title: Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is estimated to affect 1/600-1/1000 individuals worldwide. The disease is characterized by age dependent renal cyst formation that results in kidney failure during adulthood. Although ultrasound imaging may be an adequate diagnostic tool in at risk individuals older than 30, this modality may not be sufficiently sensitive in younger individuals or for those from PKD2 families who have milder disease. DNA based assays may be indicated in certain clinical situations where imaging cannot provide a definitive clinical diagnosis. The goal of this study was to evaluate the utility of direct DNA analysis in a test sample of 82 individuals who were judged to have polycystic kidney disease by standard clinical criteria. The samples were analyzed using a commercially available assay that employs sequencing of both genes responsible for the disorder. Definite disease causing mutations were identified in 34 (approximately 42%) study participants. An additional 30 (approximately 37%) subjects had either in frame insertions/deletions, non-canonical splice site alterations or a combination of missense changes that were also judged likely to be pathogenic. We noted striking sequence variability in the PKD1 gene, with a mean of 13.1 variants per participant (range 0-60). Our results and analysis highlight the complexity of assessing the pathogenicity of missense variants particularly when individuals have multiple amino acid substitutions. We conclude that a significant fraction of ADPKD mutations are caused by amino acid substitutions that need to be interpreted carefully when utilized in clinical decision-making.
authors.affiliation: Johns Hopkins University School of Medicine, Department of Medicine, Division of Nephrology, Baltimore, MD 21205, USA, and Laboratorio de Investigación en Nefroloxía, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Garcia-Gonzalez
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Jones
authors.forename: Susan K
authors.initials: SK
authors.lastname: Allen
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Palatucci
authors.forename: Sat D
authors.initials: SD
authors.lastname: Batish
authors.forename: William K
authors.initials: WK
authors.lastname: Seltzer
authors.forename: Zheng
authors.initials: Z
authors.lastname: Lan
authors.forename: Erica
authors.initials: E
authors.lastname: Allen
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Xose M
authors.initials: XM
authors.lastname: Lens
authors.forename: York
authors.initials: Y
authors.lastname: Pei
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Germino
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Watnick
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D017353:Gene Deletion; D005820:Genetic Testing / Q000706:statistics & numerical data*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D008969:Molecular Sequence Data; D016891:Polycystic Kidney, Autosomal Dominant / Q000175:diagnosis* / Q000235:genetics*; D011110:Polymorphism, Genetic; D022821:RNA Splice Sites; D017386:Sequence Homology, Amino Acid; D050396:TRPP Cation Channels / Q000032:analysis
chemical_list: D018389:Codon, Nonsense; D022821:RNA Splice Sites; D050396:TRPP Cation Channels