Clinical Heterogeneity in Two Siblings Harbouring a Heterozygous PRPH2 Pathogenic Variant

Abstract

Purpose The aim of the study was to describe the clinical and genetic correlation of a c.469 G>A p.(Asp157Asn) heterozygous pathogenic variant in PRPH2 in two siblings of Italian origin.

Patients and Methods Both patients underwent ophthalmic examination, electrophysiological testing, autofluorescence imaging, and optical coherence tomography (OCT). Screening for pathogenic variants of the obtained DNA from the family members was carried out.

Results The 52-year-old (♀, index patient) and 50-year-old (♂) siblings had BCVA (OD and OS) of 20/20 and 20/16 (♀) and 20/25 and 20/40 (♂), respectively, and suffered increased sensitivity to glare. Yellow irregular macular deposits, numerous small irregular hypo- and hyperreflective spots at the posterior pole, a patchy loss of photoreceptors, and retinal pigment epithelium (RPE) in the perifoveal region were seen. Electrophysiology showed dysfunction of rods and cones, with more affected cone dysfunction in the index patient, contrary to the generalised rod dysfunction in the brother of the index patient. The clinical, electrophysiological, and multimodal imaging findings of both siblings pointed towards Stargardt retinopathy with heterogenic presentation. The DNA analysis identified an autosomal dominant c.469 G>A p.(Asp157Asn) heterozygous pathogenic variant in PRPH2 associated with autosomal dominant cone-rod dystrophy and rod-cone dystrophy. PRPH2 codes for peripherin-2, a membrane protein that consists of 346 amino acids.

Conclusions Our findings confirm a heterogeneity in clinical presentation associated with pathogenic variants in PRPH2. It may follow either an autosomal dominant or an autosomal recessive mode of inheritance and show a very heterogeneous clinical manifestation of retinal degeneration, e.g., autosomal dominant retinitis pigmentosa (♂ sibling; II-3) and autosomal dominant cone-rod dystrophy (index ♀ sibling; II-2), autosomal dominant macular dystrophy, and also autosomal recessive retinitis pigmentosa.

Zusammenfassung

Hintergrund Ziel der Studie ist die Beschreibung der klinischen und genetischen Korrelation einer c.469 G>A p.(Asp157Asn) heterozygoten pathogenen Variante in PRPH2 bei 2 Geschwistern italienischer Herkunft.

Patienten und Methoden Bei beiden Patienten wurden eine augenärztliche Untersuchung, elektrophysiologische Tests, Autofluoreszenz-Bildgebung und optische Kohärenztomografie (OCT) durchgeführt. Es wurde ein Screening auf pathogene Varianten der von den Familienmitgliedern gewonnenen DNA durchgeführt.

Ergebnisse Die 52 (♀, Indexpatientin) und 50 Jahre (♂) alten Geschwister hatten einen Visus (OD und OS) von 20/20 bzw. 20/16 (♀) und 20/25 bzw. 20/40 (♂) und litten unter erhöhter Blendempfindlichkeit. Es zeigten sich gelbe unregelmäßige Makulaablagerungen, zahlreiche kleine unregelmäßige hypo- und hyperreflektive Flecken am hinteren Pol, ein fleckenartiger Verlust von Photorezeptoren und retinalem Pigmentepithel (RPE) in der perifovealen Region. Die Elektrophysiologie zeigte eine Störung der Stäbchen und Zapfen, wobei die Zapfenstörung bei der Indexpatientin stärker ausgeprägt war als die generalisierte Stäbchenstörung beim Bruder der Indexpatientin. Die klinischen, elektrophysiologischen und multimodalen Bildgebungsbefunde beider Geschwister wiesen auf eine Stargardt-Retinopathie mit heterogenem Erscheinungsbild hin. Die DNA-Analyse identifizierte eine autosomal-dominante c.469 G>A p.(Asp157Asn) heterozygote pathogene Variante in PRPH2, die mit autosomal-dominanter Zapfen-Stäbchen-Dystrophie und Stäbchen-Zapfen-Dystrophie assoziiert ist. PRPH2 codiert für Peripherin-2, ein Membranprotein, das aus 346 Aminosäuren besteht.

Schlussfolgerungen Unsere Ergebnisse bestätigen eine Heterogenität in der klinischen Präsentation im Zusammenhang mit pathogenen Varianten in PRPH2. Sie kann entweder einem autosomal-dominanten oder einem autosomal-rezessiven Vererbungsmodus folgen und eine sehr heterogene klinische Manifestation der Netzhautdegeneration zeigen, z. B. autosomal-dominante Retinitis pigmentosa (♂ Geschwister; II-3), autosomal-dominante Zapfen-Stäbchen-Dystrophie (Index ♀ Geschwister; II-2), autosomal-dominante Makuladystrophie, aber auch autosomal rezessive Retinitis pigmentosa.

