{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:12:58Z","timestamp":1787987578438,"version":"build-2784847793"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T00:00:00Z","timestamp":1470614400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T00:00:00Z","timestamp":1470614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed\n                    <jats:italic>PKD1<\/jats:italic>\n                    and\n                    <jats:italic>PKD2<\/jats:italic>\n                    , 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\n                    <jats:italic>PKD1<\/jats:italic>\n                    , 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with\n                    <jats:italic>PKD2<\/jats:italic>\n                    . 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.\n                  <\/jats:p>","DOI":"10.1038\/srep30850","type":"journal-article","created":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T05:21:48Z","timestamp":1470633708000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)"],"prefix":"10.1038","volume":"6","author":[{"given":"Paola","family":"Carrera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Calzavara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Magistroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan T.","family":"den Dunnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Rigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Stenirri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Testa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piergiorgio","family":"Messa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Cerutti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Scolari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Izzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Edefonti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Negrisolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Benetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa Sciarrone","family":"Alibrandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Manunta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Boletta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,8,8]]},"reference":[{"key":"BFsrep30850_CR1","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/S0140-6736(07)60601-1","volume":"369","author":"VE Torres","year":"2007","unstructured":"Torres, V. E., Harris, P. C. & Pirson, Y. Autosomal dominant polycystic kidney disease. The Lancet 369, 1287\u20131301 (2007).","journal-title":"The Lancet"},{"key":"BFsrep30850_CR2","doi-asserted-by":"publisher","first-page":"2157","DOI":"10.1016\/S0140-6736(07)61005-8","volume":"369","author":"C Bergmann","year":"2007","unstructured":"Bergmann, C. & Zerres, K. Early manifestations of polycystic kidney disease. The Lancet 369, 2157 (2007).","journal-title":"The Lancet"},{"key":"BFsrep30850_CR3","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1056\/NEJMc0801868","volume":"359","author":"C Bergmann","year":"2008","unstructured":"Bergmann, C., Ortiz Bruchle, N., Frank, V., Rehder, H. & Zerres, K. Perinatal deaths in a family with autosomal dominant polycystic kidney disease and a PKD2 mutation. N. Engl. J. Med. 359, 318\u2013319 (2008).","journal-title":"N. Engl. J. Med."},{"key":"BFsrep30850_CR4","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/ki.2008.686","volume":"75","author":"S Rossetti","year":"2009","unstructured":"Rossetti, S. et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int. 75, 848\u2013855 (2009).","journal-title":"Kidney Int."},{"key":"BFsrep30850_CR5","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1681\/ASN.2009101070","volume":"21","author":"M Vujic","year":"2010","unstructured":"Vujic, M. et al. Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD. J. Am. Soc. Nephrol. 21, 1097\u20131102 (2010).","journal-title":"J. Am. Soc. Nephrol."},{"key":"BFsrep30850_CR6","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1681\/ASN.2012070650","volume":"24","author":"E Cornec-Le Gall","year":"2013","unstructured":"Cornec-Le Gall, E. et al. Type of PKD1 mutation influences renal outcome in ADPKD. J. Am. Soc. Nephrol. 24, 1006\u20131013 (2013).","journal-title":"J. Am. Soc. Nephrol."},{"key":"BFsrep30850_CR7","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1681\/ASN.V125955","volume":"12","author":"B Phakdeekitcharoen","year":"2001","unstructured":"Phakdeekitcharoen, B., Watnick, T. J. & Germino, G. G. Mutation analysis of the entire replicated portion of PKD1 using genomic DNA samples. J. Am. Soc. Nephrol. 12, 955\u2013963 (2001).","journal-title":"J. Am. Soc. Nephrol."},{"key":"BFsrep30850_CR8","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.1046\/j.1523-1755.2002.00326.x","volume":"61","author":"S Rossetti","year":"2002","unstructured":"Rossetti, S. et al. A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int. 61, 1588\u20131599 (2002).","journal-title":"Kidney Int."},{"key":"BFsrep30850_CR9","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1002\/humu.22103","volume":"33","author":"MP Audrezet","year":"2012","unstructured":"Audrezet, M. P. et al. Autosomal Dominant Polycystic Kidney Disease. Comprehensive Mutation Analysis of PKD1 and PKD2 in 700 Unrelated Patients. Hum. Mutat. 33, 1239\u20131250 (2012).","journal-title":"Hum. Mutat."},{"key":"BFsrep30850_CR10","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.1681\/ASN.2006121387","volume":"18","author":"S Rossetti","year":"2007","unstructured":"Rossetti, S. et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney diasease. J. Am. Soc. Nephrol. 18, 2143\u20132160 (2007).","journal-title":"J. Am. Soc. Nephrol."},{"key":"BFsrep30850_CR11","doi-asserted-by":"crossref","unstructured":"Hwang, Y.-H. et al. Refining genotype-phenotype correlation in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 27, doi: 10.1681\/ASN.2015060648 (2015).","DOI":"10.1681\/ASN.2015060648"},{"key":"BFsrep30850_CR12","unstructured":"Heyer C. M. et al. Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotypes correlations in Autoosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 27, doi: 10.1681\/ASN2015050583 (2016)."},{"key":"BFsrep30850_CR13","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.ejmg.2005.01.008","volume":"48","author":"M Velinov","year":"2005","unstructured":"Velinov, M. et al. Polycystic kidneys and del(4)(q21.1q21.3): further delineation of a distinct phenotype. Eur. J. Med. Genet. 