Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models

Recruiting

• Conditions: Inherited Retinal Dystrophy; Retinitis Pigmentosa; Macular Dystrophy
• Interventions: Diagnostic Test: whole genome sequencing

• Registration Number: NCT05793515
• Lead Sponsor: Istituto Superiore di Sanità

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.

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 Timeline

• Study Start: 2022-11-15
• Status Verified: 2023-03
• Study First Submitted: 2023-03-20
• Study First Submitted QC: 2023-03-30
• Last Update Submitted: 2023-03-30
• Study First Posted: 2023-03-31
• Last Update Posted: 2023-03-31
• Primary Completion: 2024-05-02
• Study Completion: 2025-11-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

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.

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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.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
FB_0020	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0012	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0019	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_008	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_009	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0010	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0014	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0016	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0018	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_001	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_006	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0017	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0025	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_003	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_005	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0011	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0013	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0021	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0022	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0026	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0027	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0023	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0024	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_002	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_004	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_007	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0015	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0030	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0028	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.
FB_0029	whole genome sequencing	Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.

Primary Outcome Measures

Name	Time	Method
Understanding genetic missing pathogenetic variants in IRD	two years	Identification of genetic variants causative of the clinical phenotype

Secondary Outcome Measures

Name	Time	Method
Gene discovery in IRD	two years	Identification of novel disease genes responsible for IRD.

Trial Locations

Locations (1)

Istituto Superiore di Sanità-Dpt. Oncology and Molecular Medicine; 🇮🇹 Rome, Italy