Abstract
ABSTRACTThe heritable disorder osteogenesis imperfecta (OI) is characterized by bone fragility and low bone mass. 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 (SERPINF1), the gene coding for pigment epithelium‐derived factor (PEDF). Here, we report a patient with OI type VI caused by a novel homozygous intronic variant in SERPINF1 identified by whole‐exome sequencing (WES). The mutation was not identified using a low bone mass gene panel based on next‐generation 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‐bp intronic fragment between exons 4 and 5 in the cDNA, a result of alternative splicing from the novel splice‐donor site. As a result, the aberrant insertion of this intronic fragment generated a frameshift pathogenic variant and induced nonsense‐mediated decay. Furthermore, gene expression by quantitative PCR showed SERPINF1 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‐donor in intron 4 of SERPINF1 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. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Osteogenesis imperfecta (OI) is a genetic disorder characterized by low bone density and bone fragility
Bone histology in OI type VI shows a mineralization defect and a large amount of unmineralized osteoid.[5]. Bone biopsies from individuals with OI type VI have a “fish-scale” appearance, though this finding can be seen in other pathogenic states.[5,6] OI type VI is caused by pathogenic variants in the serpin peptidase inhibitor, clade F, member 1 (SERPINF1), the gene coding for pigment epitheliumderived factor (PEDF).(6–9) A missense variant in IFITM5 has been reported in one case.[10]. More than 25 disease-causing
SERPINF1 variants have been reported including frameshift, nonsense variants, and in-frame insertion or deletion variants, which caused reduced expression or altered intracellular localization of PEDF (Osteogenesis Imperfecta Variant Database, Leiden University Medical Center, Leiden, The Netherlands; https://oi.gene.le.ac.uk/home.php).(11–15) Most of the reported variants are exonic and located in coding regions of SERPINF1.(16) Recently, a novel splice site in intron 6 of SERPINF1 (c.787–10C>G) has been identified in two individuals with OI type VI.[17]. The variant led to an in-frame addition of three amino acids to PEDF and a decreased secretion of PEDF.[17]. In the present study, we report a novel and deeper pathogenic intronic variant of SERPINF1 discovered by whole-exome sequencing (WES) in a young man with OI type VI
Summary
Osteogenesis imperfecta (OI) is a genetic disorder characterized by low bone density and bone fragility. SERPINF1 variants have been reported including frameshift, nonsense variants, and in-frame insertion or deletion variants, which caused reduced expression or altered intracellular localization of PEDF (Osteogenesis Imperfecta Variant Database, Leiden University Medical Center, Leiden, The Netherlands; https://oi.gene.le.ac.uk/home.php).(11–15) Most of the reported variants are exonic and located in coding regions of SERPINF1.(16) Recently, a novel splice site in intron 6 of SERPINF1 (c.787–10C>G) has been identified in two individuals with OI type VI.[17] The variant led to an in-frame addition of three amino acids to PEDF and a decreased secretion of PEDF.[17] In the present study, we report a novel and deeper pathogenic intronic variant of SERPINF1 discovered by whole-exome sequencing (WES) in a young man with OI type VI This intronic variant introduces a novel splicedonor site and results in the aberrant insertion of a 32-bp intronic fragment that produces a frameshift variant and induces nonsense-mediated decay
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