{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:10:36Z","timestamp":1793261436188,"version":"4.5.0"},"reference-count":26,"publisher":"American Medical Association (AMA)","issue":"24","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2022,12,27]]},"abstract":"\n Importance<\/jats:title>\n \n Most studies of autosomal dominant polycystic kidney disease (ADPKD) genetics have used kidney specialty cohorts, focusing on\n PKD1<\/jats:italic>\n and\n PKD<\/jats:italic>\n 2. These can lead to biased estimates of population prevalence of ADPKD-associated gene variants and their phenotypic expression.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To determine the prevalence of ADPKD and contributions of\n PKD1<\/jats:italic>\n ,\n PKD2<\/jats:italic>\n , and other genes related to cystic kidney disease in a large, unselected cohort.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This retrospective observational study used an unselected health system\u2013based cohort in central and northeast Pennsylvania with exome sequencing (enrolled from 2004 to 2020) and electronic health record data (up to October 2021). The genotype-first approach included the entire cohort and the phenotype-first approach focused on patients with ADPKD diagnosis codes, confirmed by chart and imaging review.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n Loss-of-function (LOF) variants in\n PKD1<\/jats:italic>\n ,\n PKD2<\/jats:italic>\n , and other genes associated with cystic kidney disease (ie,\n ALG8<\/jats:italic>\n ,\n ALG9<\/jats:italic>\n ,\n DNAJB11<\/jats:italic>\n ,\n GANAB<\/jats:italic>\n ,\n HNF1B<\/jats:italic>\n ,\n IFT140<\/jats:italic>\n ,\n SEC61B<\/jats:italic>\n ,\n PKHD1<\/jats:italic>\n ,\n PRKCSH<\/jats:italic>\n ,\n SEC63)<\/jats:italic>\n ; likely pathogenic missense variants in\n PKD1<\/jats:italic>\n and\n PKD2<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n Genotype-first analysis: ADPKD diagnosis code (Q61.2, Q61.3, 753.13, 753.12); phenotype-first analysis: presence of a rare variant in\n PKD1<\/jats:italic>\n ,\n PKD2,<\/jats:italic>\n or other genes associated with cystic kidney disease.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of 174\u202f172 patients (median age, 60 years; 60.6% female; 93% of European ancestry), 303 patients had ADPKD diagnosis codes, including 235 with sufficient chart review data for confirmation. In addition to\n PKD1<\/jats:italic>\n and\n PKD2<\/jats:italic>\n , LOF variants in\n IFT140<\/jats:italic>\n ,\n GANAB<\/jats:italic>\n , and\n HNF1B<\/jats:italic>\n were associated with ADPKD diagnosis after correction for multiple comparisons. Among patients with LOF variants in\n PKD1<\/jats:italic>\n , 66 of 68 (97%) had ADPKD; 43 of 43 patients (100%) with LOF variants in\n PKD2<\/jats:italic>\n had ADPKD. In contrast, only 24 of 77 patients (31.2%) with a\n PKD1<\/jats:italic>\n missense variant previously classified as \u201clikely pathogenic\u201d had ADPKD, suggesting misclassification or variable penetrance. Among patients with ADPKD diagnosis confirmed by chart review, 180 of 235 (76.6%) had a potential genetic cause, with the majority being rare variants in\n PKD1<\/jats:italic>\n (127 patients) or\n PKD2<\/jats:italic>\n (34 patients); 19 of 235 (8.1%) had variants in other genes associated with cystic kidney disease. Of these 235 patients with confirmed ADPKD, 150 (63.8%) had a family history of ADPKD. The yield for a genetic determinant of ADPKD was higher for those with a family history of ADPKD compared with those without family history (91.3% [137\/150] vs 50.6% [43\/85]; difference, 40.7% [95% CI, 29.2%-52.3%];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). Previously unreported\n PKD1<\/jats:italic>\n ,\n PKD2<\/jats:italic>\n , and\n GANAB<\/jats:italic>\n variants were identified with pedigree data suggesting pathogenicity, and several\n PKD1<\/jats:italic>\n missense variants previously reported as likely pathogenic appeared to be benign.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2022.22847","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T11:01:10Z","timestamp":1672138870000},"page":"2412","source":"Crossref","is-referenced-by-count":98,"title":["Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.1001","volume":"328","author":[{"given":"Alexander R.","family":"Chang","sequence":"first","affiliation":[{"name":"Center for Kidney 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