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Recently, it was discovered that mutations in<jats:italic>SGMS2<\/jats:italic>, encoding sphingomyelin synthetase 2, result in aberrant sphingomyelin metabolism and lead to a novel form of OI termed osteoporosis with calvarial doughnut lesions (OP-CDL) with moderate to severe skeletal fragility and variable cranial hyperostotic lesions. This study describes a Japanese family with the skeletal phenotype of OP-CDL. The affected individuals have moderately severe, childhood-onset skeletal fragility with multiple long-bone fractures, scoliosis and bone deformities. In addition, they exhibit multiple CDLs or calvarial bumps with central radiolucency and peripheral radiopacity. However,<jats:italic>SGMS2<\/jats:italic>sequencing was normal. Instead, whole-exome sequencing identified a novel<jats:italic>IFITM5<\/jats:italic>missense mutation c.143A&gt;G (p.N48S) (classified as a VUS by ACMG).<jats:italic>IFITM5<\/jats:italic>encodes an osteoblast-restricted protein BRIL and a recurrent c.-14C&gt;T mutation in its 5' UTR region results in OI type V, a distinctive subtype of OI associated with hyperplastic callus formation and ossification of the interosseous membranes. The patients described here have a phenotype clearly different from OI type V and with hyperostotic cranial lesions, feature previously unreported in association with<jats:italic>IFITM5.<\/jats:italic>Our findings expand the genetic spectrum of OP-CDL, indicate diverse phenotypic consequences of pathogenic<jats:italic>IFITM5<\/jats:italic>variants, and imply an important role for BRIL in cranial skeletogenesis.<\/jats:p>","DOI":"10.1007\/s00223-021-00878-5","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T10:03:16Z","timestamp":1624356196000},"page":"626-632","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut Lesions: A Case Report"],"prefix":"10.1007","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-3348","authenticated-orcid":false,"given":"R. 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