
  
  METHODS
  DNA from the cohort was analyzed for background haplotypes and the p.M627K mutation previously identified in two unrelated Afrikaner patients. The clinical phenotype of the homozygous group was characterized.
  
  
  RESULTS
  Analysis of 36 Afrikaner families revealed that 27 patients, from 24 (67 %) families, were homozygous for the p.M627K substitution, occurring on a common haplotype. The clinical phenotype of the homozygous individuals was variable.
  
  
  CONCLUSIONS
  Our data provide strong evidence that the p.M627K substitution is a founder mutation in the Afrikaner population and can be used for streamlined diagnostic testing for at-risk pregnancies. The observed clinical variability suggests that disease expression is modulated by other genetic loci or by gene-environment interactions.
authors.affiliation: Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Lambie
authors.forename: Rasheda
authors.initials: R
authors.lastname: Amin
authors.forename: Fahmida
authors.initials: F
authors.lastname: Essop
authors.forename: Avital
authors.initials: A
authors.lastname: Cnaan
authors.forename: Amanda
authors.initials: A
authors.lastname: Krause
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guay-Woodford
mesh_terms: D017668:Age of Onset; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D010641:Phenotype; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics* / Q000401:mortality; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics*; D013019:South Africa
chemical_list: C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface