Autori: Monica Bodria1, Claudio La Scola2, Claudia Izzi32, Davide Meneghesso,3 Ilaria Luongo4, Stefano Guarino5, Francesca Taroni6, Valentina Capone6, Roberta Camilla7, Isabella Pisani8, Milena Brugnara9 , Susanna Negrisolo3, Sonia Marre10, Giulia Ingrasciotta11, Alba Carrea1, Valeria Grandinetti12, Dacia di Renzo33, Girolamo Mattioli34, Andrea Pasini2, Cristina Pertulli2, Elena Caramella25, Teresa Rampino25,Ines Minnell8, Silvio Maringhini13, Roberto Chimez14, Gaetano La Manna15, Gianluigi Zaza16, Vincenzo Cantaluppi17, Giuliano Boscutti18, Piergiorgio Messa19, Giovanni Frasca12, Adele Mitrotti20, Mario Giordano21, Maddalena Gigante22, Vinicio Goj23, Mario Bonomini24, Carmine Pecoraro4, Angela La Manna5, Pasquale Esposito25, Giovanni Montini6, Pasquale Zamboli26, Licia Peruzzi7, Luisa Murer3, Giuseppe Masnata27, Giovanni Conti14, Daniele Cusi28, Domenico Santoro29, Antonio Amoroso30, Loreto Gesualdo22-31, Ali G. Gharavi20, Landino Allegri8, Francesco Scolari32, Simone Sanna-Cherchi20, Gian Marco Ghiggeri1
Affiliazioni: 1 Nefrologia, Dialisi e Trapianto IRCCS Gaslini, Genova 2 Nefrologia e Dialisi, Azienda Ospedaliero Universitaria Sant’Orsola-Malpighi, Bologna 3 Nefrologia Pediatrica, Dialisi e Trapianto, Ospedale Universitario di Padova, Padova, Italia 4 Nefrologia e Dialisi, Ospedale pediatrico Santobono, Napoli 5 Dipartimento della donna e del bambino, e della chirurgia generale e specialistica, Università della Campania “Luigi Vanvitelli”, Napoli 6 Nefrologia Pediatrica, Dialisi e Trapianto Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università di Milano, Milano 7 Nefrologia Pediatrica, Ospedale Pediatrico Regina Margherita, Torino 8 Nefrologia, Università di Parma, Dipartimento di Medicina e Chirurgia, Parma 9 Divisione di Pediatria, Dipartimento della Vita e delle Scienze della Riproduzione, Università di Verona, Verona 10 Università degli Studi e IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova 11 Pediatria, Università degli Studi di Brescia, Spedali Civili di Brescia, Brescia 12 Nefrologia, Dialisi e Trapianto Renale, Ospedali Riuniti, Ancona 13 Nefrologia Pediatrica, Ospedale Pediatrico ‘G. Di Cristina’, A.R.N.A.S. ‘Civico’, Palermo 14 Unità di Nefrologia pediatrica e Reumatologia, Università di Messina 15 Nefrologia, Dialisi e Trapianto, Ospedale St Orsola, Università di Bologna, Bologna 16 Nefrologia, Ospedale Universitario di Verona, Verona 17 Nefrologia e Trapianto, Università del Piemonte dell’Est, Novara 18 Azienda Ospedaliero-Universitaria Ospedali Riuniti di Trieste, Trieste 19 Università di Milano, Milano; Ospedale Maggiore-Policlinico, Milano 20 Division of Nephrology, Columbia University, New York, USA 21 Nefrologia e Dialisi Pediatrica, Ospedale Pediatrico Giovanni XXIII, Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari 22 Dipartimento di Scienze Mediche e Chirurgiche, Università di Foggia, Foggia 23 SC di Pediatria, Ospedale Fatebenefratelli , Milano 24 Clinica Nefrologica e Dialisi, Università di Chieti-Pescara, Chieti 25 Dialisi e Trapianto Policlinico, IRCCS Fondazione San Matteo e Università di Pavia, Pavia 26 Unità di Emodialisi, Clinica Maria Rosaria, Pompei 27 Urologia e Nefrologia Pediatrica, Azienda Ospedaliera G. Brotzu – Cagliari. 28 Istituto di Tecnologie Biomedicali, Centro di Ricerca Nazionale (ITB-CNR), Segrate-Milano 29 Dipartimento di Medicina Clinica e Sperimentale, Università di Messina AOU G. Martino, Messina 30 Centro Regionale Trapianti, Piemonte, Ospedale Molinette, Torino 31 Divisione di Nefrologia, Dialisi e Trapianto Università di Bari, Bari 32 Divisione di Nefrologia, Azienda Ospedaliera Spedali Civili di Brescia, Ospedale di Montichiari, Università di Brescia, Brescia 33 Divisone di Chirurgia Pediatrica, Università D’Annunzio e Ospedale dello Spirito Santo, Chieti-Pescara 34 Unità di Chirurgia Pediatrica, IRCCS Gaslini, Genova
