Multicenter Study

. 2024 May 1;65(5):22.

doi: 10.1167/iovs.65.5.22.

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients

Rachael C Heath Jeffery^{1

2

3}, Jennifer A Thompson⁴, Johnny Lo⁵, Enid S Chelva⁴, Sean Armstrong^{1

4}, Jose S Pulido⁶, Rebecca Procopio⁶, Andrea L Vincent^{7

8}, Lorenzo Bianco⁹, Maurizio Battaglia Parodi⁹, Lucia Ziccardi¹⁰, Giulio Antonelli¹⁰, Lucilla Barbano¹⁰, João P Marques¹¹, Sara Geada¹¹, Ana L Carvalho¹², Wei C Tang^{13

14}, Choi M Chan^{13

14}, Camiel J F Boon^{15

16}, Jonathan Hensman¹⁶, Ta-Ching Chen^{17

18}, Chien-Yu Lin¹⁷, Pei-Lung Chen¹⁷, Ajoy Vincent¹⁹, Anupreet Tumber¹⁹, Elise Heon¹⁹, John R Grigg^{20

21}, Robyn V Jamieson^{20

21}, Elisa E Cornish²⁰, Benjamin M Nash^{21

22}, Shyamanga Borooah^{23

24}, Lauren N Ayton^{25

26

27}, Alexis Ceecee Britten-Jones^{25

26

27}, Thomas L Edwards^{25

26

27}, Jonathan B Ruddle^{25

26}, Abhishek Sharma²⁸, Rowan G Porter²⁹, Tina M Lamey⁴, Terri L McLaren^{1

4}, Samuel McLenachan¹, Danial Roshandel¹, Fred K Chen^{1

2

3

4

26

27}

Affiliations

¹ Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia.
² Ocular Tissue Engineering Laboratory, Lions Eye Institute, Nedlands, Western Australia, Australia.
³ Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
⁴ Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁵ School of Science, Edith Cowan University, Perth, Western Australia, Australia.
⁶ Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, PA, United States.
⁷ Department of Ophthalmology, FMHS, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
⁸ Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
⁹ Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
¹⁰ IRCCS-Fondazione Bietti, Rome, Italy.
¹¹ Ophthalmology Unit, Centro Hospitalar e Universitário de Coimbra (CHUC), Clinical and Academic Centre of Coimbra (CACC), Coimbra, Portugal.
¹² Medical Genetics Unit, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
¹³ Singapore National Eye Centre, Singapore, Singapore.
¹⁴ Singapore Eye Research Institute, Singapore, Singapore.
¹⁵ Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
¹⁶ Department of Ophthalmology, Amsterdam University Medical Center, University of Amsterdam, the Netherlands.
¹⁷ Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.
¹⁸ Center of Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁹ Department of Ophthalmology, Hospital for Sick Children, Toronto, Ontario, Canada.
²⁰ Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
²¹ Eye Genetics Research Unit, Children's Medical Research Institute, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
²² Sydney Genome Diagnostics, Western Sydney Genetics Program, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.
²³ University of California San Diego, La Jolla, California.
²⁴ The Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA, United States.
²⁵ Department of Optometry and Vision Sciences, University of Melbourne, Melbourne, Victoria, Australia.
²⁶ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
²⁷ Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia.
²⁸ Ophthalmology Department, Royal Brisbane and Women's Hospital, Brisbane, Australia.
²⁹ Southern Queensland Centre of Excellence, Inala, Australia.

PMID: 38743414
PMCID: PMC11098050
DOI: 10.1167/iovs.65.5.22

Multicenter Study

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients

Rachael C Heath Jeffery et al. Invest Ophthalmol Vis Sci. 2024.

. 2024 May 1;65(5):22.

doi: 10.1167/iovs.65.5.22.

