Variants in RCBTB1 are Associated with Autosomal Recessive Retinitis Pigmentosa but Not Autosomal Dominant FEVR.

Purpose: Variants in RCBTB1 have been reported in autosomal recessive inherited retinal dystrophies and autosomal dominant familial exudative vitreoretinopathy (FEVR). This study aims to verify the correlation between RCBTB1 variations and phenotypes.
Methods: Variants in RCBTB1 were selected from 6303 unrelated families with different forms of eye conditions based on whole exome sequencing and targeted exome sequencing. Potential pathogenic truncation variants were filtered by multistep bioinformatics analysis and identified by Sanger sequencing. Segregation and enrichment analysis were used to evaluate the association of truncation variants in RCBTB1 with phenotypes.
Results: Biallelic damaging variants in RCBTB1 were found in one family while heterozygous truncation variants were detected in 28 unrelated families based on our in-house data from 6303 unrelated families. Totally, 11 variants were present in the 29 families, including seven frameshift variants, three splicing variants, and one nonsense variant. The biallelic variants, c.170delG and c.905_906insTT, were identified in an isolated case with retinitis pigmentosa (RP). Heterozygous truncation variants were distributed in different forms of eye conditions (including normal) without significant enrichment in FEVR, suggesting unrelatedness to specific eye diseases. The frequency and location of truncation variants in the 6303 samples are comparable with the East Asian data from gnomAD. Segregation analysis of available family members further demonstrated the nonpathogenic nature of heterozygous truncation variants.
Conclusions: Contrary to the previous report, heterozygous truncation variants in RCBTB1 are not associated with FEVR based on our data. The extreme rareness of biallelic truncation variants present in a singleton case with RP further suggests that variants in RCBTB1 are responsible for autosomal recessive RP. This result reminds us that variants of a gene with certain diseases should be thoroughly verified before the use of such information in clinical practice.