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Frontiers in Genetics 2019Osteogenesis imperfecta (OI) is a hereditary bone disorder caused by defects of type I collagen. Although up to 90% of patients harbor pathogenic variants in the gene,...
Osteogenesis imperfecta (OI) is a hereditary bone disorder caused by defects of type I collagen. Although up to 90% of patients harbor pathogenic variants in the gene, which codes for collagen α1/2 chains, the spectrum of OI genotypes may differ between populations, and there is academic controversy around OI genotype-phenotype correlations. In the current study, 94 Ukrainian OI families were interviewed. Clinical and genealogical information was collected from patients in spoken form, and their phenotypes were described. To identify the spectrum of collagen I pathogenic variants, mutational analysis with Sanger sequencing was performed on the youngest affected individual of every family. Of the 143 patients investigated, 67 (46.85%) had type I OI, 24 (16.78%) had type III, 49 (34.27%) had type IV, and III (2.10%) had type V. The mean number of fractures suffered per patient per year was 1.32 ± 2.88 (type I 0.50 ± 0.43; type III 3.51 ± 6.18; type IV 1.44 ± 1.77; and type 5 0.77 ± 0.23). 87.23% of patients had skeletal deformations of different severity. Blue sclera, dentinogenesis imperfecta, and hearing loss were present in 87%, 55%, and 22% of patients, respectively. pathogenic variants were harbored by 60 patients (63.83%). 27 pathogenic variants are described herein for the first time. The majority of the pathogenic variants were located in the gene (76.19%). Half (49.21%) of the pathogenic variants were represented by structural variants. OI phenotype severity was highly correlated with type of collagen I defect. The current article presents an analysis of the clinical manifestations and mutational spectrum of 94 Ukrainian OI families with 27 novel pathogenic variants. It is hoped that this data and its analysis will contribute toward the increased understanding of the phenotype development and genetics of the disorder.
PubMed: 31447884
DOI: 10.3389/fgene.2019.00722 -
Molecular Genetics & Genomic Medicine Aug 2019Osteogenesis imperfecta (OI) is a clinically heterogeneous disease characterized by extreme skeletal fragility. It is caused by mutations in genes frequently affecting...
BACKGROUND
Osteogenesis imperfecta (OI) is a clinically heterogeneous disease characterized by extreme skeletal fragility. It is caused by mutations in genes frequently affecting collagen biosynthesis. Mutations in CREB3L1 encoding the ER stress transducer OASIS are very rare and are only reported in pediatric patients. We report a large family with a novel CREB3L1 mutation, with severe adult clinical presentation.
METHODS
Clinical examination was performed on the family members. Next generation sequencing was performed for the causative genes for OI. The mutation was confirmed in other family members with Sanger sequencing.
RESULTS
A novel homozygous mutation in CREB3L1 was identified in the three affected patients. The parents and siblings who carry the mutation in heterozygous state were clinically unaffected. The three affected siblings, who were reported to have been born healthy, presented very severe progressive skeletal malformations and joint contractures but absence of common OI characteristics including blue sclerae, deafness, and dentinogenesis imperfecta. Resorption of a part of the humerus presumably associated with fracture nonunion and pseudarthrosis.
CONCLUSION
We report a novel homozygous CREB3L1 mutation in a large Indonesian family; the homozygous affected members have survived to adulthood and they present a more severe phenotype than previously reported, expanding the clinical spectrum of OI for this gene.
Topics: Adult; Cyclic AMP Response Element-Binding Protein; DNA Mutational Analysis; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Indonesia; Male; Mutation; Nerve Tissue Proteins; Osteogenesis Imperfecta; Severity of Illness Index
PubMed: 31207160
DOI: 10.1002/mgg3.823 -
European Journal of Medical Genetics Dec 2019Osteogenesis imperfecta (OI) type V is an ultrarare heritable bone disorder caused by the heterozygous c.-14C > T mutation in IFITM5. The oro-dental and craniofacial...
Osteogenesis imperfecta (OI) type V is an ultrarare heritable bone disorder caused by the heterozygous c.-14C > T mutation in IFITM5. The oro-dental and craniofacial phenotype has not been described in detail, which we therefore undertook to evaluate in a multicenter study (Brittle Bone Disease Consortium). Fourteen individuals with OI type V (age 3-50 years; 10 females, 4 males) underwent dental and craniofacial assessment. None of the individuals had dentinogenesis imperfecta. Six of the 9 study participants (66%) for whom panoramic radiographs were obtained had at least one missing tooth (range 1-9). Class II molar occlusion was present in 8 (57%) of the 14 study participants. The facial profile was retrusive and lower face height was decreased in 8 (57%) individuals. Cephalometry, performed in three study participants, revealed a severely retrusive maxilla and mandible, and moderately to severly retroclined incisors in a 14-year old girl, a protrusive maxilla and a retrusive mandible in a 14-year old boy. Cone beam computed tomograpy scans were obtained from two study participants and demonstrated intervertebral disc calcification at the C2-C3 level in one individual. Our study observed that OI type V is associated with missing permanent teeth, especially permanent premolar, but not with dentinogenesis imperfecta. The pattern of craniofacial abnormalities in OI type V thus differs from that in other severe OI types, such as OI type III and IV, and could be described as a bimaxillary retrusive malocclusion with reduced lower face height and multiple missing teeth.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Osteogenesis Imperfecta; Phenotype
PubMed: 30593885
DOI: 10.1016/j.ejmg.2018.12.011