title: Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).
abstract: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial.
authors: IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Unit of Genomics for Human Disease Diagnosis, Milan, Italy.|Laboratory of Clinical Molecular Biology, Ospedale San Raffaele, Milan, Italy.
authors: Paola
authors: P
authors: Carrera
authors: Laboratory of Clinical Molecular Biology, Ospedale San Raffaele, Milan, Italy.
authors: Silvia
authors: S
authors: Calzavara
authors: IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell biology, Molecular Basis of Polycystic Kidney Disease Unit, Milan, Italy.|Division of Nephrology and Dialysis A.O. U. Policlinico, University of Modena and Reggio Emilia, Modena, Italy.
authors: Riccardo
authors: R
authors: Magistroni
authors: Depts. Clinical Genetics and Human Genetics, Leiden University Medical Centre, Netherlands.
authors: Johan T
authors: JT
authors: den Dunnen
authors: IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Unit of Genomics for Human Disease Diagnosis, Milan, Italy.
authors: Francesca
authors: F
authors: Rigo
authors: IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Unit of Genomics for Human Disease Diagnosis, Milan, Italy.
authors: Stefania
authors: S
authors: Stenirri
authors: Division of Nephrology and Dialysis A.O. U. Policlinico, University of Modena and Reggio Emilia, Modena, Italy.
authors: Francesca
authors: F
authors: Testa
authors: Dept. of Nephrology, Urology and Transplant, IRCCS Cà Granda Policlinico, Milan, Italy.
authors: Piergiorgio
authors: P
authors: Messa
authors: Dept. of Nephrology, Urology and Transplant, IRCCS Cà Granda Policlinico, Milan, Italy.
authors: Roberta
authors: R
authors: Cerutti
authors: Center for Prenatal Diagnosis and Nephrology, A.O. Spedali Civili, Brescia, Italy.
authors: Francesco
authors: F
authors: Scolari
authors: Center for Prenatal Diagnosis and Nephrology, A.O. Spedali Civili, Brescia, Italy.
authors: Claudia
authors: C
authors: Izzi
authors: Dept. of Paediatric Nephrology and Dialysis, IRCCS Cà Granda Policlinico, Milan, Italy.
authors: Alberto
authors: A
authors: Edefonti
authors: Laboratory of Immunopathology and Molecular Biology of the Kidney, Dept. SDB, Padova, Italy.
authors: Susanna
authors: S
authors: Negrisolo
authors: Pediatric Nephrology, Dialysis and Transplant Unit; Department of Women's and Children's Health, Padova, Italy.
authors: Elisa
authors: E
authors: Benetti
authors: Vita-Salute San Raffaele University, chair of Nephrology, IRCCS Ran Raffaele Scientific Institute, Genomics of Renal Disease and Hypertension Unit, Milan, Italy.
authors: Maria Teresa Sciarrone
authors: MT
authors: Alibrandi
authors: Vita-Salute San Raffaele University, chair of Nephrology, IRCCS Ran Raffaele Scientific Institute, Genomics of Renal Disease and Hypertension Unit, Milan, Italy.
authors: Paolo
authors: P
authors: Manunta
authors: IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell biology, Molecular Basis of Polycystic Kidney Disease Unit, Milan, Italy.
authors: Alessandra
authors: A
authors: Boletta
authors: IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Unit of Genomics for Human Disease Diagnosis, Milan, Italy.|Laboratory of Clinical Molecular Biology, Ospedale San Raffaele, Milan, Italy.|Vita-Salute San Raffaele University, chair of Clinical Pathology, Milan, Italy.
authors: Maurizio
authors: M
authors: Ferrari
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007558:Italy / Q000453:epidemiology; D007668:Kidney / Q000000981:diagnostic imaging / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D016891:Polycystic Kidney, Autosomal Dominant / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D050396:TRPP Cation Channels / Q000235:genetics*; D055815:Young Adult
chemical_list: D050396:TRPP Cation Channels