48, 51\u201355 (2005).","journal-title":"Eur. J. Med. Genet."},{"key":"BFsrep30850_CR14","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1038\/ki.2008.485","volume":"74","author":"MB Consugar","year":"2008","unstructured":"Consugar, M. B. et al. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1\/TSC2 contiguous gene syndrome. Kidney Int. 74, 1468\u20131479 (2008).","journal-title":"Kidney Int."},{"key":"BFsrep30850_CR15","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1002\/humu.9208","volume":"23","author":"Y Ariyurek","year":"2004","unstructured":"Ariyurek, Y. et al. Large deletions in the polycystic kidney disease 1 (PKD1) gene. Hum. Mutat. 23, 99 (2004).","journal-title":"Hum. Mutat."},{"key":"BFsrep30850_CR16","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1002\/humu.21438","volume":"32","author":"IF Fokkema","year":"2011","unstructured":"Fokkema, I. F. et al. LOVD v.2.0: the next generation in gene variant databases. Hum. Mutat. 32, 557\u2013563 (2011).","journal-title":"Hum. Mutat."},{"key":"BFsrep30850_CR17","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/ng.2854","volume":"46","author":"BA Thompson","year":"2013","unstructured":"Thompson, B. A. et al. Application of a 5-tiered scheme for standardized classification of 2360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat. Genet. 46, 107\u2013115 (2013).","journal-title":"Nat. Genet."},{"key":"BFsrep30850_CR18","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1681\/ASN.2008050507","volume":"20","author":"Y Pei","year":"2009","unstructured":"Pei, Y. et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J. Am. Soc. Nephrol. 20, 205\u2013212 (2009).","journal-title":"J. Am. Soc. Nephrol."},{"key":"BFsrep30850_CR19","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1681\/ASN.2014030297","volume":"26","author":"Y Pei","year":"2015","unstructured":"Pei, Y. et al. Imaging-based diagnosis of autosomal dominant polycistic kidney disease. J Am Soc Nephrol 26, 746\u201353 (2015).","journal-title":"J Am Soc Nephrol"},{"key":"BFsrep30850_CR20","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1002\/humu.20892","volume":"29","author":"SV Tavtigian","year":"2008","unstructured":"Tavtigian, S. V., Greenblatt, M. S., Lesueur, F. & Byrnes, G. B. In silico analysis of missense substitutions using sequence-alignment based methods. Hum. Mutat. 29, 1327\u20131336 (2008).","journal-title":"Hum. Mutat."},{"key":"BFsrep30850_CR21","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1093\/protein\/12.5.387","volume":"12","author":"SR Sunyaev","year":"1999","unstructured":"Sunyaev, S. R. et al. PSIC: profile extraction from sequence alignments with position-specific counts of independent observations. Protein. Eng. 12, 387\u2013394 (1999).","journal-title":"Protein. Eng."},{"key":"BFsrep30850_CR22","doi-asserted-by":"publisher","first-page":"3894","DOI":"10.1093\/nar\/gkf493","volume":"30","author":"V Ramensky","year":"2002","unstructured":"Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894\u20133900 (2002).","journal-title":"Nucleic Acids Res."},{"key":"BFsrep30850_CR23","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1101\/gr.176601","volume":"11","author":"PC Ng","year":"2001","unstructured":"Ng, P. C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863\u2013874 (2001).","journal-title":"Genome Res."},{"key":"BFsrep30850_CR24","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1101\/gr.212802","volume":"12","author":"PC Ng","year":"2002","unstructured":"Ng, P. C. & Henikoff, S. Accounting for human polymorphisms predicted to affect protein function. Genome Res. 12, 436\u201346 (2002).","journal-title":"Genome Res."},{"key":"BFsrep30850_CR25","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/nmeth0810-575","volume":"7","author":"JM Schwarz","year":"2010","unstructured":"Schwarz, J. M., Rodelsperger, C., Schuelke, M. & Seelow, D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat. Methods 7, 575\u2013576 (2010).","journal-title":"Nat. Methods"},{"key":"BFsrep30850_CR26","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1101\/gr.097857.109","volume":"20","author":"K Pollard","year":"2010","unstructured":"Pollard, K. et al. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20, 110\u2013121 (2010).","journal-title":"Genome Res."},{"key":"BFsrep30850_CR27","doi-asserted-by":"crossref","unstructured":"Siepel, A. & Haussler, D., Phylogenetic hidden Markov models. In Nielsen, R. ed., Statistical Methods in Molecular Evolution, pp. 325\u2013351, Springer, New York. (2005).","DOI":"10.1007\/0-387-27733-1_12"},{"key":"BFsrep30850_CR28","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1101\/gr.3715005","volume":"15","author":"A Siepel","year":"2005","unstructured":"Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034\u20131050 (2005).","journal-title":"Genome Res."},{"key":"BFsrep30850_CR29","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1002\/humu.21646","volume":"33","author":"M Vihinen","year":"2012","unstructured":"Vihinen, M., den Dunnen, J. T., Dalgleish, R. & Cotton, R. G. Guidelines for establishing locus specific databases. Hum. Mutat. 33, 298\u2013305 (2012).","journal-title":"Hum. Mutat."},{"key":"BFsrep30850_CR30","doi-asserted-by":"publisher","first-page":"D966","DOI":"10.1093\/nar\/gkt1026","volume":"42","author":"S K\u00f6hler","year":"2014","unstructured":"K\u00f6hler, S. et al. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acid Research 42, D966\u201374 (2014).","journal-title":"Nucleic Acid Research"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep30850.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep30850","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep30850.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T01:15:26Z","timestamp":1672881326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep30850"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,8]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,8,26]]}},"alternative-id":["BFsrep30850"],"URL":"https:\/\/doi.org\/10.1038\/srep30850","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,8]]},"assertion":[{"value":"2 March 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"30850"}}