Submission Details

CYP4V2 was first reported in relation to Bietti crystalline corneoretinal dystrophy (BCD) in 2004 (Li et al, PMID 15042513). Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessively inherited disorder characterized by the presence of multiple shimmering yellow-white deposits in the posterior pole of the retina in association with atrophy of the retinal pigment epithelium (RPE) and chorioretinal atrophy (Garcia-Garcia et al, 2019, PMID PMID: 31440027). Over 60 variants in CTP4V2 in patients with BCD have been reported (Ng et al, 2016, PMID 27228076; Garcia-Garvia et al, 2019, PMID PMID: 31440027). The mechanism of pathogenicity is loss of function. This curation includes six variants (nonsense, missense, small deletion) in 44 probands from 3 publications (Lin et al, 2005, PMID 15937078; Xie et al, 2020, PMID 33306817; Murakami et al, 2021, PMID 33636399). One of these variants curated, c.802-8_810delinsGC, is the most common variant in East Asian individuals with BCD. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by RT-PCR data showing highest expression in retina (Li et al, 2004; PMID 150425130), functional studies of CYP4V2 variants (Nakano et al, 2012, PMID 22772592; Hata et al, 2018, PMID 29581279) and the features noted in a knockout mouse model (Lockhart et al, 2014, PMID 25118264). In summary, CYP4V2 is definitively associated with Bietti crystalline corneoretinal dystrophy, inherited in an autosomal recessive manner. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on April 1st, 2021.