Genetic analysis of osteogenesis imperfecta in the <scp>P</scp>alestinian population: molecular screening of 49 affected families

Essawi, Osama; Symoens, Sofie; Fannana, Maha; Darwish, M.A.; Farraj, Mohammad; Willaert, Andy; Essawi, Tamer; Callewaert, Bert; Paepe, Anne De; Malfait, Fransiska; Coucke, Paul

doi:10.1002/mgg3.331

Cited by 28 publications

(18 citation statements)

References 65 publications

(107 reference statements)

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“…No biallelic mutations associated with recessive OI were observed in our study. This is totally different from the findings in a report by Essawi et al, which showed that 61% of individuals in their study were affected with autosomal recessive OI in a Palestinian population [22]. The prevalence of recessive OI may depend on geographical area, as recessive disorders can be more frequent where consanguinity is common.…”

Section: Discussioncontrasting

confidence: 96%

Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta

et al. 2019

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To elucidate mutation spectrum and genotype-phenotype correlations in Japanese patients with OI, we conducted comprehensive genetic analyses using NGS, as this had not been analyzed comprehensively in this patient population. Most mutations were located on COL1A1 and COL1A2. Glycine substitutions in COL1A1 resulted in the severe phenotype. Introduction Most cases of osteogenesis imperfecta (OI) are caused by mutations in COL1A1 or COL1A2, which encode α chains of type I collagen. However, mutations in at least 16 other genes also cause OI. The mutation spectrum in Japanese patients with OI has not been comprehensively analyzed, as it is difficult to identify using classical Sanger sequencing. In this study, we aimed to reveal the mutation spectrum and genotype-phenotype correlations in Japanese patients with OI using next-generation sequencing (NGS). Methods We designed a capture panel for sequencing 15 candidate OI genes and 19 candidate genes that are associated with bone fragility or Wnt signaling. Using NGS, we examined 53 Japanese patients with OI from unrelated families. Results Pathogenic mutations were detected in 43 out of 53 individuals. All mutations were heterozygous. Among the 43 individuals, 40 variants were identified including 15 novel mutations. We found these mutations in COL1A1 (n = 30, 69.8%), COL1A2 (n = 12, 27.9%), and IFITM5 (n = 1, 2.3%). Patients with glycine substitution on COL1A1 had a higher frequency of fractures and were more severely short-statured. Although no significant genotype-phenotype correlation was observed for bone mineral density, the trabecular bone score was significantly lower in patients with glycine substitutions. Conclusion We identified pathogenic mutations in 81% of our Japanese patients with OI. Most mutations were located on COL1A1 and COL1A2. This study revealed that glycine substitutions on COL1A1 resulted in the severe phenotype among Japanese patients with OI.

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Section: Discussioncontrasting

confidence: 96%

Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta

et al. 2019

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“…As an endoplasmic reticulum localization protein, FKBP65 binds to tropoelastin throughout the secretory process (32). Investigations into FKBP10 have primarily focused on pulmonary fibrosis and osteochondrosis; FKBP10 mutations has been linked to the onset of many diseases (33,34). As a connective tissue disease, Bruck syndrome is mainly characterized by the loss of endopeptide lysine hydroxylation at the molecular level, leading to the reduction of collagen pyrimidine cross-linking (35).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive evaluation of FKBP10 expression and its prognostic potential in gastric cancer

et al. 2019

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FK506 binding protein 10 (FKBP10) has been reported to be dysregulated in numerous types of cancer; however, few reports have investigated FKBP10 in gastric cancer (GC). The aim of the present study was to investigate FKBP10 expression in GC and to analyze its association with the prognosis of patients with GC. FKBP10 mRNA expression was evaluated using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The standardized mean differences of the meta-analysis were comprehensively evaluated for FKBP10 expression from a series of GEO datasets. Kaplan-Meier survival and Cox regression analyses were applied to predict the prognostic value of FKBP10 in patients with GC. Additionally, the protein expression levels of FKBP10 were validated by immunohistochemistry (IHC) in 40 GC and adjacent tissues. FKBP10 co-expression network and bioinformatics analyses were then used to explore the potential functional mechanisms of FKBP10. The results revealed that the mRNA expression levels of FKBP10 were significantly increased in GC within the TCGA and GEO databases. Survival analysis revealed that high FKBP10 expression results in poorer overall survival and disease-free survival (P<0.05). Multivariate cox regression analysis indicate FKBP10 as a dependent prognostic factor. The results of IHC indicated that the protein expression levels of FKBP10 were higher in GC tissues than in adjacent non-GC tissues (P<0.001). Co-expression networks and functional enrichment analysis suggested that FKBP10 may be involved in the development of GC via cell adhesion molecules and extracellular matrix-receptor interaction pathways. Therefore, the findings of the present study indicated that FKBP10 is upregulated in GC tissues, and suggests its potential prognostic value. Therefore FKBP10 may be a potential therapeutic target for the treatment of GC.

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“…According to our results, out of 337 OI patients in the UT OI biobank, less than 2% suffered from OI type V (five individuals). Interestingly, in a cohort of Palestinian OI patients, there were no carriers of the IFITM5 pathogenic variants, as well as among our Estonian OI population [40]. We do not have evidence to assume, that such differences might come from distinctions in the population genetics of different ethnic groups.…”

Section: Discussionmentioning

confidence: 78%

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

et al. 2019

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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.

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Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families

Cited by 28 publications

References 65 publications

Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta

Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta

Comprehensive evaluation of FKBP10 expression and its prognostic potential in gastric cancer

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

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