Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients

You Na Kim, Joon Seon Song, Seak Hee Oh, Yoon Jeon Kim, Young Hee Yoon, Eul-Ju Seo, Chang Ahn Seol, Sae-Mi Lee, Jong-Moon Choi, Go Hun Seo, Changwon Keum, Beom Hee Lee, Joo Yong Lee, You Na Kim, Joon Seon Song, Seak Hee Oh, Yoon Jeon Kim, Young Hee Yoon, Eul-Ju Seo, Chang Ahn Seol, Sae-Mi Lee, Jong-Moon Choi, Go Hun Seo, Changwon Keum, Beom Hee Lee, Joo Yong Lee

Abstract

Due to the genotype-phenotype heterogeneity in retinitis pigmentosa (RP), molecular diagnoses and prediction of disease progression is difficult. This study aimed to report ocular and genetic data from Korean patients with PDE6B-associated RP (PDE6B-RP), and establish genotype-phenotype correlations to predict the clinical course. We retrospectively reviewed targeted next-generation sequencing or whole exome sequencing data for 305 patients with RP, and identified PDE6B-RP in 15 patients (median age, 40.0 years). Amongst these patients, ten previously reported PDE6B variants (c.1280G > A, c.1488del, c.1547T > C, c.1604T > A, c.1669C > T, c.1712C > T, c.2395C > T, c.2492C > T, c.592G > A, and c.815G > A) and one novel variant (c.712del) were identified. Thirteen patients (86.7%) experienced night blindness as the first symptom at a median age of 10.0 years. Median age at diagnosis was 21.0 years and median visual acuity (VA) was 0.20 LogMAR at the time of genetic analysis. Nonlinear mixed models were developed and analysis revealed that VA exponentially decreased over time, while optical coherence tomography parameters linearly decreased, and this was related with visual field constriction. A high proportion of patients with the c.1669C > T variant (7/9, 77.8%) had cystoid macular edema; despite this, patients with this variant did not show a higher rate of functional or structural progression. This study will help clinicians predict functional and structural progression in patients with PDE6B-RP.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Pedigrees of 15 Korean patients from 14 families who had retinitis pigmentosa associated with PDE6B variants.
Figure 2
Figure 2
Typical ophthalmologic findings in patients with retinitis pigmentosa. From top to bottom: fundus photography images, fundus autofluorescence images, optical coherence tomography images, Goldmann kinetic visual field test results, and electroretinograms (from top to bottom) are shown for two patients, (a) Subject No. 2-III-2, a young patient with cystoid macular edema, and (b) Subject No. 9-II-3, a patient with advanced disease associated with diffuse foveal atrophy.
Figure 3
Figure 3
Fundus autofluorescence and optical coherence tomography images from patients homozygous for the c.1669C > T missense variant; images are ordered based on patient age. (a) Color fundus photography images showing the progression of pigmentary changes with age, from sparse mid-peripheral pigmentation in younger patients to coarse pigmentation invading the macula in older patients. (b) Fundus autofluorescence images showing a bull’s eye pattern of autofluorescence. (c) On optical coherence tomography images, perifoveal retinal pigment epithelium atrophy with a spared foveal anatomy and cystoid macular edema is apparent in younger patients. Diffuse neurosensory and retinal pigment epithelium atrophy involving the fovea can be observed in older patients. (d) Progressive visual field constriction with aging.
Figure 4
Figure 4
Trends in visual function and retinal morphology with disease progression; analysis based on the application of nonlinear mixed models. (a) Deterioration of visual acuity. (b) Constriction of the visual field. (c) Reduction in the width of the inner segment/outer segment (IS/OS) band. (d) Reduction in outer nuclear layer (ONL) thickness. (e) Changes in central retinal thickness (CRT). MD mean deviation.

