{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:36:08Z","timestamp":1776126968553,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health Commission","doi-asserted-by":"publisher","award":["202240361"],"award-info":[{"award-number":["202240361"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hundreds of <jats:italic>NPC1<\/jats:italic> variants cause highly heterogeneous phenotypes. This study aims to explore the genotype\u2013phenotype correlation of NPC1, especially for missense variants. In a well\u2010characterized cohort, phenotypes are graded into three clinical forms: mild, intermediate, and severe. Missense residue structural location was stratified into three categories: surface, partially, and fully buried. The association of phenotypes with the topography of the amino acid substitution in the protein structure was investigated in our cohort and validated in two reported cohorts. One hundred six unrelated NPC1 patients were enrolled. A significant correlation of genotype\u2013phenotype was found in 81 classified individuals with two or one (the second was null variant) missense variant (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001): of 25 patients with at least one missense variant of surface (group A), 19 (76%) mild, six (24%) intermediate, and none severe; of 31 cases with at least one missense variant of partially buried without surface variants (group B), 11 (35%) mild, 16 (52%) intermediate, and four (13%) severe; of the remaining 25 patients with two or one buried missense variants (group C), eight (32%) mild, nine (36%) intermediate, and eight (32%) severe. Additionally, 7\u2010ketocholesterol, the biomarker, was lower in group A than in group B (<jats:italic>p<\/jats:italic>\u2009=\u20090.024) and group C (<jats:italic>p<\/jats:italic>\u2009=\u20090.029). A model was proposed that accurately predicted phenotypes of 72 of 90 (80%), 73 of85 (86%), and 64 of 69 (93%) patients in our cohort, Italian, and UK cohort, respectively. This study proposed a novel genotype\u2013phenotype correlation in NPC1, linking the underlying molecular pathophysiology with clinical phenotype and aiding genetic counseling and evaluation in clinical practice.<\/jats:p>","DOI":"10.1002\/jimd.12705","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T10:20:15Z","timestamp":1703240415000},"page":"317-326","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Development and validation of a new genotype\u2013phenotype correlation for <scp>Niemann\u2010Pick<\/scp> disease type <scp>C1<\/scp>"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2774-1556","authenticated-orcid":false,"given":"Huan","family":"Liang","sequence":"first","affiliation":[{"name":"Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Institute for Pediatric Research Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Zhan","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Institute for Pediatric Research Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Institute for Pediatric Research Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo H. 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