Identification and population history of CYP4V2 mutations in patients with Bietti crystalline corneoretinal dystrophy

To identify known and novel CYP4V2 mutations in patients with Bietti crystalline cornea (BCD), expand the spectrum of CYP4V2 mutations, and characterize the population history of the c.802-8-810del17insGC mutation common in Asian populations, genomic DNA was isolated from peripheral blood samples from 58 unrelated patients with clinical diagnoses of BCD. Exons and flanking intronic regions of the CYP4V2 gene were dideoxy DNA sequenced. Nonpathogenic polymorphisms were excluded and known mutations were identified by sequencing 192 unaffected individuals from similar ethnic backgrounds and examination of online databases. The age of the c.802-8-810del17insGC mutation was estimated using three independent approaches. A total of 28 CYP4V2 mutations, 9 of which were novel, were detected in the 58 patients with BCD. These included 19 missense, 4 nonsense, 2 deletion, 2 splice site, and 1 insertion-deletion mutations. Two missense variants of uncertain significance were also detected. The age of the c.802-8-810del17insGC mutation was estimated to be 1040-8200 generations in the Chinese and 300-1100 generations in the Japanese populations. These results expand the mutation spectrum of CYP4V2, and provide insight into the origin of the c. 802-8-810del17insGC mutation in the Chinese population and its transmission to the Japanese population.