Nasal Brushing for the Diagnosis and Understanding of Telomeropathies

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Nasal Brushing for the Diagnosis and Understanding of Telomeropathies

Conditions
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Telomere Disease, Telomere Shortening

Intervention / Treatment
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* Diagnostic Test: Nasal brushing
* Diagnostic Test: Sniffin' Sticks


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients : Having a suspicion of or a confirmed telomeropathy Exclusion Criteria: Patients and controls:No access to the olfactory cleft Patients and controls: Abnormal endoscopic finding (i.e. meningocele, vascular ectasia) Specific exclusion criteria for smell assessment (outcome 3): Patients and controls: History of neurological or psychiatric disorder known to interfere with olfactory function or olfactory trouble (postinfectious, posttraumatic, toxic) Patients and controls: History of chronic rhinosinusitis
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective interventional study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with confirmed or suspected telomeropathy<br>Patients with idiopathic pulmonary fibrosis, adult or pediatric medullar dysplasia or myelodysplasia, unexplained liver cirrhosis or unexplained liver regenerative nodular hyperplasia. | Diagnostic Test: Nasal brushing<br>* Nasal brushing to harvest nasal cells and perform staining experiments<br>Diagnostic Test: Sniffin' Sticks<br>* Assessment of olfactory function<br>|
| Other: Controls<br>Age and sex-matched control participants | Diagnostic Test: Nasal brushing<br>* Nasal brushing to harvest nasal cells and perform staining experiments<br>Diagnostic Test: Sniffin' Sticks<br>* Assessment of olfactory function<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the suitability of nasal brushing analysis for the diagnosis of telomeropathies through evaluation of cellular senescence (SA-B-gal activity) and damaged telomeres (FISH/IF) | Investigators will evaluate if it is possible to detect damaged telomeres (via FISH/IF - Fluorescence In Situ Hybridation /ImmunoFluoresence -) and premature cellular senescence in patients (via SA-B-gal activity - Senescence Associated Beta-galactosidase activity measurement - and senescence associated biomarkers by qRT-PCR - quantitative Reverse Transcription - Polymerase Chain Reaction - ), in comparison to healthy controls. | 5 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To develop primary cell cultures to study how the germline mutation affects telomere integrity in vitro through functional telomere assays | Cells harvested from the nasal mucosa will be cultived and analysed to detect telomeric DNA damage and premature cellular senescence | 5 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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telomere, cellular senescence, smell