To identify genetic variants for the development and progression of keratoconus using Whole Exome Sequencing and Whole Genome Sequencing approaches on keratoconus families with index patients originating from the Rotterdam Eye Hospital and Erasmus…
ID
Source
Brief title
Condition
- Anterior eye structural change, deposit and degeneration
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Genomic DNA will be extracted from saliva and/or blood according to standard
protocols. Genetic sequencing will be performed
according to standard protocols and quality control of the Erasmus MC Human
Genomics Facility HuGe-F. We will perform an
extensive quality control procedure which includes filtering on coverage (>10x)
and quality of the detection variants. Next, we will
annotate the variants using wAnnovar (wANNOVAR (wglab.org)).
Segregation analysis will be performed, with cases being carriers and controls
being non-carriers. We will look for variants
shared across families and/or within each family, and we will evaluate these
variants based on the biological information
available to us such as the gene function and involvement with other diseases.
This will help us identify the most likely causal
variants.
In case of a suspected autosomal dominant inheritance pattern, we will focus on
heterozygous variants. In case of a recessive
inheritance pattern, we will focus on homozygous variants which are present in
a heterozygous manner in the parents. As a first
step, we will employ a candidate-gene approach using a panel of genes which
previously have been associated with
keratoconus. This will be followed by an open exome approach to identify new
genes.
To identify causal variants, we will perform a prioritization procedure using
an allele frequency cut-off (<1%) in control databases
such as gnomAD v3.1.2., GoNL (https://www.nlgenome.nl/) and TOPMed
(https://topmed.nhlbi.nih.gov/). We will also assess the
pathogenicity using several in silico prediction tools implemented in several
annotation programs such as SIFT 6.2.1,
PolyPhen-2, MutationTaster2021 and CADD v1.6. All variants will be confirmed
using sanger sequencing and segregation
analysis in other family members
Secondary outcome
Following ophthalmic imaging with Pentacam and Corvis, assessment of the scans
will be performed using topographical maps
and a selection of parameters provided by the default setting of the Pentacam
and Corvis. Examples of such parameters are the
degree of astigmatism, K1, K2, Kmax, final D and thinnest pachymetry. Corvis
scans will also be analyzed in a similar fashion.
For the assessment of the association of environmental and genetic risk
factors, an analysis of lifestyle, ocular history and
systemic involvement will be performed.
Estimation of the heritability of corneal morphologic features as measured by
Pentacam and Corvis will be performed, and an
analysis of the morphologic features of the corneas of non-affected family
members of keratoconus patients will also be carried
out.
The association of corneal parameters (measured be Corvis or Pentcaam) with
specific genetic variants will be assessed as a
part of this study as well.
Background summary
Keratoconus is one of the most prevalent corneal disorders, leading to visual
deterioration and necessitating in many cases corneal surgery. Multifactorial
pathophysiology including both genetic and environmental factors is suspected.
Currently, keratoconus is one of the most frequent indications for corneal
transplantation (keratoplasty). Although keratoplasty is an effective
treatment, it is a very intensive, time-consuming and expensive treatment
modality. Relatively little is known about the causes and pathophysiology of
keratoconus. There is evidence for a multifactorial etiology, including complex
interactions of genetically determined mechanisms and environmental factors. In
the meantime, the majority of genes and mutations involved still remain to be
identified. By identifying new genes and mutations, more insight may be gained
into the causal effects or mechanisms of some of the implicated environmental
factors, as per further elucidating the molecular pathways involved. These
findings can eventually aid in early prediction and prevention of keratoconus.
Study objective
To identify genetic variants for the development and progression of keratoconus
using Whole Exome Sequencing and Whole Genome Sequencing approaches on
keratoconus families with index patients originating from the Rotterdam Eye
Hospital and Erasmus Medical Center
Study design
Case-control family-based study.
Study burden and risks
There is no direct benefit or compensation for participation, and besides some
negligible or rare complications which are
associated with blood withdrawal, there is no major burden or risk for
participants.
Ophthalmic measurements and WES or WGS will be performed for research purposes.
Incidental ophthalmic, karyotypic or
Genetic findings which are deemed by the researchers to be relevant for the
patient or their families will be communicated with
the family physician and/or treating ophthalmologist as per the informed
consent granted by every participant.
Dr Molewaterplein 40
Rotterdam 3015GD
NL
Dr Molewaterplein 40
Rotterdam 3015GD
NL
Listed location countries
Age
Inclusion criteria
Keratoconus patients suspect of monogenetic course of disease and their healthy
and affected family members
Exclusion criteria
keratoconus, non familial course
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL82389.078.22 |