Nasal Brushing for the Diagnosis and Understanding of Telomeropathies

Overview

To date, the diagnosis of telomeropathies is based on telomere length measured in blood cells. However, this type of analysis is not always sufficient because some mutations underlying the development of telomeropathies are not associated with abnormal shortened telomeres. Since telomere dysfunction analysis cannot be performed on blood cells, it is mandatory to have access to another cellular material. To date, skin biopsies are performed to obtain fibroblasts. However, this technique is relatively invasive. The aim of this project is to assess whether nasal epithelial cells obtained through nasal brushing could offer the opportunity to detect cellular alterations and mutations involved in telomeropathies, in a mildly invasive way. If successful, this technique could become a non-invasive clinical tool for the diagnosis work-up of telomeropathies. Moreover, investigators aim to assess whether olfactory function is impaired in patients with telomeropathies.

Endpoint #1: To assess the suitability of nasal brushing analyses for the diagnosis of telomeropathies. To date, the complete diagnosis of telomeropathies, including the identification of responsible mutations, is based on blood samples and fibroblast cultures obtained through skin biopsies. Cells obtained through nasal brushing offer the opportunity to detect cellular alterations and mutations involved in telomeropathies, in a mildly invasive way. Investigators will thus assess a population of patients with a suspicion of telomeropathy, using a nasal brushing, and will compare their nasal brushing results to those of age-matched healthy controls. In patients, results of nasal brushing will be compared to standard of care blood test (leukocyte telomere length using Flow-FISH technique). If investigators confirm that the nasal brushing offers the opportunity to i) detect damaged telomeres and premature cellular senescence and ii) identify mutations related to telomeropathies, this technique could become a non-invasive clinical tool for the diagnosis work-up of telomeropathies. Endpoint #2: To develop primary cell cultures for the functional study of new germline mutations. To date, various germline mutations have already been identified in telomeropathy patients, in a total of 17 genes. Understanding how these mutations were affecting telomere biology relied on in vitro studies with either patient-derived fibroblasts or engineered human cell lines recapitulating the mutation. This was a mandatory step towards the molecular understanding of these pathologies. Because olfactory neural precursors have the capacity to grow in culture, this offers the additional possibility to perform functional studies on primary cultures of nasal brushing-derived cells for novel mutations, with still unknown impact on telomeres, that would be identified. Again, this could advantageously replace patients' fibroblast cultures established through skin biopsy. Endpoint #3: To evaluate whether patients with telomeropathies have impaired olfactory function. Olfactory function is decreased in several diseases and is increasingly recognized as an indicator of biological aging. To date, no data exist regarding the impact of telomeropathies on olfactory function. Therefore, investigators aim to psychophysically assess olfactory function in patients with telomeropathies, in comparison to age-matched healthy controls.