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

NCT ID: NCT05793515

Last Updated: 2025-04-18

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 120 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2022-11-15
• Study Completion Date: 2024-11-02

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.

Conditions

Inherited Retinal Dystrophy; Retinitis Pigmentosa; Macular Dystrophy

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

FB_001

Proband affected by IRD and affected and/or unaffected relatives without molecular diagnosis.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

whole genome sequencing

Intervention Type: DIAGNOSTIC_TEST

Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.

Interventions

whole genome sequencing

Whole genome sequencing will be performed in patients whose test was negative for the targeted resequencing and/or clinical exome sequencing.

Intervention Type: DIAGNOSTIC_TEST

Eligibility 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.

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione G.B. Bietti, IRCCS

OTHER

Sponsor Role: collaborator

Ospedale Pediatrico Bambin Gesù

OTHER

Sponsor Role: collaborator

Istituto Superiore di Sanità

OTHER

Sponsor Role: lead

Responsible Party

Viviana Cordeddu

PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Viviana Cordeddu, PhD

Role: PRINCIPAL_INVESTIGATOR

Istituto Superiore di Sanità

Locations

Istituto Superiore di Sanità-Dpt. Oncology and Molecular Medicine

Rome, Italy, Italy

Countries

Italy

References

Brugger M, Lauri A, Zhen Y, Gramegna LL, Zott B, Sekulic N, Fasano G, Kopajtich R, Cordeddu V, Radio FC, Mancini C, Pizzi S, Paradisi G, Zanni G, Vasco G, Carrozzo R, Palombo F, Tonon C, Lodi R, La Morgia C, Arelin M, Blechschmidt C, Finck T, Sorensen V, Kreiser K, Strobl-Wildemann G, Daum H, Michaelson-Cohen R, Ziccardi L, Zampino G, Prokisch H, Abou Jamra R, Fiorini C, Arzberger T, Winkelmann J, Caporali L, Carelli V, Stenmark H, Tartaglia M, Wagner M. Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy. Am J Hum Genet. 2024 Mar 7;111(3):594-613. doi: 10.1016/j.ajhg.2024.02.005. Epub 2024 Feb 28.

Reference Type: DERIVED

PMID: 38423010 (View on PubMed)

Other Identifiers

ISS20-5656c541c257

Identifier Type: -

Identifier Source: org_study_id