Researchers investigating the genetic causes of familial exudative vitreoretinopathy (FEVR) in a Korean clinical study have found that patients with TSPAN12 large deletions appear to be more common than patients with single nucleotide variants in the same gene. The finding, if representative of the rare disorder, may suggest that clinical evaluation in new suspect cases should include analysis for large deletions and duplications in the TSPAN12, and potentially other, FEVR associated genes. According to the authors of the study, including a broader array of potential genetic origins is likely to improve diagnostic accuracy and clinical management.
FEVR is generally described as a rare disorder however, the actual prevalence of the disease is not clear. Diagnosis of FEVR is generally based on the taking of an accurate family history and on the existence of bilateral peripheral retinal avascularity and scleral indentation, assessed by fundus fluorescein angiography. Clinical management may involve prophylactic cryotherapy or argon laser photocoagulation, in addition to treatment similar to that for retinal holes. Autosomal dominant inheritance is the most common form of the disorder and the disease has been shown to be associated with the FZD4, LRP5, ZNF408, KIF11 and TSPAN12 genes.
The present study, conducted by researchers from the Seoul National University College of Medicine, and Seoul National University Hospital, examined thirty-three Korean FEVR patients who had previously being screened, and found negative, for known TSPAN12 mutations, and negative for mutations in other FEVR-associated genes, including NDP, FZD4, LRP5. The cohort was also ruled out for large deletions and duplications of NDP, FZD4, and LRP5. Despite the clinical diagnosis of FEVR, no known mutations or gene lesions were identifiable until, in three of thirty-three patients, a large TSPAN12 deletion was detected. In two of the patients a whole-gene deletion of TSPAN12 was observed, while the third patient harboured a deletion in exon 4 of the TSPAN12 gene. Interestingly, the clinical FEVR phenotype in the three patients was not more severe than in a patient with a TSPAN12 point mutation. In other words, the patients in this study had a similar outcome whether they lost the entire TSPAN12 gene, or had a single base-pair change in that gene. In concluding their study, the Korean research team commented that, “large deletion/duplication analyses of TSPAN12 should be taken into consideration and evaluated in routine genetic workups for FEVR patients as gene dosage abnormalities and copy number variation of FEVR-related genes may be more prevalent than originally suspected”.