{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T03:09:38Z","timestamp":1781060978316,"version":"3.54.1"},"reference-count":21,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T00:00:00Z","timestamp":1695254400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NINDS NS085238"],"award-info":[{"award-number":["NINDS NS085238"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NINDS NS085238"],"award-info":[{"award-number":["NINDS NS085238"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in the setting of cascade testing. We use simulations to show that for a rare (dominant) disorder where a variant is identified in a small number of small pedigrees, the penetrance estimate can both have large uncertainty and be drastically inflated, due to underlying ascertainment bias. We have developed PenEst, an app that allows users to investigate the phenomenon across ranges of parameter settings. We also illustrate robust ascertainment corrections via the LOD (logarithm of the odds) score, and recommend a LOD-based approach to assessing pathogenicity of rare variants in the presence of reduced penetrance.<\/jats:p>","DOI":"10.1371\/journal.pone.0290336","type":"journal-article","created":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T17:48:30Z","timestamp":1695318510000},"page":"e0290336","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9169-118X","authenticated-orcid":true,"given":"Andrew D.","family":"Paterson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Cheol","family":"Seok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica J.","family":"Vieland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,9,21]]},"reference":[{"issue":"5","key":"pone.0290336.ref001","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"S Richards","year":"2015","journal-title":"Genet Med"},{"issue":"7616","key":"pone.0290336.ref002","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"M Lek","year":"2016","journal-title":"Nature"},{"issue":"7809","key":"pone.0290336.ref003","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"KJ Karczewski","year":"2020","journal-title":"Nature"},{"issue":"7886","key":"pone.0290336.ref004","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/s41586-021-04103-z","article-title":"Exome sequencing and analysis of 454,787 UK Biobank participants","volume":"599","author":"JD Backman","year":"2021","journal-title":"Nature"},{"issue":"3","key":"pone.0290336.ref005","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/genetics\/144.3.1215","article-title":"The essence of single ascertainment","volume":"144","author":"SE Hodge","year":"1996","journal-title":"Genetics"},{"issue":"3","key":"pone.0290336.ref006","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1086\/378100","article-title":"A full-likelihood method for the evaluation of causality of sequence variants from family data","volume":"73","author":"D Thompson","year":"2003","journal-title":"Am J Hum Genet"},{"issue":"6","key":"pone.0290336.ref007","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.ajhg.2016.04.003","article-title":"Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants","volume":"98","author":"GP Jarvik","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"7497","key":"pone.0290336.ref008","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"508","author":"DG MacArthur","year":"2014","journal-title":"Nature"},{"issue":"4","key":"pone.0290336.ref009","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1469-1809.1986.tb01760.x","article-title":"The limits of ascertainment","volume":"50","author":"WJ Ewens","year":"1986","journal-title":"Ann Hum Genet"},{"issue":"3","key":"pone.0290336.ref010","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/0040-5809(86)90042-0","article-title":"A resolution of the ascertainment sampling problem. 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