title: Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome.
abstract: Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Consugar
authors.forename: Wai C
authors.initials: WC
authors.lastname: Wong
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lundquist
authors.forename: Sandro
authors.initials: S
authors.lastname: Rossetti
authors.forename: Vickie J
authors.initials: VJ
authors.lastname: Kubly
authors.forename: Denise L
authors.initials: DL
authors.lastname: Walker
authors.forename: Laureano J
authors.initials: LJ
authors.lastname: Rangel
authors.forename: Richard
authors.initials: R
authors.lastname: Aspinwall
authors.forename: W Patrick
authors.initials: WP
authors.lastname: Niaudet
authors.forename: Seza
authors.initials: S
authors.lastname: Ozen
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Milen
authors.initials: M
authors.lastname: Velinov
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bergstralh
authors.forename: Kyongtae T
authors.initials: KT
authors.lastname: Bae
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dawson
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods / Q000592:standards; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D016891:Polycystic Kidney, Autosomal Dominant / Q000175:diagnosis / Q000235:genetics*; D050396:TRPP Cation Channels / Q000235:genetics*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D050396:TRPP Cation Channels; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624653:TSC2 protein, human