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OI type VI is an autosomal recessive form of the disorder with moderate to severe bone fragility. OI type VI is caused by mutations in the serpin peptidase inhibitor, clade F, member 1 (<jats:italic>SERPINF1<\/jats:italic>), the gene coding for pigment epithelium\u2010derived factor (PEDF). Here, we report a patient with OI type VI caused by a novel homozygous intronic variant in <jats:italic>SERPINF1<\/jats:italic> identified by whole\u2010exome sequencing (WES). The mutation was not identified using a low bone mass gene panel based on next\u2010generation sequencing. This variant creates a novel consensus splice donor site (AGGC to AGGT) in intron 4. Analysis of cDNA generated from fibroblasts revealed retention of a 32\u2010bp intronic fragment between exons 4 and 5 in the cDNA, a result of alternative splicing from the novel splice\u2010donor site. As a result, the aberrant insertion of this intronic fragment generated a frameshift pathogenic variant and induced nonsense\u2010mediated decay. Furthermore, gene expression by quantitative PCR showed <jats:italic>SERPINF1<\/jats:italic> expression was dramatically reduced in patient fibroblasts, and PEDF level was also significantly reduced in the patient's plasma. In conclusion, we report a novel homozygous variant that generates an alternative splice\u2010donor in intron 4 of <jats:italic>SERPINF1<\/jats:italic> which gives rise to severe bone fragility. The work also demonstrates clinical utility of WES analysis, and consideration of noncoding variants, in the diagnostic setting of rare bone diseases. \u00a9 2018 The Authors. <jats:italic>JBMR Plus<\/jats:italic> is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jbm4.10044","type":"journal-article","created":{"date-parts":[[2018,2,21]],"date-time":"2018-02-21T20:44:32Z","timestamp":1519245872000},"page":"235-239","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Whole\u2010Exome Sequencing Identifies an Intronic Cryptic Splice Site in <i>SERPINF1<\/i> Causing Osteogenesis Imperfecta Type VI"],"prefix":"10.1093","volume":"2","author":[{"given":"Zixue","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsay C","family":"Burrage","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA"},{"name":"Texas Children's Hospital Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming\u2010Ming","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi\u2010Chien","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry","family":"Bertin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alyssa","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard A","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shalini","family":"Jhangiani","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V 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