{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:42:17Z","timestamp":1791380537581,"version":"4.3.3"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","funder":[{"DOI":"10.13039\/100011022","name":"Vertex Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011022","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,12]]},"abstract":"\n Significance Statement<\/jats:title>\n \n Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in\n PKD1<\/jats:italic>\n and\n PKD2<\/jats:italic>\n (\n PKD1\/2<\/jats:italic>\n ) in renal tubular epithelium.\n PKD1\/2<\/jats:italic>\n somatic mutations were previously implicated in cyst formation, but studies of this second-hit model in ADPKD had significant technical limitations. Comprehensive analysis of renal cyst epithelium by whole-genome sequencing identified pathogenic inactivating somatic mutations of\n PKD1\/2<\/jats:italic>\n in all 24 patients and in 93% of their 90 cysts. Short variant mutations occurred in 77% of cysts, and another 18% acquired chromosomal loss of heterozygosity encompassing\n PKD1\/2,<\/jats:italic>\n frequently at chromosomal fragile sites or in regions comprising chromosome microdeletion diseases\/syndromes. These findings support a cellular recessive mechanism for renal cystogenesis in ADPKD caused by inactivating germline and somatic variants of\n PKD1\/2<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of multiple cysts in the kidneys. It is often caused by pathogenic mutations in\n PKD1<\/jats:italic>\n and\n PKD2<\/jats:italic>\n genes that encode polycystin proteins. Although the molecular mechanisms for cystogenesis are not established, concurrent inactivating germline and somatic mutations in\n PKD1<\/jats:italic>\n and\n PKD2<\/jats:italic>\n have been previously observed in renal tubular epithelium (RTE).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n To further investigate the cellular recessive mechanism of cystogenesis in RTE, we conducted whole-genome DNA sequencing analysis to identify germline variants and somatic alterations in RTE of 90 unique kidney cysts obtained during nephrectomy from 24 unrelated participants.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Kidney cysts were overall genomically stable, with low burdens of somatic short mutations or large-scale structural alterations. Pathogenic somatic \u201csecond hit\u201d alterations disrupting\n PKD1<\/jats:italic>\n or\n PKD2<\/jats:italic>\n were identified in 93% of the cysts. Of these, 77% of cysts acquired short mutations in\n PKD1<\/jats:italic>\n or\n PKD2<\/jats:italic>\n ; specifically, 60% resulted in protein truncations (nonsense, frameshift, or splice site) and 17% caused non-truncating mutations (missense, in-frame insertions, or deletions). Another 18% of cysts acquired somatic chromosomal loss of heterozygosity (LOH) events encompassing\n PKD1<\/jats:italic>\n or\n PKD2<\/jats:italic>\n ranging from 2.6 to 81.3 Mb. 14% of these cysts harbored copy number neutral LOH events, while the other 3% had hemizygous chromosomal deletions. LOH events frequently occurred at chromosomal fragile sites, or in regions comprising chromosome microdeletion diseases\/syndromes. Almost all somatic \u201csecond hit\u201d alterations occurred at the same germline mutated\n PKD1\/2<\/jats:italic>\n gene.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These findings further support a cellular recessive mechanism for cystogenesis in ADPKD primarily caused by inactivating germline and somatic variants of\n PKD1<\/jats:italic>\n or\n PKD2<\/jats:italic>\n genes in kidney cyst epithelium.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2021050690","type":"journal-article","created":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T13:40:10Z","timestamp":1635514810000},"page":"3114-3129","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":48,"title":["Detection of PKD1 and PKD2 Somatic Variants in Autosomal Dominant Polycystic Kidney Cyst Epithelial Cells by Whole-Genome Sequencing"],"prefix":"10.1681","volume":"32","clinical-trial-number":[{"clinical-trial-number":"nct00792155","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-0331","authenticated-orcid":false,"given":"Zhengmao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanwen","family":"Bai","sequence":"additional","affiliation":[{"name":"Vertex Pharmaceuticals Inc., Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Blumenfeld","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medicine, New York, New York"},{"name":"The Rogosin Institute, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Ramnauth","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Barash","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medicine, New York, New York"},{"name":"The Rogosin Institute, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Prince","sequence":"additional","affiliation":[{"name":"Department of Radiology, Weill Cornell Medicine, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian Y.","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York"},{"name":"Department of Medicine, Weill Cornell Medicine, New York, New 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Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stavros","family":"Giannakopoulos","sequence":"additional","affiliation":[{"name":"Vertex Pharmaceuticals Inc., Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Larbi","sequence":"additional","affiliation":[{"name":"Vertex Pharmaceuticals Inc., Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Hughes","sequence":"additional","affiliation":[{"name":"Vertex Pharmaceuticals Inc., Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Salvatore","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Pathology and 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