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Our approach using complementary RNA\u2010seq and targeted long\u2010read DNA sequencing can prioritize identification of non\u2010coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the <jats:italic>SPAG1<\/jats:italic> gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern. RNA sequencing revealed reduced <jats:italic>SPAG1<\/jats:italic> transcript levels and exclusive allele specific expression of the known pathogenic allele, suggesting the presence of a non\u2010coding variant on the second allele that impacts transcription. Targeted long\u2010read DNA sequencing identified a heterozygous 3 kilobase deletion of the 5\u2032 untranslated region of <jats:italic>SPAG1<\/jats:italic>, overlapping the promoter and first non\u2010coding exon. This non\u2010coding deletion was missed by whole exome sequencing and gene\u2010specific deletion\/duplication analysis, highlighting the importance of investigating the non\u2010coding genome in patients with \u201cmissing\u201d disease\u2010causing variation. This paradigm demonstrates the utility of both RNA and long\u2010read DNA sequencing in identifying pathogenic non\u2010coding variants in patients with unexplained genetic disease.<\/jats:p>","DOI":"10.1002\/ajmg.a.63880","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T09:18:38Z","timestamp":1728033518000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia"],"prefix":"10.1002","volume":"197","author":[{"given":"M. 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