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In <jats:italic>PLOD1<\/jats:italic>\u2010kEDS, deleterious variants are typically loss\u2010of\u2010function alleles. Therefore, the identification of private non\u2010canonical splicing variants might deserve functional studies to refine their clinical interpretation. In a 7\u2010year\u2010old boy with congenital hypotonia, kyphoscoliosis, joint hypermobility, and arachnodactyly, exome sequencing revealed the homozygous variant c.1756\u201013C &gt; A in <jats:italic>PLOD1<\/jats:italic>. This variant was previously annotated in public databases with conflicting pathogenicity criteria. In contrast to other EDS subtypes whose causative gene is not expressed in peripheral lymphocytes, whole blood RNA sequencing demonstrated a deleterious effect of the identified variant, which resulted in the incorporation of 11 intronic nucleotides and the generation of a premature stop codon. In this work, multi\u2010OMIC analysis on peripheral blood was a rapid and reliable tool to clinically characterize a non\u2010canonical splice site variant in <jats:italic>PLOD1<\/jats:italic>\u2010kEDS.<\/jats:p>","DOI":"10.1002\/ajmg.a.64085","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T07:45:01Z","timestamp":1744271101000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Whole Blood Multi\u2010<scp>OMIC<\/scp> Analysis Is Effective in Clinical Interpretation of Splicing Aberrations in <scp><i>PLOD1<\/i><\/scp>\u2010Related Kyphoscoliotic Ehlers\u2010Danlos Syndrome"],"prefix":"10.1002","volume":"197","author":[{"given":"Federica","family":"Russo","sequence":"first","affiliation":[{"name":"UOC Genetica Medica Fondazione IRCCS\u2010Casa Sollievo Della Sofferenza  San Giovanni Rotondo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Daolio","sequence":"additional","affiliation":[{"name":"Pediatrics, Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Di Muro","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica Fondazione IRCCS\u2010Casa Sollievo Della Sofferenza  San Giovanni Rotondo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Pezzoli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics ASST Papa Giovanni XXIII  Bergamo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucrezia","family":"Goisis","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics ASST Papa Giovanni XXIII  Bergamo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Vaccaro","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM) Armenise\/Harvard Laboratory of Integrative Genomics  Pozzuoli Italy"},{"name":"Department of Translational Medicine University of Naples \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics ASST Papa Giovanni XXIII  Bergamo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Cacchiarelli","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM) Armenise\/Harvard Laboratory of Integrative Genomics  Pozzuoli Italy"},{"name":"Department of Translational Medicine University of Naples \u201cFederico II\u201d  Naples Italy"},{"name":"Genomics and Experimental Medicine Program Scuola Superiore Meridionale (SSM, School of Advanced Studies)  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6069-0993","authenticated-orcid":false,"given":"Marco","family":"Castori","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica Fondazione IRCCS\u2010Casa Sollievo Della Sofferenza  San Giovanni Rotondo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3604-194X","authenticated-orcid":false,"given":"Lucia","family":"Micale","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica Fondazione IRCCS\u2010Casa Sollievo Della Sofferenza  San Giovanni Rotondo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096\u20108628(19980428)77:1<31::AID\u2010AJMG8>3.0.CO;2\u2010O"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31550"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ccr3.6760"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.01.012"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15824"},{"key":"e_1_2_11_9_1","unstructured":"Krueger F. 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