Background. Congenital anomalies of the kidneys and urinary tract (CAKUT) represent25% of all malformationsfound by prenatal ultrasound and are the leading cause of end stage renal disease (ESRD) in children and young adults.CAKUT diagnosis is currently based on imaging studies and the disease is classified using descriptive anatomic criteria which omit the underlying pathogenetic and molecular mechanisms. Prior studies from our group indicate that a large fraction of CAKUT is attributable to rare genetic variants with large effect size. In particular, both point mutations and structural genomic variants (copy number variations, or CNVs), detectable by whole exome sequencing (WES) or DNA microarrays, respectively, account for 10 to 30% of the cases. Nevertheless, genetic tests are often not performed or not clinically indicated, thus limiting prognosis and medical management.
Objectives. Here we present a new multi-institutional Italian study group on CAKUT, composed of a network of clinical and basic investigators in adult and pediatric nephrology and urology. The group aims at the recruitment and clinical characterization of 5,000 patients affected by CAKUT to a) conduct detailed clinical characterization and prospective studies, b) perform research DNA microarrays and WES in all patients (in collaboration with Columbia University), c) to perform clinically certified CLIA confirmation of positive genetic results via aCGH and Sanger sequencing, d) to implement genetic results into clinical practice in order to inform parental planning, genetic counseling, and prognosticate risk for disease that develop later in life (ex endocrine and neurodevelopmental diseases), and e) to devise novel precision medicine approaches to guide clinical decision making in patients with CAKUT.
Preliminary results. To date, 15 Italian centers have an approved IRB are actively enrolling for these studies, and additional 13 centers are in the process of submitting or activating the IRB in order to start enrolling patients. We currently recruited and characterized 1,482 independent index patients and over 1,000 relatives (about 50% enrolled at Gaslini Institute, 18% at the University of Parma, 15% at the University of Brescia, and 8% at the University of Bari). Of these, 658 patients (44.4%) have been subjected to DNA microarrays for GWAS and CNVs, and 393 (26.5%) have been subjected to WES. The most commonly identified CNVs were the 17q12 deletion (RCAD), the 22q11.2 deletion (DiGeorge syndrome), the 1q21 deletion, and the 16p11.2 deletion. The most commonly identified point mutations were inPAX2, EYA1, HNF1B, SIX5, and GATA3. Most of these genetic lesions, both CNVs and SNVs, predispose to extra-renal diseases that manifest later in life and would benefit for early intervention strategies. The remaining samples are currently undergoing DNA microarrays and WES.
Conclusions and future directions. We plan to reach the target goal of 5,000 patients in four years. The deep clinical and phenotypic characterization will allow precise anatomical classification of disease. Genetic data will be use to guide deep phenotyping (ex imaging studies, metabolic tests, neurodevelopmental tests, etc). The longitudinal design will allow identification of both genetic and non genetic prognostic factors. Finally, this project aims at a reclassification of CAKUT based on underlying molecular genetics mechanisms, in order to improve renal and overall patient outcome.
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