{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T11:12:55Z","timestamp":1779361975581,"version":"3.51.4"},"reference-count":22,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["K08HG012811"],"award-info":[{"award-number":["K08HG012811"]}],"id":[{"id":"10.13039\/100000051","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"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Mucopolysaccharidosis type I (MPS I), a lysosomal disorder caused by variants in\n                    <jats:italic>IDUA<\/jats:italic>\n                    , was added to the Recommended Uniform Screening Panel for newborn screening in 2016. Positive screening results for MPS I are commonly due to variants known as \u201cpseudodeficiency alleles,\u201d which decrease in\u00a0vitro alpha\u2010L\u2010iduronidase enzyme activity but are thought to provide sufficient in\u00a0vivo activity. Despite the historic assumption that these variants are biologically benign, the possibility that they could give rise to complex, multigenic, or attenuated phenotypes has not been systemically evaluated in adults. We completed a retrospective matched cohort study using a hospital\u2010based biorepository with data from 65,309 participants, we identified 1803 individuals harboring homozygous\n                    <jats:italic>IDUA<\/jats:italic>\n                    pseudodeficiency alleles. Using electronic medical records (EMR), we compared the prevalence of features of MPS I in participants with homozygous pseudodeficiency alleles to a cohort of matched control participants. We found no clinically relevant significant differences between cases and controls nor genotype\u2013phenotype associations across four alleles. These findings provide empiric support that adults with homozygous\n                    <jats:italic>IDUA<\/jats:italic>\n                    pseudodeficiency alleles are unlikely to develop mild symptoms of disease compared with controls. This study provides a proof\u2010of\u2010concept model for other nonclassical disease variants related to other inherited metabolic disorders, which is necessary as newborn screening expands.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.63940","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T05:33:38Z","timestamp":1731994418000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Long\u2010Term Health Outcomes of Individuals With Pseudodeficiency Alleles in\n                    <scp>\n                      <i>IDUA<\/i>\n                    <\/scp>\n                    May Inform Newborn Screening Practices for Mucopolysaccharidosis Type I"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6721-4191","authenticated-orcid":false,"given":"Lauren O\u2032","family":"Grady","sequence":"first","affiliation":[{"name":"Division of Medical Genetics and Metabolism Massachusetts General Hospital for Children  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilie S.","family":"Zoltick","sequence":"additional","affiliation":[{"name":"Department of Population Medicine Harvard Pilgrim Health Care Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hana","family":"Zouk","sequence":"additional","affiliation":[{"name":"Department of Pathology Laboratory for Molecular Medicine at Mass General Brigham Personalized Medicine, Mass General Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Perez","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital, Mass General Brigham Personalized Medicine  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0512-7281","authenticated-orcid":false,"given":"Lorne","family":"Clarke","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and the BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics Northwell Health  New Hyde Park New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alanna","family":"Strong","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Center for Applied Genomics, Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inderneel","family":"Sahai","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Metabolism Massachusetts General Hospital for Children  Boston Massachusetts USA"},{"name":"New England Newborn Screening Program and UMass Chen Medical School  Worcester Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Yeo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Metabolism Massachusetts General Hospital for Children  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert C.","family":"Green","sequence":"additional","affiliation":[{"name":"Mass General Brigham  Boston Massachusetts USA"},{"name":"Broad Institute  Cambridge Massachusetts USA"},{"name":"Ariadne Labs  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5781-9824","authenticated-orcid":false,"given":"Amel","family":"Karaa","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Metabolism Massachusetts General Hospital for Children  Boston Massachusetts USA"},{"name":"Department of Pediatrics Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina B.","family":"Gold","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Metabolism Massachusetts General Hospital for Children  Boston Massachusetts USA"},{"name":"Department of Pediatrics Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2023.2680"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.10.005"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61930"},{"key":"e_1_2_11_5_1","first-page":"4","article-title":"Newborn Screening for Pompe Disease in Illinois: Experience With 684,290 Infants","volume":"6","author":"Burton B. 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