Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients

Abstract

BackgroundThe genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.MethodsA total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.ResultsWe successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.ConclusionsEast Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

Systematic detection of Mendelian and non-Mendelian variants associated with retinitis pigmentosa by genome-wide association study

“…To search for undetected genetic risks contributing to ARRP, we carried out a meta-GWAS using two independent data sets (Table S1). Of the 644 cases and 620 controls genotyped in the first GWAS, 432 cases and 603 controls were used for analysis after removing 63 cases and 21 controls that failed quality control (QC) and an additional 149 "solved" cases in which targeted re-sequencing identified pathogenic mutations to account for the cause of disease 11 . Similarly, after removing 14 cases and 13 controls that failed QC and excluding 78 cases genetically solved with targeted re-sequencing 11 , the second GWAS included 208 cases and 287 controls.…”

“…Subsequent conditional analysis of the EYS locus detected 3 independent genome-wide significant signals (P < 5.0x10 -8 ; Peaks 1 -3 in the order of significance, Table 1 and Figure 1B). We then checked the associations of the most significant variants (lead variants), tagging each locus and nonsynonymous and splice site variants in the 640 cases using the targeted re-sequencing results 11 . While Peak 1 and Peak 3 were each linked to a low frequency variant (AF < 0.05), Peak 2 was associated with a common nonsynonymous variant.…”

“…More specifically, Peak 1 (rs76960013, allele frequency (AF) = 0.0414, odds ratio (OR) = 3.95, P = 1.18x10 -13 ) was in linkage disequilibrium (LD; r 2 = 0.68) with c.2528G>A (p.G843E; hereafter termed G843E; Table 1). G843E with an AF (0.0171) unusually high for ARRP has been described in conflicting ways in past reports, as having uncertain significance 23 , being non-pathogenic 24 , possibly being pathogenic (although without sufficient supporting evidence) 25 , and was unreported in the two largest genetic screening projects targeting Japanese RP patients 9,11 .…”

“…The second peak, with much higher allele frequency and lower OR (Peak 2; rs59178556, AF = 0.2161, OR = 1.83, P = 3.79 x10 -10 ), was in strong LD (r 2 = 0.97) with a common nonsynonymous variant, i.e., c.7666A>T (p.S2556C; hereafter termed S2556C variant; Table 1) registered as benign/likely benign in the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). Peak 3 (rs79476654, AF = 0.0005, OR = 16.46, P = 2.45x10 -8 ) was in LD (r 2 = 0.78) with c.4957dupA (p.S1653Kfs*2) (hereafter termed S1653Kfs; Table 1), recognized as a founder AR mutation 11 . It was detected even after removing solved cases with biallelic EYS mutations (including homozygotes and compound heterozygotes with S1653Kfs) screened by target resequencing prior to GWAS, because a large number of heterozygous carriers of S1653Kfs mutation remained genetically unsolved 9,11,24 .…”

“…However, despite numbers of reports of non-Mendelian inheritance causing RP, its significance in the context of overall genetic pathology of the disease is yet to be demonstrated. In Japan, the genetic basis of RP remains unknown in up to 70% of cases even after targeted re-sequencing, whole-exome sequencing, or whole-genome sequencing 4,11,12,13 . There is an urgent need for genetic diagnosis of these unsolved cases, particularly those with the autosomal recessive (AR) inheritance pattern of RP (ARRP), caused by lossof-function mutations, because such patients may be amenable to adeno-associated virus (AAV)-mediated gene supplementation therapy 14 .…”