{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:19:47Z","timestamp":1785284387909,"version":"3.55.0"},"reference-count":14,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,7]]},"abstract":"ABSTRACT<\/jats:title>An illustration of the importance of manual data review for identifying rare intronic variants adjacent to homopolymers is presented here. A 14\u2010year\u2010old male with Niemann\u2010Pick Type C disease confirmed biochemically was only found to have a heterozygous pathogenic variant by molecular analysis. A manual review of the Next Generation Sequencing (NGS) data identified a c.709C>T; p.Pro237Ser variant, which was likely not reported initially because it is consistently classified as benign or likely benign. A rare association of the c.709C>T variant with a second intronic NPC1<\/jats:italic> variant (c.1947\u2009+\u20095G>C) leading to the use of a cryptic splice donor site has been reported before. Further evaluation with Sanger sequencing detected the c.1947\u2009+\u20095G>C variant as the second causative variant in this patient. Detection of a second allelic change in autosomal recessive inborn errors of metabolism and other genetic disorders is vital in establishing a diagnosis, initiating new therapies, and testing at risk family members. The case presented here illustrates a rare intronic splice site NPC1<\/jats:italic> variant that may not be readily detected by current short\u2010read NGS technologies due to the downstream homopolymers and should be evaluated regularly, especially in the presence of another heterozygous variant.<\/jats:p>","DOI":"10.1002\/ajmg.a.64012","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:55:31Z","timestamp":1741758931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Detecting the Difficult: An Intronic NPC1<\/i><\/scp> Variant Hiding in Plain Sight"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8174-0592","authenticated-orcid":false,"given":"Caroline Gully","family":"Brown","sequence":"first","affiliation":[{"name":"M Health Fairview Masonic Children's Hospital Minneapolis Minnesota USA"},{"name":"Division of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Bower","sequence":"additional","affiliation":[{"name":"M Health Fairview Masonic Children's Hospital Minneapolis Minnesota USA"},{"name":"M Health Fairview University of Minnesota Medical Center, Molecular Diagnostics Laboratory Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Schomaker","sequence":"additional","affiliation":[{"name":"M Health Fairview Masonic Children's Hospital Minneapolis Minnesota USA"},{"name":"M Health Fairview University of Minnesota Medical Center, Molecular Diagnostics Laboratory Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Goldstein","sequence":"additional","affiliation":[{"name":"M Health Fairview Masonic Children's Hospital Minneapolis Minnesota USA"},{"name":"Division of Pediatric Neurology, Department of Pediatrics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine","family":"Jarnes","sequence":"additional","affiliation":[{"name":"M Health Fairview Masonic Children's Hospital Minneapolis Minnesota USA"},{"name":"Division of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chester B.","family":"Whitley","sequence":"additional","affiliation":[{"name":"M Health Fairview Masonic Children's Hospital Minneapolis Minnesota USA"},{"name":"Division of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishitha R.","family":"Pillai","sequence":"additional","affiliation":[{"name":"M Health Fairview Masonic Children's Hospital Minneapolis Minnesota USA"},{"name":"Division of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201006112\u2010y"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010014\u20107619\u2010x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.YMGME.2017.11.004"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.YMGME.2021.06.011"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2021.02.029"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41525\u2010023\u201000365\u2010w"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20108\u2010166"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1086\/302626"},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","unstructured":"Patterson M. C. P.Clayton P.Gissen et\u00a0al.2017.\u201cNeurology\u00ae Clinical Practice Recommendations for the Detection and Diagnosis of Niemann\u2010Pick Disease Type C an Update.\u201d","DOI":"10.1212\/CPJ.0000000000000399"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38104"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232112850"},{"issue":"1","key":"e_1_2_7_13_1","first-page":"118","article-title":"Genetic Heterogeneity in Niemann\u2010Pick C Disease: A Study Using Somatic Cell Hybridization and Linkage Analysis","volume":"58","author":"Vanier M. 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