{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T17:45:33Z","timestamp":1774633533076,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01HD068250"],"award-info":[{"award-number":["P01HD068250"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,3]]},"abstract":"ABSTRACT<\/jats:title>\n \n LONP1<\/jats:italic>\n encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in\n LONP1<\/jats:italic>\n are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel\n LONP1<\/jats:italic>\n variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease\u2010associated missense variants revealed phenotype\u2010specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss\u2010of\u2010function mechanisms. Both monoallelic and biallelic variants are associated with LONP1\u2010related NDD, suggesting complex mechanisms such as dominant\u2010negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1\u2010associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.\n <\/jats:p>","DOI":"10.1111\/cge.70057","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T03:15:32Z","timestamp":1757560532000},"page":"437-457","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["\n LONP1<\/i>\n <\/scp>\n Variants Are Associated With Clinically Diverse Phenotypes"],"prefix":"10.1111","volume":"109","author":[{"given":"Randee E.","family":"Young","sequence":"first","affiliation":[{"name":"Department of Pediatrics Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Columbia University Irving Medical Center New York New York USA"},{"name":"Department of Systems Biology Columbia University Irving Medical Center New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Hernan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Sweetser","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Metabolism, Department of Pediatrics; and Center for Genomic Medicine Massachusetts General Hospital Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Waxler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daryl A.","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiana M.","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seema R.","family":"Lalani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahshid S.","family":"Azamian","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill A.","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bret","family":"Bostwick","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5108-8861","authenticated-orcid":false,"given":"Lindsay C.","family":"Burrage","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA"},{"name":"Texas Children's Hospital Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lance H.","family":"Rodan","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics and Department of Neurology, Boston Children's Hospital Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3934-9800","authenticated-orcid":false,"given":"Bianca E.","family":"Russell","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Division of Clinical Genetics, Department of Pediatrics, David Geffen School of Medicine University of California Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Dutra\u2010Clarke","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Division of Clinical Genetics, Department of Pediatrics, David Geffen School of Medicine University of California Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Kruer","sequence":"additional","affiliation":[{"name":"Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute Phoenix Children's Hospital Phoenix Arizona USA"},{"name":"Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics University of Arizona College of Medicine\u2013Phoenix Phoenix Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Somayeh","family":"Bakhtiarim","sequence":"additional","affiliation":[{"name":"Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute Phoenix Children's Hospital Phoenix Arizona USA"},{"name":"Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics University of Arizona College of Medicine\u2013Phoenix Phoenix Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hossein","family":"Darvish","sequence":"additional","affiliation":[{"name":"Neuroscience Research Center, Faculty of Medicine Golestan University of Medical Sciences Gorgan Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Amor","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics Royal Children's Hospital Melbourne Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shamima","family":"Rahman","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, and Metabolic Department Great Ormond Street Hospital for Children London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Stals","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory Royal Devon University Healthcare NHS Foundation Trust Exeter UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Bradley","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and Department of Neurology Children's Health Ireland (CHI) at Crumlin Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Byrne","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and Department of Neurology Children's Health Ireland (CHI) at Crumlin Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leandra K.","family":"Tolusso","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrix","family":"Wong","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Benedict","sequence":"additional","affiliation":[{"name":"Center for Human Genetics University Hospitals Cleveland Medical Center Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly","family":"Wallis","sequence":"additional","affiliation":[{"name":"Center for Human Genetics University Hospitals Cleveland Medical Center Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kestutis","family":"Micke","sequence":"additional","affiliation":[{"name":"Colorado Fetal Care Center Children's Hospital Colorado Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy","family":"Colson","sequence":"additional","affiliation":[{"name":"Univ. Lille, CHU Lille, ULR7364\u2014RADEME\u2014Maladies RAres du DEveloppement Embryonnaire et du M\u00e9tabolisme, CRMR Anomalies du D\u00e9veloppement et Syndromes Malformatifs Lille France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Smol","sequence":"additional","affiliation":[{"name":"Univ. Lille, CHU Lille, ULR7364\u2014RADEME\u2014Maladies RAres du DEveloppement Embryonnaire et du M\u00e9tabolisme, CRMR Anomalies du D\u00e9veloppement et Syndromes Malformatifs Lille France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina V.","family":"Southwick","sequence":"additional","affiliation":[{"name":"Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics Johns Hopkins Hospital Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8567-3850","authenticated-orcid":false,"given":"Kristen A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics Johns Hopkins Hospital Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle L.","family":"Kush","sequence":"additional","affiliation":[{"name":"Center for Fetal Therapy, Department of Gynecology & Obstetrics Johns Hopkins University Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Odelia","family":"Chorin","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, Edmond and Lily Safra Hospital for Children, the Danek Gertner Institute of Genetics Sheba Medical Center Ramat Gan Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annick","family":"Rothschild","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, Edmond and Lily Safra Hospital for Children, the Danek Gertner Institute of Genetics Sheba Medical Center Ramat Gan Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"GeneDx, LLC Gaithersburg Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufeng","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology Columbia University Irving Medical Center New York New York USA"},{"name":"Department of Biomedical Informatics Columbia University Irving Medical Center New York New York USA"},{"name":"JP Sulzberger Columbia Genome Center Columbia University Irving Medical Center New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2016.06.031"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb836"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u201000300\u20102"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20597-z"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611540200"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u201094\u2010007\u20105940\u20104_2"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23495-0"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-025-10500-8"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2023.2298358"},{"key":"e_1_2_11_11_1","article-title":"Phenotypes of Recessive Pediatric Cataract in A Cohort of Children With Identified Homozygous Gene Mutations (An American Ophthalmological Society Thesis)","volume":"113","author":"Khan A. O.","year":"2015","journal-title":"Transactions of the American Ophthalmological Society"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1747-6"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37029"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.12.003"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2017.11"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000015908"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.1031856"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radcr.2022.11.085"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.08.011"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2020.01.004"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00981"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy351"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy080"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22844"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22769"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1714458"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.277908.123"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4582"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw408"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0430-y"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2022.167504"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky427"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs\u20101910518\/v1"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-77039-9"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep33631"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0908-0"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.08.024"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.06.018"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2024.08.001"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0458"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.754127"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2024.102934"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1159\/000517870"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70057","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70057","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70057","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T04:34:41Z","timestamp":1770870881000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1111\/cge.70057"],"URL":"https:\/\/doi.org\/10.1111\/cge.70057","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]},"assertion":[{"value":"2025-03-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}