ClinVar Genomic variation as it relates to human health

In 19 Korean individuals (13 from 3 families and 6 simplex individuals) with osteogenesis imperfecta type V (OI5; 610967), Cho et al. (2012) identified a C-T transition 5-prime UTR of the IFITM5 gene (-14C-T). Semler et al. (2012) identified the same mutation in 2 unrelated individuals with OI5. The mutation was predicted to generate an in-frame translation start codon that would add 5 amino acids (Met-Ala-Leu-Glu-Pro) to the N terminus of IFITM5, which was confirmed in transfection experiments. Rauch et al. (2013) sequenced exon 1 of the IFITM5 gene in 42 patients with OI5 from 23 different families and identified the c.-14C-T mutation in all. The authors noted that despite the presence of the same mutation, the patients exhibited marked interindividual phenotypic variability. In 17 affected individuals from 12 families with OI5, Shapiro et al. (2013) identified heterozygosity for the c.-14C-T mutation in the IFITM5 gene. The authors noted strikingly variable phenotypic expressivity, both within and between affected OI5 families. In a 5.5-year-old Hispanic girl with OI, Grover et al. (2013) identified heterozygosity for a de novo c.-14C-T mutation in IFITM5 that was not present in her unaffected parents. The patient did not exhibit any of the classic features of OI type V described in previous patients with this mutation, including hyperplastic callus formation, calcification of interosseous membranes, or radial head dislocation. In 9 patients from 8 families with OI5, Lazarus et al. (2014) identified heterozygosity for the c.-14C-T mutation. The mutation occurred de novo in the 3 simplex cases for whom parental DNA was available. All 9 patients exhibited classic features of OI5 but varied markedly in terms of bone fragility, with 1 adult patient having no history of clinical fracture. IFITM5 expression analysis in a bone sample from a 14-year-old female patient confirmed the presence of both wildtype and mutant transcripts. Lazarus et al. (2014) noted that all 95 reported OI5 patients who had been investigated for this mutation had been found to be heterozygous for it. In a 30-year-old woman of Lithuanian origin with a history of multiple fractures in childhood, who had short stature due to progressively severe skeletal deformities and loss of mobility, Guillen-Navarro et al. (2014) identified heterozygosity for the c.-14C-T mutation in IFITM5. Radiologic examination revealed some of the typical clinical features of OI5, including fracture-related hyperplastic callus formation and calcification of the interosseous membrane of the forearm; however, dislocation of the radial head and radiodense metaphysical banding were not detected. Lietman et al. (2015) generated transgenic mice with the variant corresponding to the human mutation c.-14C-T and observed perinatal lethality. Skeletal preparations and radiographs of embryonic day (E) 15.5 and E18.5 transgenic embryos revealed delayed/abnormal mineralization and skeletal defects, including abnormal rib cage formation, long bone deformities, and fractures. Primary osteoblast cultures derived from mutant calvaria at E18.5 showed decreased mineralization and reduced expression of osteoblast differentiation markers, such as osteocalcin (OC; 112260), compared to wildtype. Overexpression of wildtype Ifitm5 did not, however, manifest a significant bone phenotype. Noting that previous studies had shown that knockout of Ifitm5 did not result in significant bone abnormalities, Lietman et al. (2015) concluded that the c.-14C-T mutation acts in a neomorphic fashion. (less)