Key words

PRPH2 mutation - inherited retinal degeneration - cone-rod dystrophy - rod-cone dystrophy - Stargardt retinopathy

Schlüsselwörter

PRPH2-Mutation - hereditäre Netzhautdegeneration - Zapfen-Stäbchen-Dystrophie - Stäbchen-Zapfen-Dystrophie - Stargardt-Retinopathie

Publication History

Received: 15 October 2022

Accepted: 06 February 2023

Article published online:
25 April 2023

• References

• 1 Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certifications in England and Wales in working age adults (16–64 years), 1999–2000 with 2009–2010. BMJ Open 2014; 4: e004015 DOI: 10.1136/bmjopen-2013-004015.
• 2 Finger RP, Fimmers R, Holz FG. et al. Prevalence and causes of registered blindness in the largest federal state of Germany. Br J Ophthalmol 2011; 95: 1061-1067 DOI: 10.1136/bjo.2010.194712.
• 3 Keeffe JE, McCarty CA, Hassell JB. et al. Description and measurement of handicap caused by vision impairment. Aust N Z J Ophthalmol 1999; 27: 184-186 DOI: 10.1046/j.1440-1606.1999.00179.x.
• 4 Genc AM, Makia MS, Sinha T. et al. Retbindin: A riboflavin Binding Protein, Is Critical for Photoreceptor Homeostasis and Survival in Models of Retinal Degeneration. Int J Mol Sci 2020; 21: 8083 DOI: 10.3390/ijms21218083.
• 5 Kajiwara K, Sandberg MA, Berson EL. et al. A null mutation in the human peripherin/RDS gene in a family with autosomal dominant retinitis punctata albescens. Nat Genet 1993; 3: 208-212 DOI: 10.1038/ng0393-208.
• 6 Kelley RA, Al-Ubaidi MR, Sinha T. et al. Ablation of the riboflavin-binding protein retbindin reduces flavin levels and leads to progressive and dose-dependent degeneration of rods and cones. J Biol Chem 2017; 292: 21023-21034 DOI: 10.1074/jbc.M117.785105.
• 7 Boon CJ, van Schooneveld MJ, den Hollander AI. et al Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br J Ophthalmol 2007; 91: 1504-1511 DOI: 10.1136/bjo.2007.115659.
• 8 Boon CJ, den Hollander AI. Hoyng CB. et al. The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog Retin Eye Res 2008; 27: 213-235 DOI: 10.1016/j.preteyeres.2008.01.002.
• 9 Reeves MJ, Goetz KE, Guan B. et al. Genotype-phenotype associations in a large PRPH2-related retinopathy cohort. Hum Mutat 2020; 41: 1528-1539 DOI: 10.1002/humu.24065.
• 10 Conley SM, Naash MI. Gene therapy for PRPH2-associated ocular disease: challenges and prospects. Cold Spring Harb Perspect Med 2014; 4: a017376 DOI: 10.1101/cshperspect.a017376.
• 11 Robson AG, Frishman LJ, Grigg J. et al. ISCEV Standard for full-field clinical electroretinography (2022 update). Doc Ophthalmol 2022; 144: 165-177 DOI: 10.1007/s10633-022-09872-0.
• 12 Peeters MHCA, Khan M, Rooijakkers AAMB. et al. PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease. Hum Mutat 2021; 42: 1521-1547 DOI: 10.1002/humu.24275.
• 13 Oishi A, Fujinami K, Mawatari G. et al. Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan. Genes (Basel) 2021; 12: 1817 DOI: 10.3390/genes12111817.
• 14 Michaelides M, Holder GE, Bradshaw K. et al. Cone-rod dystrophy, intrafamilial variability, and incomplete penetrance associated with the R172 W mutation in the peripherin/RDS gene. Ophthalmology 2005; 112: 1592-1598 DOI: 10.1016/j.ophtha.2005.04.004.
• 15 Nakazawa M, Kikawa E, Chida Y. et al. Autosomal dominant cone-rod dystrophy associated with mutations in codon 244 (Asn244His) and codon 184 (Tyr184Ser) of the peripherin/RDS gene. Arch Ophthalmol 1996; 114: 72-78 DOI: 10.1001/archopht.1996.01100130068011.
• 16 Oishi M, Oishi A, Ogino K. et al. Wide-field fundus autofluorescence abnormalities and visual function in patients with cone and cone-rod dystrophies. Invest Ophthalmol Vis Sci 2014; 55: 3572-3577 DOI: 10.1167/iovs.14-13912.
• 17 Fujinami-Yokokawa Y, Fujinami K, Kuniyoshi K. et al. Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association. Sci Rep 2020; 10: 9531 DOI: 10.1038/s41598-020-65737-z.
• 18 Inui E, Oishi A, Oishi M. et al. Tomographic comparison of cone-rod and rod-cone retinal dystrophies. Graefes Arch Clin Exp Ophthalmol 2014; 252: 1065-1069 DOI: 10.1007/s00417-014-2570-1.
• 19 Lima LH, Zett C, Kniggendorf V. et al. Progressive expansion of the hyperautofluorescent ring in cone-rod dystrophy patients. Ophthalmic Genet 2018; 39: 492-499 DOI: 10.1080/13816810.2018.1461911.
• 20 Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 1994; 264: 1604-1608 DOI: 10.1126/science.8202715.
• 21 Koenekoop RK. The gene for Stargardt disease, ABCA4, is a major retinal gene: a mini-review. Ophthalmic Genet 2003; 24: 75-80 DOI: 10.1076/opge.24.2.75.13996.
• 22 Poloschek CM, Bach M, Lagrèze WA. et al. ABCA4 and ROM1: implications for modification of the PRPH2-associated macular dystrophy phenotype. Invest Ophthalmol Vis Sci 2010; 51: 4253-4265 DOI: 10.1167/iovs.09-4655.