We read with interest the article entitled “Whole-exome sequencing identifies
OR2W3 mutation as a cause of autosomal dominant retinitis pigmentosa” by Ma et al.,
1 who described a novel missense mutation (c.C424T/p.R142W) in
OR2W3 as a potentially causative mutation for autosomal dominant retinitis pigmentosa (RP) in two Chinese families.
Retinitis pigmentosa is an inherited retinal disease with an incidence of approximately 1 in every 3000 to 5000 people.
2,3 Due to the rarity of RP, the frequency of a high-penetrance mutation associated with autosomal dominant RP should be very low in the general population, and should certainly not exceed the incidence of RP. However, the variant (rs189993261, c.C424T/p.R142W in
OR2W3) has been reported to have a minor allele frequency of 2/1008 and 4/8652 in East Asians in the 1000 Genomes Project database
4 and Exome Aggregation Consortium (ExAC) database,
5 respectively. The minor allele frequency of the variant in Chinese (1/206, 0.005) has been reported to reach the threshold of low-frequency variants in the 1000 Genomes Project database.
4 The region with the p.R142W variant is not conserved in mammals (see
Figure). Further, computational prediction of the variant using dbNSFP database does not support it as a deleterious mutation (see
Table).
6
The results of allele frequency, protein conservation, and bioinformatics analyses suggest that the variant (rs189993261, c.C424T/p.R142W) in
OR2W3 is likely to be a single nucleotide polymorphism, but that it is not causative on its own. Although the variant has been reported to be cosegregated with RP in a large Chinese family,
1 the possibility of linkage disequilibrium between the variant and the potential causative mutation should be further considered. Whether variants in
OR2W3 have any bearing on the development of RP remains undetermined.