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

NCT05793515 | Completed DMC

• 1 other identifier: ISS20-5656c541c257
• Study Type: observational
• Target: 120
• Locations: 1 country
• Sites: 1

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.

Conditions

Inherited Retinal Dystrophy; Retinitis Pigmentosa; Macular Dystrophy

Keywords

IRD, RP, WGS, molecular diagnosis

Outcome Measures

Primary Outcomes (1)

• Understanding genetic missing pathogenetic variants in IRD

  Identification of genetic variants causative of the clinical phenotype

  two years

Secondary Outcomes (1)

• Gene discovery in IRD

  two years

Other Outcomes (1)

• Assessment of the pathogenicity of the newly identified variant(s) by functional studies.

  three years

Study Arms (30)

FB_001

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

Diagnostic Test: whole genome sequencing

FB_002

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

Diagnostic Test: whole genome sequencing

FB_003

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

Diagnostic Test: whole genome sequencing

FB_004

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

Diagnostic Test: whole genome sequencing

FB_005

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

Diagnostic Test: whole genome sequencing

FB_006

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

Diagnostic Test: whole genome sequencing

FB_007

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

Diagnostic Test: whole genome sequencing

FB_008

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

Diagnostic Test: whole genome sequencing

FB_009

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

Diagnostic Test: whole genome sequencing

FB_0010

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

Diagnostic Test: whole genome sequencing

FB_0011

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

Diagnostic Test: whole genome sequencing

FB_0012

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

Diagnostic Test: whole genome sequencing

FB_0013

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

Diagnostic Test: whole genome sequencing

FB_0014

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

Diagnostic Test: whole genome sequencing

FB_0015

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

Diagnostic Test: whole genome sequencing

FB_0016

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

Diagnostic Test: whole genome sequencing

FB_0017

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

Diagnostic Test: whole genome sequencing

FB_0018

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

Diagnostic Test: whole genome sequencing

FB_0019

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

Diagnostic Test: whole genome sequencing

FB_0020

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

Diagnostic Test: whole genome sequencing

FB_0021

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

Diagnostic Test: whole genome sequencing

FB_0022

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

Diagnostic Test: whole genome sequencing

FB_0023

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

Diagnostic Test: whole genome sequencing

FB_0024

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

Diagnostic Test: whole genome sequencing

FB_0025

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

Diagnostic Test: whole genome sequencing

FB_0026

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

Diagnostic Test: whole genome sequencing

FB_0027

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

Diagnostic Test: whole genome sequencing

FB_0028

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

Diagnostic Test: whole genome sequencing

FB_0029

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

Diagnostic Test: whole genome sequencing

FB_0030

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

Diagnostic Test: whole genome sequencing

Interventions

whole genome sequencing DIAGNOSTIC_TEST

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

FB_001; FB_0010; FB_0011; FB_0012; FB_0013; FB_0014; FB_0015; FB_0016; FB_0017; FB_0018; FB_0019; FB_002; FB_0020; FB_0021; FB_0022; FB_0023; FB_0024; FB_0025; FB_0026; FB_0027; FB_0028; FB_0029; FB_003; FB_0030; FB_004; FB_005; FB_006; FB_007; FB_008; FB_009

Eligibility Criteria

• Age: 5 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Istituto Superiore di Sanità: lead
• Fondazione G.B. Bietti, IRCCS: collaborator
• Ospedale Pediatrico Bambin Gesù: collaborator

Study Sites (1)

Istituto Superiore di Sanità-Dpt. Oncology and Molecular Medicine

Rome, Italy, 00161, Italy

Location

Related Publications (1)

• 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.

  PMID: 38423010 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples, saliva samples

MeSH Terms

Conditions

Retinitis Pigmentosa; Macular Degeneration

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Retinal Dystrophies; Retinal Degeneration; Retinal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Viviana Cordeddu, PhD

  Istituto Superiore di Sanità

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD

Study Record Dates

• First Submitted: March 20, 2023
• First Posted: March 31, 2023
• Study Start: November 15, 2022
• Primary Completion: November 2, 2024
• Study Completion: November 2, 2024
• Last Updated: April 18, 2025

Record last verified: 2025-04

Locations

IT (1)