Clinical trial NCT05793515: Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
Official title: "Understanding Genetic Missing Variability and Pathogenetic Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models"
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Inherited Retinal Dystrophy
Retinitis Pigmentosa
Macular Dystrophy
Keywords: IRD, RP, WGS, molecular diagnosis
Lead sponsor: Istituto Superiore di Sanità
Sponsor class: OTHER
Collaborators: name: Fondazione G.B. Bietti, IRCCS
name: Ospedale Pediatrico Bambin Gesù
First posted: 2023-03-31
Enrollment: 120
Sex: ALL
Minimum age (years): 5
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Primary outcomes:
measure: Understanding genetic missing pathogenetic variants in IRD
timeFrame: two years
Secondary outcomes:
measure: Gene discovery in IRD
timeFrame: two years
Other outcomes:
measure: Assessment of the pathogenicity of the newly identified variant(s) by functional studies.
timeFrame: three years
Locations:
city: Rome
country: Italy
facility: Istituto Superiore di Sanità-Dpt. Oncology and Molecular Medicine
Study officials:
affiliation: Istituto Superiore di Sanità
name: Viviana Cordeddu, PhD
role: PRINCIPAL_INVESTIGATOR
References: