Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
Study Details
Study Description
Brief Summary
Inherited retinal dystrophies (IRDs), a large group of heterogeneous and rare disorders, may result in irreversible bilateral visual loss and blindness. Characterizing the genetic bases of IRDs will help to understand the pathogenesis underlying the development of retinal damage. Despite the advances in molecular identification of genes causing disease, unsolved IRDs constitute about 40% of all cases.
Goal of this study is to solve missing heritability in IRD using whole genome sequencing (WGS) to identify the genetic causes in clinically well-characterized patients without a molecular diagnosis.
The identification of novel genes that have a role in the development or maintenance of retinal function will lead to the development of new therapeutic approaches and will favour a more prompt diagnosis and improvement of patient management.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Detailed Description
IRDs are rare neurodegenerative and genetically heterogeneous conditions with a wide spectrum of presentations, even among affected members of the same family. These disorders exhibit a large range of phenotypes with significant overlap, that can be broadly divided into three main groups: those principally affecting the periphery such as retinitis pigmentosa (RP) and choroideremia; those primarily involving the macula, known as 'macular' or 'central' dystrophies; and those affecting both the centre and periphery as seen in cone-rod or rod-cone dystrophies. Collectively, IRDs have an incidence of 1:2000, impacting approx. 2 million people worldwide and patients are progressively visually impaired. Affected individuals can be followed-up by visual acuity measurements, visual field evaluations, electroretinography recordings (ERG), structural imaging with autofluorescence, spectral-domain optical coherence tomography (OCT), and OCT angiography. Although an accurate clinical diagnosis can be reached by these innovative and non-invasive tools, genetic testing is necessary to confirm a specific phenotype, and segregation analysis can address the inheritance pattern. Gene discovery approaches clarified that mutations of about 280 different genes involved in eyes development, photoreceptor survival, phototransduction mechanisms, retinoid cycle, retinal enzymatic function, or cell structure are responsible for these degenerative diseases (RetNet. Available at: https://sph.uth.edu/retnet/) and the inheritance pattern can be autosomal dominant, recessive, or X-linked.
To improve the success rate of genetic/genomic diagnosis, new sequencing technologies have been explored, starting from targeted sequencing focused on multigene panels to whole exome sequencing (WES) and sequencing of the entire genome (WGS). Because of the genetic heterogeneity of IRDs, the congruence of clinical and molecular diagnosis is a necessary goal to characterize exactly the phenotype and to increase the chance of therapeutically beneficial strategies.
A major challenge consists in identifying novel genes encoding for the diseases. This extreme genetic heterogeneity accounts for about 30% of the detection failure of molecular diagnosis. With the possibility of investigating WES or WGS, broader windows are opened for gene discovery.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| FB_001 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_002 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_003 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_004 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_005 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_006 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_007 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_008 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_009 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0010 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0011 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0012 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0013 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0014 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0015 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0016 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0017 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0018 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0019 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0020 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0021 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0022 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0023 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0024 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0025 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0026 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0027 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0028 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0029 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
| FB_0030 Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis. |
Diagnostic Test: whole genome sequencing
Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.
|
Outcome Measures
Primary Outcome Measures
- Understanding genetic missing pathogenetic variants in IRD [two years]
Identification of genetic variants causative of the clinical phenotype
Secondary Outcome Measures
- Gene discovery in IRD [two years]
Identification of novel disease genes responsible for IRD.
Other Outcome Measures
- Assessment of the pathogenicity of the newly identified variant(s) by functional studies. [three years]
Functional characterization of new variants by in vivo and in vitro models
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients with retinal and optic nerve dystrophy of suspected hereditary nature.
-
Probands with clinical follow-up of at least 12 months.
-
Patients with an inconclusive molecular diagnosis by means of molecular-genetic tests for the genes known to date for the diagnosed pathology.
Exclusion Criteria:
-
Patients with a clinical diagnosis of no proven genetic origin.
-
Patients whose parents' or second degree relatives' samples are not available.
-
Patients who refuse to be informed of the genetic results obtained, including incidental clinically relevant, validated and actionable for the patient himself and/or his family.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Istituto Superiore di Sanità-Dpt. Oncology and Molecular Medicine | Rome | Italy | 00161 |
Sponsors and Collaborators
- Istituto Superiore di Sanità
- Fondazione G.B. Bietti, IRCCS
- Ospedale Pediatrico Bambin Gesù
Investigators
- Principal Investigator: Viviana Cordeddu, PhD, Istituto Superiore di Sanità
Study Documents (Full-Text)
None provided.More Information
Publications
- Cordeddu V, Redeker B, Stellacci E, Jongejan A, Fragale A, Bradley TE, Anselmi M, Ciolfi A, Cecchetti S, Muto V, Bernardini L, Azage M, Carvalho DR, Espay AJ, Male A, Molin AM, Posmyk R, Battisti C, Casertano A, Melis D, van Kampen A, Baas F, Mannens MM, Bocchinfuso G, Stella L, Tartaglia M, Hennekam RC. Mutations in ZBTB20 cause Primrose syndrome. Nat Genet. 2014 Aug;46(8):815-7. doi: 10.1038/ng.3035. Epub 2014 Jul 13.
- Cremers FPM, Boon CJF, Bujakowska K, Zeitz C. Special Issue Introduction: Inherited Retinal Disease: Novel Candidate Genes, Genotype-Phenotype Correlations, and Inheritance Models. Genes (Basel). 2018 Apr 16;9(4):215. doi: 10.3390/genes9040215.
- Musacchia F, Ciolfi A, Mutarelli M, Bruselles A, Castello R, Pinelli M, Basu S, Banfi S, Casari G, Tartaglia M, Nigro V; TUDP. VarGenius executes cohort-level DNA-seq variant calling and annotation and allows to manage the resulting data through a PostgreSQL database. BMC Bioinformatics. 2018 Dec 12;19(1):477. doi: 10.1186/s12859-018-2532-4.
- Ziccardi L, Cordeddu V, Gaddini L, Matteucci A, Parravano M, Malchiodi-Albedi F, Varano M. Gene Therapy in Retinal Dystrophies. Int J Mol Sci. 2019 Nov 14;20(22):5722. doi: 10.3390/ijms20225722.
- ISS20-5656c541c257