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Excision repair cross\u2010complementation group 6 (<jats:italic>ERCC6<\/jats:italic> OMIM: *609413) is the gene most frequently mutated in CS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole\u2010exome sequencing, was screened for causal variants with whole\u2010genome sequencing (WGS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>WGS identified biallelic <jats:italic>ERCC6<\/jats:italic> variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of <jats:italic>ERCC6<\/jats:italic> mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV\u2010irradiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1623","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T17:12:54Z","timestamp":1622653974000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3188-3788","authenticated-orcid":false,"given":"Jennifer","family":"Friedman","sequence":"first","affiliation":[{"name":"Department of Neurosciences University of California San Diego San Diego CA USA"},{"name":"Department of Pediatrics University of California San Diego San 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