Possible position effect on TRPS1 in a patient carrying t(2;8)(p16.1;q23.3) translocation with phenotype referring to trichorhinopahalangeal syndrome

We describe a 54 year-old female come at endocrinologist’s attention for secondary hyperparathyroidism. Physical examination revealed facial dysmorphisms, alopecia and cardiomyopathy. Conventional cytogenetic analysis evidenced a 46,XX,t(2;8)(p15;q24.1) karyotype, where the translocation was apparently balanced and de novo. High resolution aCGH analysis excluded the presence of duplications/deletions at the translocation breakpoints and across the whole genome. Aiming at identifying disease-causing genes the translocation breakpoints have been refined at 8q23.3 and 2p16.1 by means of BAC-FISH. The chromosome 8 breakpoint maps about 267 kb from the 5’terminal of the gene TRPS1, which disruption or mutation leads to the trichorhinopahalangeal syndrome (TRPS). Upon this finding, the phenotype of the patient has been reevaluated and diagnosed as TRPS based on the presence of the main clinical signs of the syndrome, including craniofacial abnormalities (deep-set-eyes, bulbous-pear shaped nose, elongated philtrum, thin upper lip, high-arched palate), alopecia and skeletal abnormalities (hypoplastic mandibular condyles, cone-shaped epiphyses, olecranon exostose and scoliosis). The hypothesis that the translocation breakpoint might lead to the observed clinical phenotype through altered TRPS1 expression by a “position effect”, was then addressed by quantitative gene expression analysis of TRPS1 on the patient’s blood. A highly variable TRPS1 gene expression was found, making a significantly different expression level between patient and controls hard to be assessed. Moreover as the “position effect” might be exerted only in the tissues which are specially sensitive to slight fluctuation in the dosage of the TRPS1 protein, we are now investigating TRPS1 expression in fibroblasts, that are for embryonic origin close to the cells in the tissues affected by the disease. Since our patient presents exostoses, a specific sign of TPRS II, characterized by deletions involving EXT1 and TPRS1 genes, the expression analysis will be also extended to the EXT1 gene, distant about 1,8 Mb from the translocation 8q breakpoint.