title: Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients.
abstract: Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is caused by mutations in PKD1 or PKD2. The molecular diagnosis of ADPKD is complicated by extensive allelic heterogeneity and particularly by the presence of six highly homologous sequences of PKD1 exons 1-33. Here, we screened PKD1 and PKD2 for both conventional mutations and gross genomic rearrangements in up to 700 unrelated ADPKD patients--the largest patient cohort to date--by means of direct sequencing, followed by quantitative fluorescent multiplex polymerase chain reaction or array-comparative genomic hybridization. This resulted in the identification of the largest number of new pathogenic mutations (n = 351) in a single publication, expanded the spectrum of known ADPKD pathogenic mutations by 41.8% for PKD1 and by 23.8% for PKD2, and provided new insights into several issues, such as the population-dependent distribution of recurrent mutations compared with founder mutations and the relative paucity of pathogenic missense mutations in the PKD2 gene. Our study, together with others, highlights the importance of developing novel approaches for both mutation detection and functional validation of nondefinite pathogenic mutations to increase the diagnostic value of molecular testing for ADPKD.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Brest, France. marie-pierre.audrezet@univ-brest.fr
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Audrézet
authors.forename: Emilie
authors.initials: E
authors.lastname: Cornec-Le Gall
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Redon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Quéré
authors.forename: Joelle
authors.initials: J
authors.lastname: Creff
authors.forename: Caroline
authors.initials: C
authors.lastname: Bénech
authors.forename: Sandrine
authors.initials: S
authors.lastname: Maestri
authors.forename: Yann
authors.initials: Y
authors.lastname: Le Meur
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D006801:Humans; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D050396:TRPP Cation Channels / Q000235:genetics*
chemical_list: D050396:TRPP Cation Channels