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A novel phenotype in a family with autosomal dominant retinal dystrophy due to c.1430A > G in retinoid isomerohydrolase (RPE65) and c.37C > T in bestrophin 1 (BEST1)

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Abstract

Purpose

The c.1430A > G (Asp477Gly) variant in RPE65 has been reported in Irish and Scottish families with either an autosomal dominant retinal dystrophy (adRD) that resembles choroideremia, a vitelliform macular dystrophy or an isolated macular atrophy. We report novel features on multimodal imaging and the natural history of a family harbouring this variant in combination with the BEST1 c.37C > T (Arg13Cys) variant.

Methods

Members of a family with an adRD were examined clinically to ascertain phenotype and underwent genetic testing. Multimodal imaging included widefield colour fundus photography, quantitative autofluorescence (qAF) and spectral domain optical coherence tomography. Electrophysiology and microperimetry were also performed.

Results

Vision loss was attributed to foveal atrophy in the proband and choroidal neovascularisation and a vitello-eruptive lesion in one affected son. Peripheral retinal white dots corresponding to subretinal deposits were seen in three patients. The median qAF8 values in the proband (I:1) were low (40 and 101 in OD and OS) at age 79. Similarly, the qAF8 values for the middle son (II:2) were also low (100 and 87 in ODS and OS) at age 60. Electrophysiology showed disproportionate reduction in Arden ratio prior to the gradual loss of full-field responses. Microperimetry demonstrated an enlarging scotoma in the proband.

Conclusions

The coexistence of the pathogenic BEST1 c.37C > T variant may modify clinical features observed in RPE65 adRD. This study expands our understanding of RPE65 adRD as a retinoid cycle disorder supported by the reduced qAF, fine white retinal dots and corresponding subretinal deposits on OCT in affected members.

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Data availability

Data sharing is not applicable to this article as no datasets were generated or analysed during this study.

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Acknowledgements

The authors would like to thank Amanda Scurry and Jayme Glynn for their assistance in organising the patient appointments for the clinical assessments. The AIRDR acknowledges the assistance of Ling Hoffman and Isabella Urwin from the Department of Medical Technology and Physics at Sir Charles Gairdner Hospital.

Funding

This work was supported by the Australian National Health and Medical Research Council under GNT116360 (FKC), GNT1188694 (FKC), GNT1054712 (FKC) and MRF1142962 (FKC), McCusker Foundation (FKC), Miocevich Retina Fellowship (RCHJ) and Retina Australia (JAT, TL, JNDR, TLM). The sponsor or funding organisation had no role in the design or conduct of this research.

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Author notes

  1. Juanita Pappalardo and Rachael C. Heath Jeffery have contributed equally.

Authors and Affiliations

  1. Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), The University of Western Australia, 2 Verdun Street, Nedlands, WA, Australia

    Juanita Pappalardo, Rachael C. Heath Jeffery, Quang Pham, Ian J. Constable, Terri L. McLaren, Tina M. Lamey, John N. De Roach & Fred K. Chen

  2. Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, WA, Australia

    Jennifer A. Thompson, Enid Chelva, Terri L. McLaren, Tina M. Lamey, John N. De Roach & Fred K. Chen

  3. Department of Ophthalmology, Royal Perth Hospital, Perth, WA, Australia

    Rachael C. Heath Jeffery & Fred K. Chen

  4. Department of Ophthalmology, Perth Children’s Hospital, Nedlands, WA, Australia

    Fred K. Chen

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  1. Juanita Pappalardo
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Correspondence to Fred K. Chen.

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Conflict of interest

The authors declare they have no conflict of interest or competing interests.

Consent to participate

Written informed consent was obtained from all participants included in this case series.

Consent for publication

Written informed consent for publication of clinical information, test results and images was obtained from all participants included in this case series.

Ethical approval

The WARD study and Australian Inherited Retinal Disease Registry and DNA bank study protocols adhered to the tenets of the Declaration of Helsinki, and ethics approval was obtained from the Human Ethics Office of Research Enterprise, The University of Western Australia (RA/4/1/8932 and RA/4/1/7916) and Sir Charles Gairdner Hospital Human Research Ethics Committee (approval number 2001–053).

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Pappalardo, J., Heath Jeffery, R.C., Thompson, J.A. et al. A novel phenotype in a family with autosomal dominant retinal dystrophy due to c.1430A > G in retinoid isomerohydrolase (RPE65) and c.37C > T in bestrophin 1 (BEST1). Doc Ophthalmol 143, 61–73 (2021). https://doi.org/10.1007/s10633-021-09819-x

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