Authors

Affiliations

¹ Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia.
² Ocular Tissue Engineering Laboratory, Lions Eye Institute, Nedlands, Western Australia, Australia.
³ Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
⁴ Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁵ School of Science, Edith Cowan University, Perth, Western Australia, Australia.
⁶ Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, PA, United States.
⁷ Department of Ophthalmology, FMHS, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
⁸ Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
⁹ Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
¹⁰ IRCCS-Fondazione Bietti, Rome, Italy.
¹¹ Ophthalmology Unit, Centro Hospitalar e Universitário de Coimbra (CHUC), Clinical and Academic Centre of Coimbra (CACC), Coimbra, Portugal.
¹² Medical Genetics Unit, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
¹³ Singapore National Eye Centre, Singapore, Singapore.
¹⁴ Singapore Eye Research Institute, Singapore, Singapore.
¹⁵ Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
¹⁶ Department of Ophthalmology, Amsterdam University Medical Center, University of Amsterdam, the Netherlands.
¹⁷ Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.
¹⁸ Center of Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁹ Department of Ophthalmology, Hospital for Sick Children, Toronto, Ontario, Canada.
²⁰ Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
²¹ Eye Genetics Research Unit, Children's Medical Research Institute, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
²² Sydney Genome Diagnostics, Western Sydney Genetics Program, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.
²³ University of California San Diego, La Jolla, California.
²⁴ The Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA, United States.
²⁵ Department of Optometry and Vision Sciences, University of Melbourne, Melbourne, Victoria, Australia.
²⁶ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
²⁷ Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia.
²⁸ Ophthalmology Department, Royal Brisbane and Women's Hospital, Brisbane, Australia.
²⁹ Southern Queensland Centre of Excellence, Inala, Australia.

PMID: 38743414
PMCID: PMC11098050
DOI: 10.1167/iovs.65.5.22

Abstract

Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene.

Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations.

Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability.

Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

PubMed Disclaimer

Conflict of interest statement

Disclosure: R.C. Heath Jeffery, None; J.A. Thompson, Retina Australia; J. Lo, None; E.S. Chelva, None; S. Armstrong, None; J.S. Pulido, None; R. Procopio, None; A.L. Vincent, None; L. Bianco, None; M. Battaglia Parodi, None; L. Ziccardi, None; G. Antonelli, None; L. Barbano, None; J.P. Marques, None; S. Geada, None; A. L. Carvalho, None; W. Chao Tang, None; C. Mun Chan, None; C.J.F. Boon, None; J. Hensman, None; T.-C. Chen, None; C.-Y. Lin, None; P.-L. Chen, None; A. Vincent, None; A. Tumber, None; E. Heon, None; J.R. Grigg, NHMRC APP1116360, APP1099165, APP1109056; R.V. Jamieson, NHMRC APP1116360, APP1099165, APP1109056; E.E. Cornish, None; B.M. Nash, None; S. Borooah, Foundation Fighting Blindness Grant CD-GT-0918-0746-SEI and Nixon Visions Foundation; L.N. Ayton, Novartis, Apellis, National Health & Medical Research Council (NHMRC) GNT1195713; A.C. Britten-Jones, None; T.L. Edwards, None; J.B. Ruddle, None; A. Sharma, None; R.G. Porter, None; T.M. Lamey, Retina Australia; T.L. McLaren, Retina Australia; S. McLenachan, None; D. Roshandel, None; F.K. Chen, Future Health Research and Innovation Fund, the McCusker Charitable Foundation, Channel 7 Telethon Trust, Retina Australia, NHMRC GNT1116360, GNT1188694, GNT1054712 and MRF1142962

Figures

**Figure 1.**
Locally estimated scatterplot smoothing (LOESS) curve using VA from the better-seeing eye illustrating the average evolution of VA with age across the entire cohort (A). Proportion (%) of *PRPH2* patients with normal, mild (VA, <20/40 and ≥20/60), moderate (VA, <20/60 and ≥20/200), severe visual impairment (VA, <20/200 and ≥20/400) and blindness (VA, <20/400) by age at imaging (B).

**Figure 2.**
Optos pseudocolor, FAF, and SD-OCT imaging of a 40-year-old woman (A, B, C), a 39-year-old woman (D, E, F), and a 40 year-old-man (G, H, I) harboring the p.(Asp207_Val209del), p.(Try204Ter), and p.(Ser198Arg) *PRPH2* variants respectively. All three patients show normal pseudocolor and FAF imaging with thickening of band 2 on SD-OCT.

