The IFITM5 mutation c.-14C > T results in an elongated transcript expressed in human bone; and causes varying phenotypic severity of osteogenesis imperfecta type V

Background The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C > T) in the 5’ untranslated region (UTR) of IFITM5, a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V. Methods Sanger sequencing of the IFITM5 5’ UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone sample from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5. Results All nine subjects with OI type V were heterozygous for the c.-14C > T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone. Conclusions The c.-14C > T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family

"ADVANTAGES OF A TWO-STEP PROCEDURE FOR SCHOOL-BASED SCOLIOSIS SCREENING"

PURPOSE: To verify if a "two step" school-based scoliosis screening procedure could reduce childhood radiation exposure and, if so, to estimate the subsequent reduction in radiogenic cancer fatalities and in socio-economic burden. MATERIAL AND METHODS: Data from two different scoliosis screening programs (A and B) performed on a total of 8,995 children (age range 9-14) were examined. Children in program A (5,731 children) were screened using a "two-step" procedure in which school physicians performed the first clinical examination and uncertain cases were referred to an orthopaedist. The school physicians were previously instructed by orthopaedists in the recognition of a number of simple clinical signs. Children in program B (3,264 children) were screened using a "one-step" procedure in which the initial clinical examination was performed directly by an orthopedist. In both programs, suspected cases of scoliosis were then ascertained by the orthopaedist with Radiography. To evaluate the lifetime attributable risk of cancer mortality the guidelines of the International Commission on Radiological Protection Publication 60 were followed. The economic cost of the performed X-ray examination was calculated assuming the current National Health Service's reimbursement to hospitals of euro 35 per X-Ray exam. The statistic significance of the difference in these estimates between the two programs was assessed using the proportions z-test. The issues of the relative sensitivity and specificity of the two programs were also examined. RESULTS: In programs A and B, 86 (1.5 %) and 95 (2.91 %) X-ray examinations were performed respectively (z=4.452, p<0.001). Based on these observations, a screening of 10,000 children directly performed by orthopaedists would result in 291 X-ray exams (2.91 %). A screening of the same number of children using a two-step procedure would result in 150 X-ray exams (1.5 %), with a savings of euro 4,935 for the National Health Care System, a reduction of 0.283 Sv of collective dose, and an estimated 50% reduction in the number of radiogenic malignant tumours. CONCLUSIONS: Using a two-step scoliosis screening procedure provides reasonable sensitivity and specificity while reducing costs and radiation exposure to children