TSPAN12 – Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disorder characterized by incomplete peripheral retinal vascularization and a highly variable clinical course. Mutations in TSPAN12, a component of the Norrin–β-catenin signaling complex, are causative for both autosomal dominant and autosomal recessive forms of FEVR (PMID:20159111; PMID:22427576). Variants cluster in the extracellular loop and transmembrane domains, consistent with a role in ligand–receptor assembly.

Genetic Evidence

TSPAN12 variants have been identified in multiple unrelated probands with FEVR, with over 100 cases reported across diverse populations. A large linkage study identified pathogenic missense substitutions segregating in five of 11 families in two Dutch pedigrees, demonstrating autosomal-dominant inheritance (PMID:20159111). Recessive cases have been documented in severely affected sibships carrying homozygous or compound heterozygous alleles, with single-allele carriers exhibiting milder or no retinal changes (PMID:22427576).

Variants include missense changes (e.g., c.668T>C (p.Leu223Pro)), start-codon and splice-site mutations, nonsense and frameshift alleles, as well as large exon deletions. Digenic occurrences with FZD4 and LRP5 have further highlighted modifier effects on phenotype severity (PMID:28211206).

Functional Evidence

In vitro luciferase reporter assays show that TSPAN12 missense and truncating variants fail to activate Norrin–β-catenin signaling, confirming a loss-of-function mechanism (PMID:21552475). Mouse models lacking Tspan12 recapitulate delayed retinal vascular outgrowth and reduced endothelial proliferation in the superficial vascular plexus, affirming the gene’s role in angiogenesis (PMID:22394677).

Clinical Correlation & Utility

Segregation analysis in a three-generation Chinese pedigree demonstrated co-segregation of a heterozygous exon 7 deletion in four additional affected relatives, supporting pathogenicity (affected_relatives: 4) (PMID:36980859). Carrier screening of TSPAN12 enables early diagnosis of peripheral vascular anomalies even in asymptomatic adults, guiding surveillance and timely intervention to preserve vision.

Key Take-home: TSPAN12 mutations disrupt Norrin–β-catenin signaling, unequivocally cause FEVR, and warrant inclusion in genetic testing panels to inform diagnosis, prognosis, and family counselling.

References

• Ophthalmic Genetics • 2014 • Familial exudative vitreoretinopathy caused by a homozygous mutation in TSPAN12 in a cystic fibrosis infant. PMID:23834558
• American Journal of Human Genetics • 2010 • Next‐generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. PMID:20159111
• Molecular Vision • 2011 • Novel TSPAN12 mutations in patients with familial exudative vitreoretinopathy and their associated phenotypes. PMID:21552475
• Investigative Ophthalmology & Visual Science • 2012 • Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR). PMID:22427576

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