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fevr [2026/09/17 12:57] – Scott Larsonfevr [2026/09/17 13:00] (current) – [Downloadable Resources] Scott Larson
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     * Chromosome Location: 3p22.1     * Chromosome Location: 3p22.1
  
-===== Genetics, Testing, and Screening ===== +===== Genotype–Phenotype Correlation ======
- +
-==== Genotype–Phenotype Correlation =====+
 A genotype–phenotype correlation exists in FEVR but is **imperfect**, limited by marked intra- and interfamilial variability and incomplete penetrance. The strongest signal (systematic review/meta-analysis of >3,200 individuals) is that **disease severity tracks with the position of the mutated gene in the Norrin/β-catenin signaling cascade**: **NDP > FZD4 > LRP5 > TSPAN12** (Wang et al., PLoS One, 2021). NDP (Norrin ligand) and FZD4 (receptor) are obligatory for pathway activation and produce the most severe phenotypes; LRP5 (co-receptor) and TSPAN12 (auxiliary complex) are non-decisive and yield milder disease. A genotype–phenotype correlation exists in FEVR but is **imperfect**, limited by marked intra- and interfamilial variability and incomplete penetrance. The strongest signal (systematic review/meta-analysis of >3,200 individuals) is that **disease severity tracks with the position of the mutated gene in the Norrin/β-catenin signaling cascade**: **NDP > FZD4 > LRP5 > TSPAN12** (Wang et al., PLoS One, 2021). NDP (Norrin ligand) and FZD4 (receptor) are obligatory for pathway activation and produce the most severe phenotypes; LRP5 (co-receptor) and TSPAN12 (auxiliary complex) are non-decisive and yield milder disease.
  
-=== Gene-specific features ===+==== Gene-specific features ====
  
 ^ Gene ^ Frequency ^ Severity / hallmark ^ Distinguishing features ^ ^ Gene ^ Frequency ^ Severity / hallmark ^ Distinguishing features ^
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   * Molecular diagnosis achieved in only **~40–50%** of clinically diagnosed cases.   * Molecular diagnosis achieved in only **~40–50%** of clinically diagnosed cases.
  
-==== 2. Genetic Testing and Family Screening (Newly Diagnosed FEVR) ====+===== Genetic Testing and Family Screening (Newly Diagnosed FEVR) =====
  
 Both **genetic testing of the proband** and **clinical/angiographic screening of at-risk relatives** are recommended. They are complementary: a molecular diagnosis enables cascade testing and counseling, but because a causative variant is found in only ~40–50% of probands, **a negative genetic test does not exclude familial disease**, and imaging-based screening of relatives remains essential. Both **genetic testing of the proband** and **clinical/angiographic screening of at-risk relatives** are recommended. They are complementary: a molecular diagnosis enables cascade testing and counseling, but because a causative variant is found in only ~40–50% of probands, **a negative genetic test does not exclude familial disease**, and imaging-based screening of relatives remains essential.
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   * Counsel that FEVR is **progressive and lifelong**; provide genetic counseling for recurrence risk and reproductive planning.   * Counsel that FEVR is **progressive and lifelong**; provide genetic counseling for recurrence risk and reproductive planning.
  
-==== 3. Pediatric Screening Age and Examination Under Anesthesia (EUA) ====+===== Pediatric Screening Age and Examination Under Anesthesia (EUA) =====
  
 **Screening should begin at birth** (neonatal fundus exam) for at-risk infants, because severe FEVR—especially LRP5- and NDP-associated—is frequently present at birth and can progress rapidly; onset before age 3 carries the worst prognosis. No formal FEVR-specific society schedule was identified; recommendations reflect expert-center practice. **Screening should begin at birth** (neonatal fundus exam) for at-risk infants, because severe FEVR—especially LRP5- and NDP-associated—is frequently present at birth and can progress rapidly; onset before age 3 carries the worst prognosis. No formal FEVR-specific society schedule was identified; recommendations reflect expert-center practice.
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 ===== References ===== ===== References =====
  
 +  - [[https://docs.eyefixer.org/vault/Retina/Inherited%20Retinal%20Disease/Autosomal%20Dominant%20Vitreoretinopathy%20Ober_1980.pdf |Autosomal dominant exudative vitreoretinopathy. Ober et al. 1980]]
 +  - [[https://docs.eyefixer.org/vault/Retina/Inherited%20Retinal%20Disease/Familial%20Exudative%20Vitreoretinopathy%20and%20Related%20Retinopathies.pdf |Familial exudative vitreoretinopthy and related retinopathies. Gilmour DF. 2015]]
   - [[https://pubmed.ncbi.nlm.nih.gov/?term=Genotype-phenotype+associations+familial+exudative+vitreoretinopathy+systematic+review+meta-analysis|Wang X, et al. Genotype-phenotype associations in FEVR: a systematic review and meta-analysis on >3200 individuals. PLoS One. 2021]]   - [[https://pubmed.ncbi.nlm.nih.gov/?term=Genotype-phenotype+associations+familial+exudative+vitreoretinopathy+systematic+review+meta-analysis|Wang X, et al. Genotype-phenotype associations in FEVR: a systematic review and meta-analysis on >3200 individuals. PLoS One. 2021]]
   - [[https://pubmed.ncbi.nlm.nih.gov/?term=Genotype-Phenotype+Spectrum+eyeGENE+Familial+Exudative+Vitreoretinopathy+Norrin+beta-catenin|Yaylacioglu Tuncay F, et al. Genotype-phenotype spectrum of eyeGENE patients with FEVR. Invest Ophthalmol Vis Sci. 2025]]   - [[https://pubmed.ncbi.nlm.nih.gov/?term=Genotype-Phenotype+Spectrum+eyeGENE+Familial+Exudative+Vitreoretinopathy+Norrin+beta-catenin|Yaylacioglu Tuncay F, et al. Genotype-phenotype spectrum of eyeGENE patients with FEVR. Invest Ophthalmol Vis Sci. 2025]]
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-===== Downloadable Resources ===== 
-  * [[https://docs.eyefixer.org/vault/Retina/Inherited%20Retinal%20Disease/Autosomal%20Dominant%20Vitreoretinopathy%20Ober_1980.pdf |Autosomal dominant exudative vitreoretinopathy. Ober et al. 1980]] 
-  * [[https://docs.eyefixer.org/vault/Retina/Inherited%20Retinal%20Disease/Familial%20Exudative%20Vitreoretinopathy%20and%20Related%20Retinopathies.pdf |Familial exudative vitreoretinopthy and related retinopathies. Gilmour DF. 2015]] 
  
 {{tag>syndrome}} {{tag>syndrome}}