CTNNB1 – Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disorder characterized by incomplete peripheral retinal vascularization, neovascular proliferation, and risk of retinal detachment. CTNNB1 encodes β-catenin, a core effector of the Norrin/β-catenin signaling pathway crucial for retinal angiogenesis. Heterozygous loss-of-function variants in CTNNB1 disrupt this pathway, leading to FEVR and variable extra-ocular manifestations such as microcephaly.

1. Clinical Validity

The gene–disease association is classified as Strong. Heterozygous truncating CTNNB1 variants have been identified in at least 17 unrelated probands across independent cohorts: 6 families in a 59-family FEVR case series ([PMID:34582765]), 8 families among 763 FEVR pedigrees (1.05%) ([PMID:36790797]), and multiple de novo frameshift/stop variants in 3 infants with FEVR ([PMID:32039639],[PMID:39647854]). Functional concordance in endothelial assays and animal models further supports pathogenicity.

2. Genetic Evidence

Mode of inheritance is Autosomal dominant. There are 0 additional affected relatives with segregating variants, as most cases arose de novo without family history. Case reports describe novel heterozygous frameshift variants: c.2046_2047del (p.Lys625ArgfsTer16) ([PMID:32039639]), c.1903G>T (p.Gly635Ter) with maternal mosaicism ([PMID:39647854]), and c.603_605delinsAATA (p.Met202IlefsTer6) ([PMID:35880249]). Multi-patient cohorts identified truncating and damaging missense CTNNB1 variants in 14 families. Variants cluster in the C-terminal domain, indicating haploinsufficiency as the likely mechanism.

3. Functional Evidence

C-terminal frameshift variants induce unstable truncated β-catenin prone to AXIN1-mediated condensate formation, resulting in impaired Norrin/β-catenin signaling, reduced endothelial proliferation, and compromised junctional integrity in primary human retinal microvascular endothelial cells. LiCl or proteasome inhibition rescues signaling and barrier function, confirming loss-of-function mechanism ([PMID:38096938]).

4. Integration & Clinical Utility

Collectively, robust genetic and experimental data demonstrate that heterozygous CTNNB1 truncating variants cause autosomal dominant FEVR. Genetic testing for CTNNB1 should be included in diagnostic panels for FEVR, particularly in sporadic cases or those with extra-ocular features. Early identification enables surveillance for retinal neovascular complications and tailored management.

Key Take-home: CTNNB1 loss-of-function variants reliably predict autosomal dominant FEVR, supporting their use in molecular diagnosis and guiding retinal surveillance.

References

• Ophthalmic genetics • 2020 • Novel mutation in CTNNB1 causes familial exudative vitreoretinopathy (FEVR) and microcephaly: case report and review of the literature. PMID:32039639
• Ophthalmic genetics • 2024 • Highly asymmetric early presentation of FEVR requiring enucleation. PMID:39647854
• American journal of human genetics • 2017 • Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR PMID:28575650
• Investigative ophthalmology & visual science • 2023 • Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations. PMID:36790797
• Journal unknown • 2021 • To characterize ocular phenotypes in patients with CTNNB1, KIF11, or NDP variants. PMID:34582765
• International journal of biological macromolecules • 2024 • Frameshift variants in the C-terminal of CTNNB1 cause familial exudative vitreoretinopathy by AXIN1-mediated ubiquitin-proteasome degradation condensation. PMID:38096938

Evidence Based Scoring (AI generated)