Study of New Mutations in Cone Disorders

Study Overview
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Brief Summary
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High throughput sequencing gives the opportunity to improve the genetic diagnosis for patients suffering from retinal dystrophies and specially from cone disorders. However, a large number of mutations are identified, mostly in introns of the genes, and in silico analysis are not sufficient to assign the pathogenicity of these mutations, without which the diagnosis confirmation cannot be done. For that purpose, a functional analysis of intronic variants of unknown significance detected in patients, with minigene splice assays in parallel with the analysis of the effect of the variant on splicing directly in the cells of the patient, by analyzing the RNA from leucocytes, fibroblasts, lymphoblastoïd cells or precursor of photoreceptor cells, which is the only proof of pathogenicity for variants

Official Title
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Functional Study of Intronic Variants in Inherited Cone Disorders

Conditions
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Retinal Dystrophy, Cone-Rod, Cone Dystrophy, Cone Rod Dystrophy, Macular Degeneration

Intervention / Treatment
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* Genetic: Blood and/or skin biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: clinical diagnosis of cone disorder identification of a variant of unknown significance possibility of samplings informed consent Exclusion Criteria: no variant of unknown significance identified no informed consent

Ages Eligible for Study
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Minimum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with an intronic variant unknown in a gene implicated in cone disorders.<br> | Genetic: Blood and/or skin biopsy<br>* Blood and/or skin biopsy will be withdrawn, for RNA extraction in order to test the effect of the variant on splicing.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of the intronic variant on RNA splicing observed in cellulo and/or on patient cells, | Analysis of RNA transcripts of the gene carrying a variant of unknown significance. | at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of the intronic variant on RNA by Minigene splice assay in transient cell cultures |  | at 2 years | 
| Effect of the intronic variant on RNA by analysis of patient RNA transcripts |  | at 2 years | 
| Effect of the intronic variant on RNA by analysis of transcripts from fibroblasts |  | at 2 years | 
| Effect of the intronic variant on RNA by analysis of transcripts from lymphoblastoid lines |  | at 2 years | 
| Effect of the intronic variant on RNA by analysis of transcripts from IPSCs (induced pluripotent stem cells) |  | at 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RNA, intronic variant, splicing, functional test, cone disorders, retinal dystrophy, minigene splice assay, cells