{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T04:02:01Z","timestamp":1784606521684,"version":"3.55.0"},"reference-count":25,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100031531","name":"Travere Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100031531","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Progressive familial intrahepatic cholestasis (PFIC) is classically caused by biallelic pathogenic variants, yet monoallelic variants of uncertain significance (VUS) in PFIC\u2010associated genes are increasingly identified in children with cholestasis, creating diagnostic uncertainty. We conducted a multicenter cohort study of children with liver disease and\/or cholestasis harboring monoallelic VUS in\n                    <jats:italic>ATP8B1<\/jats:italic>\n                    ,\n                    <jats:italic>ABCB11<\/jats:italic>\n                    ,\n                    <jats:italic>ABCB4<\/jats:italic>\n                    ,\n                    <jats:italic>TJP2<\/jats:italic>\n                    , or\n                    <jats:italic>NR1H4<\/jats:italic>\n                    . Clinical and longitudinal data were analyzed, and variant frequencies were compared with population data from gnomAD. Twenty\u2010six children with 37 monoallelic PFIC\u2010gene VUS met inclusion criteria, and multigenic variant burden was common (73.1%). PFIC\u2010like biochemical patterns were observed in 42.3% but were frequently transient, and no patient met criteria for monogenic PFIC on longitudinal follow\u2010up. Severe liver outcomes, including transplantation in two patients, occurred in a subset of patients with\n                    <jats:italic>ABCB4<\/jats:italic>\n                    and\/or\n                    <jats:italic>ATP8B1<\/jats:italic>\n                    VUS and multigenic burden, along with competing clinical factors. Among 22 variants with population data, 11 (50%) demonstrated significant enrichment after multiple\u2010testing correction, most commonly involving\n                    <jats:italic>ABCB4<\/jats:italic>\n                    . These findings suggest that monoallelic PFIC\u2010associated variants currently classified as VUS are unlikely to represent monogenic disease drivers in isolation and may instead contribute within multigenic or susceptibility\u2010based contexts. Population\u2010level enrichment, particularly involving\n                    <jats:italic>ABCB4<\/jats:italic>\n                    , further supports careful phenotype\u2010anchored, longitudinal interpretation in pediatric liver disease.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70250","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T03:06:39Z","timestamp":1784603199000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genotype\u2013Phenotype Correlations of Monoallelic\n                    <scp>PFIC<\/scp>\n                    Variants in Pediatric Liver Disease: A Multicenter Retrospective Cohort Study"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3048-5662","authenticated-orcid":false,"given":"Brett J.","family":"Hoskins","sequence":"first","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics Riley Hospital for Children, Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziano","family":"Pramparo","sequence":"additional","affiliation":[{"name":"Mirum Pharmaceuticals, Inc.  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8076-9378","authenticated-orcid":false,"given":"Chaowapong","family":"Jarasvaraparn","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics Riley Hospital for Children, Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3178-2338","authenticated-orcid":false,"given":"Michael J.","family":"Wilsey","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Johns Hopkins All Children's Hospital  St. Petersburg Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0081-3928","authenticated-orcid":false,"given":"Voytek","family":"Slowik","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition Children's Mercy Kansas City  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakshmi","family":"Kunam","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition Children's Mercy Kansas City  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9689-4675","authenticated-orcid":false,"given":"Janis M.","family":"Stoll","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1163-5202","authenticated-orcid":false,"given":"Ruben E.","family":"Quiros\u2010Tejeira","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Cumming School of Medicine, University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7288-5459","authenticated-orcid":false,"given":"Wikrom","family":"Karnsakul","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics The Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2021.04.040"},{"key":"e_1_2_12_3_1","volume-title":"GeneReviews","author":"Amendola 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