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

Retinitis Pigmentosa Clinical Trial

Official title:

"Understanding Genetic Missing Variability and Pathogenetic Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models"

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05793515
• Other study ID #: ISS20-5656c541c257
• Status: Recruiting
• Start date: November 15, 2022
• Est. completion date: November 15, 2025

Study information

• Verified date: March 2023
• Source: Istituto Superiore di Sanità
• Contact: Viviana Cordeddu, PhD
• Phone: +39-06-4990
• Email: viviana.cordeddu[@]iss.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: November 15, 2025
• Est. primary completion date: May 2, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Inherited Retinal Dystrophy
• Macular Degeneration
• Macular Dystrophy
• Retinal Dystrophies
• Retinitis
• Retinitis Pigmentosa

Intervention

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.

Locations

Country	Name	City	State
Italy	Istituto Superiore di Sanità-Dpt. Oncology and Molecular Medicine	Rome

Sponsors (3)

Lead Sponsor	Collaborator
Istituto Superiore di Sanità	Fondazione G.B. Bietti, IRCCS, Ospedale Pediatrico Bambin Gesù

Country where clinical trial is conducted

Italy, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	three years
Primary	Understanding genetic missing pathogenetic variants in IRD	Identification of genetic variants causative of the clinical phenotype	two years
Secondary	Gene discovery in IRD	Identification of novel disease genes responsible for IRD.	two years