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Jianhuan Chen, Hongjuan Wang; Loss of function variants in retinitis pigmentosa genes in NHLBI GO Exome Sequencing Project. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2755.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is a group of hereditary retinal diseases characterized by progressive degeneration of rod and cone photoreceptors. Autosomal recessive RP (arRP) and autosomal dominant RP (adRP) are two common forms of RP. Up to date, mutations that caused adRP or arRP have been reported in at least 70 genes, among which lost of function (LOF) mutations could lead to severe clinical manifestations. However, it remains unclear how LOF variants of RP genes exist in the general population.
All LOF variants including stop-gained, frameshift and splice-site variants were retrieved from the NHLBI GO Exome Sequencing Project (ESP version ESP6500, http://evs.gs.washington.edu/EVS), which consists of more than 6,500 exomes sequenced from Non-RP individuals. These variants were further annotated using Variant Effect Predictor (http://ensembl.org/Homo_sapiens/Tools/VEP). Previously reported LOF variants were identified using ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/). As the ESP samples are not provided with gender information, only autosomal casual genes of RP were analyzed, including 23 adRP genes and 47 arRP genes. Chi-squared test was used in the statistical analysis.
A total of 255 LOF variants were found in arRP and adRP genes. Among the 70 RP genes, 55 (78.57%) of them had at least one LOF variant, and 23 (32.86%) had at least one homozygous LOF variant. In particular, the fraction of genes with LOF variants was significantly smaller in pre-mRNA processing factor genes compared to that in other RP genes in the current study (P=0.017). The percentage of genes with no LOF variant was 34.78% and 14.89% for adRP and arRP genes respectively, suggesting a lower tolerance to LOF variants in adRP genes compared to that in arRP genes. In addition, 30 LOF variants were reported in previous studies to cause autosomal recessive diseases, confirming the existence of recessive mutation carriers in the general population.
In conclusion, the current study reveals the existence of LOF variants in most adRP and arRP genes in the ESP database, including previously reported pathogenic mutations. A high fraction of adRP genes with LOF variants were found, suggesting that it remains a challenge to understand the role of these LOF variants in RP and its related diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
Distribution of RP genes with different number of LOF variants
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