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Gene Variant Spectrum in Probands With Familial Exudative Vitreoretinopathy Using an Expanded Panel
Sarah van der Ende1, Karen Bedard2, Karin Wallace3
1Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
Investigative Ophthalmology & Visual Science
|February 7, 2025
Summary
Genetic testing for familial exudative vitreoretinopathy (FEVR) identified disease-causing variants (DCVs) in nearly half of patients. Four key FEVR genes were most commonly implicated, highlighting the need for further research into rarer genes.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Familial exudative vitreoretinopathy (FEVR) is a genetic disorder affecting retinal vascular development.
- Accurate genetic diagnosis is crucial for understanding FEVR's complex etiology and inheritance patterns.
Purpose of the Study:
- To comprehensively investigate the spectrum of gene variants in patients diagnosed with FEVR.
- To identify disease-causing variants (DCVs) using an expanded gene panel.
Main Methods:
- Enrolled 94 probands with FEVR and their relatives, collecting clinical data and DNA.
- Utilized targeted next-generation sequencing and Sanger sequencing with an expanded FEVR panel (6 recognized genes + 19 associated genes).
- Classified variants according to American College of Medical Genetics and Clinical Genome Resource Sequence Variant Interpretation (ClinGen SVI) recommendations.
Main Results:
- Achieved molecular diagnosis in 39 (41.5%) probands, with most having a single DCV.
- Identified 33 DCVs in four primary FEVR genes (LRP5, FZD4, TSPAN12, NDP), and 8 DCVs in associated genes (KIF11, LAMA1, DOCK6).
- Reclassification of variants using updated criteria impacted 5.3% of probands, changing classifications from likely pathogenic to variants of uncertain significance.
Conclusions:
- An expanded FEVR gene panel successfully detected DCVs in a significant portion of the cohort.
- Four FEVR genes are responsible for the majority of identified cases.
- Further investigation is warranted for the role of rare FEVR genes and candidate genes in disease pathogenesis.