References

    1. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368:1795–1809. doi: 10.1016/s0140-6736(06)69740-7.
    1. Stephen P. Daiger, P., Lori S. Sullivan, P. & Sara J. Bowne, P. RetNet: Retinal Information Network. (1996).
    1. Kim MS, et al. Genetic mutation profiles in Korean patients with inherited retinal diseases. J. Korean Med. Sci. 2019;34:e161. doi: 10.3346/jkms.2019.34.e161.
    1. Oishi M, et al. Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing. Investig. Ophthalmol. Vis. Sci. 2014;55:7369–7375. doi: 10.1167/iovs.14-15458.
    1. Stryer L. Vision: from photon to perception. Proc. Natl. Acad. Sci. USA. 1996;93:557–559. doi: 10.1073/pnas.93.2.557.
    1. McLaughlin ME, Ehrhart TL, Berson EL, Dryja TP. Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. Proc. Natl. Acad. Sci. USA. 1995;92:3249–3253. doi: 10.1073/pnas.92.8.3249.
    1. Yeo JH, et al. Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases. Investig. Ophthalmol. Vis. Sci. 2019;60:1519–1526. doi: 10.1167/iovs.18-25556.
    1. Tsang SH, et al. Transgenic mice carrying the H258N mutation in the gene encoding the beta-subunit of phosphodiesterase-6 (PDE6B) provide a model for human congenital stationary night blindness. Hum. Mutat. 2007;28:243–254. doi: 10.1002/humu.20425.
    1. Sorrentino FS, Gallenga CE, Bonifazzi C, Perri P. A challenge to the striking genotypic heterogeneity of retinitis pigmentosa: a better understanding of the pathophysiology using the newest genetic strategies. Eye. 2016;30:1542–1548. doi: 10.1038/eye.2016.197.
    1. Glockle N, et al. Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. Eur. J. Hum. Genet. 2014;22:99–104. doi: 10.1038/ejhg.2013.72.
    1. Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015;17:405–424. doi: 10.1038/gim.2015.30.
    1. Khateb S, et al. Longitudinal clinical follow-up and genetic spectrum of patients with rod-cone dystrophy associated with mutations in PDE6A and PDE6B. JAMA Ophthalmol. 2019;137:669–679. doi: 10.1001/jamaophthalmol.2018.6367.
    1. Na K-H, et al. Prevalence, age at diagnosis, mortality, and cause of death in Retinitis Pigmentosa in Korea—a nationwide population-based study. Am. J. Ophthalmol. 2017;176:157–165. doi: 10.1016/j.ajo.2017.01.014.
    1. Iftikhar M, et al. Classification of disease severity in retinitis pigmentosa. Br. J. Ophthalmol. 2019;103:1595–1599. doi: 10.1136/bjophthalmol-2018-313669.
    1. Huang XF, et al. Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing. Genet. Med. 2015;17:271–278. doi: 10.1038/gim.2014.138.
    1. Verbakel SK, et al. Non-syndromic retinitis pigmentosa. Prog. Retin. Eye Res. 2018;66:157–186. doi: 10.1016/j.preteyeres.2018.03.005.
    1. Bu SC, Kuijer R, Li XR, Hooymans JM, Los LI. Idiopathic epiretinal membrane. Retina. 2014;34:2317–2335. doi: 10.1097/iae.0000000000000349.
    1. Liew G, et al. Prevalence of cystoid macular oedema, epiretinal membrane and cataract in retinitis pigmentosa. Br. J. Ophthalmol. 2019;103:1163–1166. doi: 10.1136/bjophthalmol-2018-311964.
    1. Yeo JH, Kim YJ, Yoon YH. Optical coherence tomography angiography in patients with retinitis pigmentosa-associated cystoid macular edema. Retina. 2020 doi: 10.1097/iae.0000000000002756.
    1. Weber B, et al. Genomic organization and complete sequence of the human gene encoding the beta-subunit of the cGMP phosphodiesterase and its localisation to 4p 16.3. Nucleic Acids Res. 1991;19:6263–6268. doi: 10.1093/nar/19.22.6263.
    1. Lisman J, Fain G. Support for the equivalent light hypothesis for RP. Nat. Med. 1995;1:1254–1255. doi: 10.1038/nm1295-1254.
    1. Strong S, Liew G, Michaelides M. Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention. Br. J. Ophthalmol. 2017;101:31–37. doi: 10.1136/bjophthalmol-2016-309376.
    1. Reichenbach A, et al. Muller cells as players in retinal degeneration and edema. Graefes Arch. Clin. Exp. Ophthalmol. 2007;245:627–636. doi: 10.1007/s00417-006-0516-y.
    1. Cheng LL, et al. Novel mutations in PDE6B causing human retinitis pigmentosa. Int. J. Ophthalmol. 2016;9:1094–1099. doi: 10.18240/ijo.2016.08.02.
    1. Hajali M, Fishman GA, Anderson RJ. The prevalence of cystoid macular oedema in retinitis pigmentosa patients determined by optical coherence tomography. Br. J. Ophthalmol. 2008;92:1065–1068. doi: 10.1136/bjo.2008.138560.
    1. Murakami T, et al. Optical coherence tomographic reflectivity of photoreceptors beneath cystoid spaces in diabetic macular edema. Investig. Ophthalmol. Vis. Sci. 2012;53:1506–1511. doi: 10.1167/iovs.11-9231.
    1. Takahashi VKL, Takiuti JT, Jauregui R, Lima LH, Tsang SH. Structural disease progression in PDE6-associated autosomal recessive retinitis pigmentosa. Ophthalmic Genet. 2018;39:610–614. doi: 10.1080/13816810.2018.1509354.
    1. Colombo L, et al. Comparison of 5-year progression of retinitis pigmentosa involving the posterior pole among siblings by means of SD-OCT: a retrospective study. BMC Ophthalmol. 2018 doi: 10.1186/s12886-018-0817-z.
    1. Jauregui R, et al. Multimodal structural disease progression of retinitis pigmentosa according to mode of inheritance. Sci. Rep. 2019 doi: 10.1038/s41598-019-47251-z.
    1. Cai CX, Locke KG, Ramachandran R, Birch DG, Hood DC. A comparison of progressive loss of the ellipsoid zone (EZ) band in autosomal dominant and x-linked retinitis pigmentosa. Investig. Ophthalmol. Vis. Sci. 2014;55:7417–7422. doi: 10.1167/iovs.14-15013.
    1. Ranola JMO, Liu Q, Rosenthal EA, Shirts BH. A comparison of cosegregation analysis methods for the clinical setting. Fam. Cancer. 2018;17:295–302. doi: 10.1007/s10689-017-0017-7.
    1. Seo, G. H. et al. High diagnostic yield and clinical utility of WES for patients with undiagnosed genetic disorder by automating variant interpretation. bioRxiv. 10.1101/628438 (2019).
    1. Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–1073. doi: 10.1038/nature09534.
    1. Ioannidis NM, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 2016;99:877–885. doi: 10.1016/j.ajhg.2016.08.016.
    1. Morales A, et al. Variant Interpretation for dilated cardiomyopathy: refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM precision medicine study. Circ. Genom. Precis. Med. 2020;13:e002480. doi: 10.1161/CIRCGEN.119.002480.
    1. Tavtigian SV, et al. Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. Genet. Med. 2018;20:1054–1060. doi: 10.1038/gim.2017.210.
    1. Clarke G, et al. A one-hit model of cell death in inherited neuronal degenerations. Nature. 2000;406:195–199. doi: 10.1038/35018098.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться