An observational study in Inherited Retinal Dystrophy, Retinitis Pigmentosa and Macular Dystrophy, sponsored by Istituto Superiore di Sanità. Completed at 1 site in Italy. Open to participants aged 5 Years to 80 Years. Per ClinicalTrials.gov, last updated 2025-04-18.
Sponsored by Istituto Superiore di Sanità · Observational
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.
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.
278 studies on the registry are indexed under Retinitis Pigmentosa; 72 are open to participants now.
This study's enrollment of 120 is above the median of 52 across 87 observational studies indexed under Retinitis Pigmentosa.
Browse Retinitis Pigmentosa studies →Istituto Superiore di Sanità is the lead sponsor of 17 studies on the registry; 2 are open to participants now.
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Male and female patients, aged between 5 and 80 years, suffering from retinal or optic nerve degeneration of a hereditary nature. Patients will be recruited at the IRCSS Fondazione Bietti in Rome and undergo ophthalmological examinations and instrumental tests. Candidate subjects are a clinically well-characterized cohort of patients with ocular dystrophies, including IRDs already clinically followed for at least 12 months and without a conclusive molecular diagnosis.
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Exclusion Criteria:
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Clinically significant
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Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
Diagnostic Test: whole genome sequencing
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.
Understanding genetic missing pathogenetic variants in IRD
Identification of genetic variants causative of the clinical phenotype
Time frame: two years
Gene discovery in IRD
Identification of novel disease genes responsible for IRD.
Time frame: two years
Assessment of the pathogenicity of the newly identified variant(s) by functional studies.
Functional characterization of new variants by in vivo and in vitro models
Time frame: three years
Plan to share: Undecided — We plan to share anonymized genomic data among the three partners involved in the study by telecall meetings and shared cloud folders.
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Istituto Superiore di Sanità