{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T02:35:04Z","timestamp":1761878104451,"version":"build-2065373602"},"reference-count":12,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJNS"],"abstract":"<jats:p>Accurate variant classification is crucial for newborn screening (NBS) to prevent missed diagnoses or unnecessary interventions. The IDUA gene variant denoted as c.250G&gt;A (p.Gly84Ser) has been identified in individuals with positive NBS for Mucopolysaccharidosis Type I (MPS I). This variant has conflicting pathogenicity reports including one publication classifying this variant as associated with a severe MPS I phenotype; therefore, we aim to clarify the clinical significance of this variant by presenting a case series describing three individuals, each homozygous for c.250G&gt;A (p.Gly84Ser), identified in Michigan and California. All patients in this case series had low alpha-iduronidase (IDUA) enzyme activity with normal or mildly elevated glycosaminoglycans (GAGs) in blood or urine not falling into the range or pattern seen for affected individuals. None of these patients have developed clinical features of MPS I during follow-up ranging up to 3.5 years of age. Review of functional and population data supports a pseudodeficiency effect, resulting in no need for treatment. Based on our experience with three patients all homozygous for c.250G&gt;A (p.Gly84Ser), despite causing low in vitro IDUA activity, homozygosity for the IDUA gene variant denoted as c.250G&gt;A (p.Gly84Ser), does not cause symptoms of MPS I and may represent a pseudodeficiency allele. Caution should be exercised in newborns with this variant to help reduce unnecessary interventions and alleviate the psychosocial and economic consequences of false-positive NBS results, particularly for the South Asian population.<\/jats:p>","DOI":"10.3390\/ijns11040100","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T09:16:07Z","timestamp":1761642967000},"page":"100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reclassifying IDUA c.250G&gt;A (p.Gly84Ser): Evidence for a Possible Pseudodeficiency Allele"],"prefix":"10.3390","volume":"11","author":[{"given":"Christopher","family":"Connolly","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Genetics, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7606-1597","authenticated-orcid":false,"given":"Rachel","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Genetics, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9385-5774","authenticated-orcid":false,"given":"Chen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Genetics, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA"},{"name":"Department of Pathology, Michigan Medicine, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Schelley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics, Stanford Medicine Children\u2019s Health, 453 Quarry Road, Palo Alto, CA 94304, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8174-5116","authenticated-orcid":false,"given":"Bryce A.","family":"Mendelsohn","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Kaiser Permanente, Northern California, 3505 Broadway, Oakland, CA 94611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics, Stanford Medicine Children\u2019s Health, 453 Quarry Road, Palo Alto, CA 94304, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayesha","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Genetics, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s10038-020-0744-8","article-title":"Newborn screening of mucopolysaccharidoses: Past, present, and future","volume":"65","author":"Arunkumar","year":"2020","journal-title":"J. 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Med."}],"container-title":["International Journal of Neonatal Screening"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2409-515X\/11\/4\/100\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T02:01:10Z","timestamp":1761876070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2409-515X\/11\/4\/100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,27]]},"references-count":12,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijns11040100"],"URL":"https:\/\/doi.org\/10.3390\/ijns11040100","relation":{},"ISSN":["2409-515X"],"issn-type":[{"type":"electronic","value":"2409-515X"}],"subject":[],"published":{"date-parts":[[2025,10,27]]}}}