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IFITM5 pathogenic variant causes osteogenesis imperfecta V with various phenotype severity in Ukrainian and Vietnamese patients.

ABSTRACT: BACKGROUND:Osteogenesis 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. RESULTS:In 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. CONCLUSIONS:OI 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.

SUBMITTER: Zhytnik L

PROVIDER: S-EPMC6547447 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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IFITM5 pathogenic variant causes osteogenesis imperfecta V with various phenotype severity in Ukrainian and Vietnamese patients.

Zhytnik Lidiia L Maasalu Katre K Duy Binh Ho BH Pashenko Andrey A Khmyzov Sergey S Reimann Ene E Prans Ele E Kõks Sulev S Märtson Aare A

Human genomics 20190603 1

<h4>Background</h4>Osteogenesis 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 ...[more]

PMID: 31159867

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Project description:Osteogenesis imperfecta (OI), mainly caused by structural abnormalities of type I collagen, is a hereditary rare disease characterized by increased bone fragility and reduced bone mass. Clinical manifestations of OI mostly include multiple repeated bone fractures, thin skin, blue sclera, hearing loss, cardiovascular and pulmonary system abnormalities, triangular face, dentinogenesis imperfecta (DI), and walking with assistance. Currently, 20 causative genes with 18 subtypes have been identified for OI, of them, variations in COL1A1 and COL1A2 have been demonstrated to be major causative factors to OI. However, the complexity of the bone formation process indicates that there are potential new pathogenic genes associated with OI. To comprehensively explore the underlying mechanism of OI, we conducted association analysis between genotypes and phenotypes of OI diseases and found that mutations in COL1A1 and COL1A2 contributed to a large proportion of the disease phenotypes. We categorized the clinical phenotypes and the genotypes based on the variation types for those 155 OI patients collected from literature, and association study revealed that three phenotypes (bone deformity, DI, walking with assistance) were enriched in two variation types (the Gly-substitution missense and groups of frameshift, nonsense, and splicing variations). We also identified four novel variations (c.G3290A (p.G1097D), c.G3289C (p.G1097R), c.G3289A (p.G1097S), c.G3281A (p.G1094D)) in gene COL1A1 and two novel variations (c.G2332T (p.G778C), c.G2341T (p.G781C)) in gene COL1A2, which could potentially contribute to the disease. In addition, we identified several new potential pathogenic genes (ADAMTS2, COL5A2, COL8A1) based on the integration of protein-protein interaction and pathway enrichment analysis. Our study provides new insights into the association between genotypes and phenotypes of OI and novel information for dissecting the underlying mechanism of the disease.

Dataset Information

IFITM5 pathogenic variant causes osteogenesis imperfecta V with various phenotype severity in Ukrainian and Vietnamese patients.

Publications

IFITM5 pathogenic variant causes osteogenesis imperfecta V with various phenotype severity in Ukrainian and Vietnamese patients.

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