Dataset Information

A novel variant of the IFITM5 gene within the 5'-UTR causes neonatal transverse clavicular fracture: Expanding the genetic spectrum.

ABSTRACT: BACKGROUND:Osteogenesis imperfecta (OI) type V is a rare heritable bone disorder caused by pathogenic variants of IFITM5. Only two mutated alleles in IFITM5 have been identified worldwide, the role of which in OI pathology is not fully understood. METHODS:A neonatal case of suspected OI, clinically manifested as a rare clavicle transection fracture with delayed early fracture healing, was studied. Subtle variants of OI-associated genes were analyzed by whole exome sequencing and confirmed by Sanger sequencing. RESULTS:A de novo heterozygous pathogenic variant of IFITM5 within the 5'-UTR (c.-9C > A) was discovered in the proband. Bioinformatics analysis using a combination of various algorithms predicted that the variant would generate a new in-frame start codon 9 bp upstream of the original and express a mutant IFITM5 protein with three additional amino acids (Met-Glu-Pro). After transfection into a eukaryocyte in vitro, the mutant IFITM5 construct produced a longer transcription product than that of wild-type IFITM5. CONCLUSION:This study identified a novel pathogenic variant of IFITM5, which not only manifested the molecular characteristics of IFITM5, but also provided new evidence for the study of the molecular mechanisms of IFITM5 association with OI.

SUBMITTER: Wu D

PROVIDER: S-EPMC7336742 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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A novel variant of the IFITM5 gene within the 5'-UTR causes neonatal transverse clavicular fracture: Expanding the genetic spectrum.

Wu Dong D Wang Yuxin Y Huang Huijuan H

Molecular genetics & genomic medicine 20200508 7

<h4>Background</h4>Osteogenesis imperfecta (OI) type V is a rare heritable bone disorder caused by pathogenic variants of IFITM5. Only two mutated alleles in IFITM5 have been identified worldwide, the role of which in OI pathology is not fully understood.<h4>Methods</h4>A neonatal case of suspected OI, clinically manifested as a rare clavicle transection fracture with delayed early fracture healing, was studied. Subtle variants of OI-associated genes were analyzed by whole exome sequencing and c ...[more]

PMID: 32383316

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Project description:BackgroundOsteogenesis imperfecta (OI) covers a spectrum of bone fragility disorders. OI is classified into five types; however, the genetic causes of OI might hide in pathogenic variants of 20 different genes. Often clinical OI types mimic each other. This sometimes makes it impossible to identify the OI type clinically, which can be a risk for patients. Up to 90% of OI types I-IV are caused by pathogenic variants in the COL1A1/2 genes. OI type V is caused by the c.-14C > T pathogenic variant in the 5'UTR of the IFITM5 gene and is characterized by hyperplastic callus formation and the ossification of interosseous membranes.ResultsIn the current study, we performed IFITM5 5'UTR region mutational analysis using Sanger sequencing on 90 patients who were negative for COL1A1/2 pathogenic variants. We also investigated the phenotypes of five patients with genetically confirmed OI type V. The proportion of OI type V patients in our cohort of all OI patients was 1.48%. In one family, there was a history of OI in at least three generations. Phenotype severity differed from mild to extremely severe among patients, but all patients harbored the same typical pathogenic variant. One patient had no visible symptoms of OI type V and was suspected to have had OI type IV previously. We also identified a case of extremely severe hyperplastic callus in a 15-year-old male, who has hearing loss and brittleness of teeth.ConclusionsOI type V is underlined with some unique clinical features; however, not all patients develop them. The phenotype spectrum might be even broader than previously suspected, including typical OI features: teeth brittleness, bluish sclera, hearing loss, long bones deformities, and joint laxity. We suggest that all patients negative for COL1A1/2 pathogenic variants be tested for the presence of an IFITM5 pathogenic variant, even if they are not expressing typical OI type V symptoms. Further studies on the pathological nature and hyperplastic callus formation mechanisms of OI type V are necessary.

Project description:BackgroundAfter elbow fracture-dislocation, surgeons confront numerous treatment options in pursuing a stable joint for early motion. The relative contributions of the radial head and coronoid, in combination, to elbow stability have not been defined fully.Questions/purposesThe purpose of this study was to evaluate the effect of an approximately 50% transverse coronoid fracture and fixation in the setting of an intact or resected radial head on coronal (varus/valgus) and axial (internal and external rotational) laxity in (1) gravity varus stress; and (2) gravity valgus stress models.MethodsKinematic data were collected on six fresh-frozen cadaveric upper extremities tested with passive motion throughout the flexion arc under varus and valgus gravity stress with lateral collateral ligaments reconstructed. Testing included coronoid fracture and osteosynthesis with and without a radial head.ResultsIn the varus gravity stress model, fixation of the coronoid improved varus stability (fixed: 1.6° [95% confidence interval, 1.0-2.2], fractured: 5.6° [4.2-7.0], p < 0.001) and internal rotational stability (fixed: 1.8° [0.9-2.7], fractured: 5.4° [4.0-6.8], p < 0.001), but radial head fixation did not contribute to varus stability (intact head: 2.7° [1.3-4.1], resected head: 3.8° [2.3-5.3], p = 0.4) or rotational stability (intact: 2.7° [0.9-4.5], resected head: 3.9° [1.5-6.3], p = 0.4). With valgus stress, coronoid fixation improved valgus stability (fixed: 2.1° [1.0-3.1], fractured: 3.8° [1.8-5.8], p < 0.04) and external rotation stability (fixed: 0.8° [0.1-1.5], fractured: 2.1° [0.9-3.4], p < 0.04), but the radial head played a more important role in providing valgus stability (intact: 1.4° [0.8-2.0], resected head: 7.1° [3.5-10.7], p < 0.001).ConclusionsFixation of a 50% transverse coronoid fracture improves varus and internal rotatory laxity but is unlikely to meaningfully improve valgus or external rotation laxity. The radial head, on the other hand, is a stabilizer to resist valgus stress regardless of the status of the coronoid.Clinical relevanceDetermination as to whether it is necessary to fix a coronoid fracture should be based on the stability of the elbow when tested with a varus load. The elbow may potentially be stable with fractures involving less than 50% of the coronoid. Under all circumstances, the radial head should be fixed or replaced to ensure valgus external rotatory stability.

Dataset Information

A novel variant of the IFITM5 gene within the 5'-UTR causes neonatal transverse clavicular fracture: Expanding the genetic spectrum.

Publications

A novel variant of the IFITM5 gene within the 5'-UTR causes neonatal transverse clavicular fracture: Expanding the genetic spectrum.

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