**Figure 3.**
Optos FAF imaging of six *PRPH2* patients exhibiting focal central macula hyperautofluorescence defined as a BPD or VMD. An 88-year-old woman with a VA of 20/25 harboring exon 3 deletion (A), a 49-year-old woman with a VA of 20/20 harboring p.(Met1TyrfsTer2) (B), a 47-year-old woman with a VA of 20/16 harboring p.(Asp237_His238delinsThr) (C), a 66-year-old man with a VA of 20/25 harboring p.(Gly167Ser) (D), a 57-year-old woman with a VA of 20/20 harboring p.(Tyr204Ter) (E), and a 66-year-old woman with a VA of 20/25 harboring c.828+1G>A (F).

**Figure 4.**
Optos FAF imaging of *PRPH2* patients demonstrating the CACD phenotype. A 53-year-old woman with VA of 20/25 harboring p.(Arg142Trp) (A), a 45-year-old man with a VA of 20/60 harboring p.(Arg172Pro) (B), an 89-year-old woman with a VA of 20/250 harboring p.(Arg172Leu) (C), a 46-year-old woman with a VA of 20/20 harboring p.(Arg172Gln) (D), a 67-year-old woman with a VA of 20/60 harboring p.(Arg172Trp) (E), a 33-year-old man with a VA of 20/20 harboring p.(Asp186Asn) (F), a 53-year-old man with a VA of 20/60 harboring p.(Arg195Gln) (G), a 27-year-old man with a VA of 20/40 harboring p.(Ile196Asn) (H), a 48-year-old man with a VA of counting fingers harboring p.(Val200Ala) (I), a 68-year-old man with a VA of 20/120 harboring p.(Gly208Asp) (J), a 61-year-old woman with a VA of 20/30 harboring p.(Pro219Arg) (K), a 61-year-old man with a VA of 20/15 harboring p.(Thr228Ile), (L) and a 53-year-old woman with a VA of 20/30 harboring p.(Ala232Val) (M).

**Figure 5.**
Optos FAF imaging of *PRPH2* patients demonstrating the PSPD phenotype. A 66-year-old woman with a VA of 20/200 harboring an exon 3 deletion (A), a 55-year-old woman with a VA of 20/80 harboring p.(Gln132LysfsTer7) (B), a 59-year-old woman with a VA of 20/20 harboring p.(Lys154del) (C), a 61-year-old woman with a VA of 20/40 harboring p.(Ile196Asn) (D), a 51-year-old woman with a VA of 20/20 harboring p.(Tyr204Ter) (E), and a 67-year-old woman with a VA of 20/90 harboring c.828+3A>T (F).

**Figure 6.**
Optos FAF imaging of *PRPH2* patients demonstrating the RP phenotype. A 48-year-old woman with VA of 20/40 harboring p.(Gln132LysfsTer7) (A), a 55-year-old woman with a VA of 20/25 harboring p.(Asp237_His238delinsThr) (B), a 71-year-old woman with a VA of 20/30 harboring p.(Gly167Ser) (C), and a 36-year-old woman with a VA of 20/25 harboring p.(Tyr204Ter) (D).

**Figure 7.**
Scatter plots for electrophysiologic parameters and age. The full-field ERG component amplitudes and peak times in *PRPH2* patients (*black circles*) and unaffected controls (*grey circles*) are plotted against age. Data are shown for the DA 0.01 ERG (A and B), LA 30-Hz ERG (C and D). Regression lines are shown for the *PRPH2*-associated retinopathy (*solid line*) and control (*grey broken line*) data.

**Figure 8.**
Scatter plots for electrophysiologic parameters and age. The major full-field ERG component amplitudes and peak times in *PRPH2* patients (*black circles*) and unaffected controls (*grey circles*) are plotted against age. Data are shown for the DA3.0 ERG a-wave (A, B) and b-wave (C, D), LA 3.0 ERG a-wave (E, F) and b-wave (G, H). Regression lines are shown for the *PRPH2*-associated retinopathy (*solid line*) and control (*grey broken line*) data.

**Figure 9.**
Position and type of *PRPH2* truncating variants (nonsense, frameshift, start-loss, splice site) by exon location (A). Missense and inframe deletion variants and their protein positions within our *PRPH2* cohort (B).

See this image and copyright information in PMC

References

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Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients

Affiliations

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources