{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:01:45Z","timestamp":1790618505400,"version":"4.1.0"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022885","name":"PKD Australia","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100022885","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Autosomal dominant polycystic liver disease (ADPLD) commonly results from pathogenic variants in one of 7 genes (\n                    <jats:italic>GANAB, ALG8, ALG9, PRKCSH, SEC63<\/jats:italic>\n                    and possibly\n                    <jats:italic>LRP5<\/jats:italic>\n                    and\n                    <jats:italic>SEC61B)<\/jats:italic>\n                    . These genes are also included in kidney panels because pathogenic variants cause kidney cysts but rarely kidney failure. This study determined the population frequency of predicted pathogenic variants in the ADPLD genes in the general population. Variants for each gene were downloaded from gnomADv.2.1.1 and annotated with ANNOVAR. The population frequencies were calculated from the number of people with \u2018predicted pathogenic\u2019 variants in gnomAD: loss-of-function structural and copy number; null; and rare, computationally-damaging missense changes that affected a conserved residue. Frequencies were also estimated from the number of gnomADv.4.1 variants assessed as Pathogenic or Likely pathogenic in ClinVar. Predicted pathogenic variants affected one in 91 people using our strategy and gnomAD v.2.1.1, and one in 130 with ClinVar assessments of gnomAD v.4.1 variants.\n                    <jats:italic>LRP5<\/jats:italic>\n                    and\n                    <jats:italic>ALG8<\/jats:italic>\n                    which are associated with a milder clinical phenotype, were the commonest affected genes with both strategies. Predicted pathogenic variants in ADPLD appear more frequent in admixed American (one in 91), Finnish (one in 110) and African\/African American (one in 43) people (p all\u2009&lt;\u20090.0001 compared with Europeans (one in 187). Predicted pathogenic variants for ADPLD may be even more common with the finding of additional causative genes. Assessments will become more accurate too. However not all ADPLD variants result in liver cysts, nor indeed cystic kidneys, because of incomplete penetrance and variable expressivity.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0348109","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:39:44Z","timestamp":1790617184000},"page":"e0348109","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["The population frequency of predicted pathogenic variants in the genes associated with Autosomal Dominant Polycystic Liver Disease (ADPLD) and kidney cysts"],"prefix":"10.1371","volume":"21","author":[{"given":"Santosh","family":"Varughese","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6813-0288","authenticated-orcid":true,"given":"Judy","family":"Savige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"issue":"1","key":"pone.0348109.ref001","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1681\/ASN.2017050483","article-title":"Genetic complexity of autosomal dominant polycystic kidney and liver diseases","volume":"29","author":"E Cornec-Le Gall","year":"2018","journal-title":"J Am Soc 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implications for alport syndrome","volume":"32","author":"J Gibson","year":"2021","journal-title":"J Am Soc Nephrol"},{"key":"pone.0348109.ref023","first-page":"100602","article-title":"Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD)","volume":"24","author":"SG Kaler","year":"2020","journal-title":"Mol Genet Metab Rep"},{"issue":"1","key":"pone.0348109.ref024","doi-asserted-by":"crossref","first-page":"16099","DOI":"10.1038\/s41598-021-95521-6","article-title":"Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases","volume":"11","author":"A Kondo","year":"2021","journal-title":"Sci Rep"},{"issue":"10","key":"pone.0348109.ref025","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1681\/ASN.2018050493","article-title":"Prevalence estimates of polycystic kidney and liver disease by population sequencing","volume":"29","author":"MB 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Polycystic kidney disease, autosomal dominant. GeneRev. 2022."},{"issue":"6","key":"pone.0348109.ref034","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/ng1357","article-title":"Mutations in SEC63 cause autosomal dominant polycystic liver disease","volume":"36","author":"S Davila","year":"2004","journal-title":"Nat Genet"},{"key":"pone.0348109.ref035","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/j.bbadis.2017.08.003","article-title":"Genetics and mechanisms of hepatic cystogenesis","volume":"1864","author":"LFM van de Laarschot","year":"2018","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"issue":"3","key":"pone.0348109.ref036","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.kint.2022.11.025","article-title":"Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease","volume":"103","author":"B Apple","year":"2023","journal-title":"Kidney Int"},{"issue":"5","key":"pone.0348109.ref037","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.ajhg.2020.09.011","article-title":"Variant classification concordance using the ACMG-AMP variant interpretation guidelines across nine genomic implementation research studies","volume":"107","author":"LM Amendola","year":"2020","journal-title":"Am J Hum Genet"},{"issue":"3","key":"pone.0348109.ref038","doi-asserted-by":"crossref","first-page":"104160","DOI":"10.1016\/j.ejmg.2021.104160","article-title":"Polycystic liver disease genes: practical considerations for genetic testing","volume":"64","author":"MM Boerrigter","year":"2021","journal-title":"Eur J Med Genet"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0348109","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:39:51Z","timestamp":1790617191000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0348109"}},"subtitle":[],"editor":[{"given":"Klaus","family":"Brusgaard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0348109","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}